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Study drug: IBI308

Clinical Study Protocol

Study Title: A Single-center, Phase Ib Study of IBI308 Monotherapy as

Neoadjuvant Therapy for Resectable Non-Small Cell Lung

Cancer

Protocol No.: CIBI308Y002

Version Date and

Number:

August 12, 2017/Version 1.0

Product Name: IBI308

Phase of Study: Ib

Sponsor: Cancer Hospital Chinese Academy of Medical Sciences

(CAMS)

Contact person: Li Ning

010-87788713

No.17 Panjiayuan Nanli, Chaoyang District, Beijing, P.R. China

Confidentiality Statement

This document contains confidential information.

The contents of this document may not be disclosed to any persons other than the investigator(s),

study advisor(s) or relevant personnel, institutional review board/independent ethics committee.

Without prior written permission of the sponsor, the information contained herein may not be used

for any purpose other than the evaluation or conduct of this clinical study.

August 12, 2017 Version 1.0 Confidential 1 / 116

Study drug: IBI308

Signature Page

Protocol Title: An Open-label, Single-center, Phase Ib Study of IBI308 Monotherapy as

Neoadjuvant Therapy for Resectable Non-small Cell Lung Cancer

Project ID: CIBI308Y002

Title Name (Print) Signature Date

Investigator He Jie


Study drug: IBI308

Protocol Synopsis

Protocol No. CIBI308Y002

Sponsor Cancer Hospital Chinese Academy of Medical Sciences (CAMS)

Study Drug IBI308

Active Ingredient Recombinant fully human anti-programmed cell death receptor 1 (PD-1) monoclonal

antibody

Study Titl A Single-center, Phase Ib Study of IBI308 Monotherapy as Neoadjuvant Therapy for

Resectable Non-Small Cell Lung Cancer

Phase Ib

Estimated Duration of

Study

30 months estimated

Objectives of Study Primary:

To evaluate the study-related adverse events (90 days after the first dosing of

IBI308 or 30 days after surgery, whichever occurs later)

To evaluate the incidence of surgical complications (both intraoperative and

perioperative)

To evaluate the rate of non-delayed surgery (surgical delay is defined as no

performance of surgery for more than 43 days from the day of the first dosing)

Secondary:

To evaluate the objective response rate (ORR) and major pathologic response

(MPR) after IBI308 monotherapy as neoadjuvant therapy for resectable NSCLC

To evaluate the 1-year and 2-year DFS, the 1-year and 2-year recurrence rate (RR)

and the 2-year survival rate;

Exploratory:

To evaluate the relationship between pathological response and DFS and RR after

IBI308 monotherapy as neoadjuvant therapy


Study drug: IBI308

To evaluate the distribution of IBI308 across tumor tissues and its correlation with

efficacy.

To evaluate the relationship of biomarkers in tumor tissue with efficacy, including

but not limited to the expression of PD-L1, tumor infiltrating lymphocytes (TIL),

and tumor mutational burden (TMB)

To evaluate the relationship of biomarkers in peripheral blood with efficacy,

including but not limited to the relationship between efficacy and dynamic

changes in the overall mutational burden of ctDNA

Study Design It is a phase Ib single-center study to evaluate IBI308 monotherapy as neoadjuvant

therapy for resectable NSCLC. A safety run-in study of 6 patients will be conducted

first, and if no major safety event occurs, the study will be expanded to a total of 30

patients.

After the signing of the informed consent form (ICF), patients with treatment-naïve

operable NSCLC who are confirmed eligible for the inclusion/exclusion criteria after

screening will be administered IBI308 200 mg IV Q3W for 2 cycles, and will receive

radical operation for NSCLC within 29 to 43 days following the first dose of IBI308, as

well as standard adjuvant treatment.

Imaging assessment will be conducted per RECIST v1.1 in this study, with PET-

enhanced CT performed at baseline and prior to radical operation (after the second dose

of IBI308 but within 1 week prior to operation), as well as CT or enhanced CT on Day

30 post-operation and every 3 months post-operation, until 2 years after the operation,

disease recurrence or death. Enhanced MRI is required at baseline to rule out brain

metastases.

The subjects will be followed for safety (90 days after the first dose of IBI308 or 30

days post-operation, whichever occurs later) and post-operative recurrence-free

survival visit (every 90 ± 7 days until 2 years post-operation).

Inclusion Criteria The subjects are required to meet the following inclusion criteria:

1. Cytologically or histologically confirmed NSCLC;

2. Assent to the collection of tumor histological specimens required for this study for


Study drug: IBI308

relevant studies;

3. Presence of treatment-naïve, surgically resectable NSCLC, with a tumor diameter

of > 2 cm;

4. Consent to receive radical operation;

5. No surgical contraindications in the judgment of a thoracic surgeon;

6. Presence of at least one measurable lesion (RECIST v1.1);

7. Male or female, at an age ≥ 18 years and ≤ 75 years;

8. An ECOG score of 0;

9. Adequate functions of vital organs and bone marrow that meet the following

requirements:

- Hematology: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelets (PLT) ≥

100 × 109/L, hemoglobin (HGB) ≥ 9 g/dL;

- Liver function: serum total bilirubin (TBIL) ≤ 1.5 × ULN (upper limit of normal),

alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 ×

ULN, serum albumin (ALB) ≥ 2.8 g/dL;

- Renal function: Serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance ≥ 40

mL/min (calculated using the standard Cockcroft -Gault formula):

Females: CrCl = (140-age) x body weight (kg) x 0.85

72 x serum creatinine (mg/dL)

Males: CrCl = (140-age) x body weight (kg) x 1.00


10. Provide written ICF and could follow the visit schedule and relevant procedures

specified in the study protocol.

Exclusion Criteria A subject meeting any of the following exclusion criteria will be excluded from this

study:

1. Presence of EGFR-sensitive gene mutation in tumor tissue as revealed by

aspiration biopsy;

2. A past medical history of any anti-tumor therapy, including radiotherapy,

chemotherapy, immunotherapy and traditional Chinese medicine therapy

(excluding therapy for malignancies that were radically treated, without

recurrence or metastasis for a period of ≥5 years);


Study drug: IBI308

3. Use of immunosuppressive agents within 4 weeks prior to the first dose of the

study treatment, excluding topical glucocorticoids for intranasal, inhalation or

other routes of administration, or physiological doses of systemic glucocorticoids

(i.e., no more than 10 mg/day prednisone or equivalent of other glucocorticoids);

4. Known or suspected active autoimmune diseases (congenital or acquired), such as

interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis,

nephritis, thyroiditis, etc. (patients with vitiligo or complete remission of asthma

in childhood, without requiring any intervention after adulthood can be enrolled;

patients with type I diabetes well controlled by insulin can also be enrolled);

5. Known allotransplant (excluding corneal transplantation) or allogeneic

hematopoietic stem cell transplantation;

6. Allergy to any ingredient of the monoclonal antibody;

7. Current interstitial lung disease;

8. Presence of other uncontrolled serious medical conditions, including but not

limited to:

− Active or clinically uncontrolled severe infection;

− HIV-infection (HIV antibody positive);

− Acute or chronic active hepatitis B (HBsAg positive and HBV DNA >

1*103/mL) or acute or chronic active hepatitis C (HCV antibody positive and

HCV RNA > 15 IU/mL);

− Active pulmonary tuberculosis;

− Class III-IV congestive heart failure (New York Heart Association

classification), poorly controlled and clinically significant arrhythmia;

− Uncontrolled arterial hypertension (systolic blood pressure ≥ 160 mmHg or

diastolic blood pressure ≥ 100 mmHg);

− Any arterial thrombosis, embolism or ischemia within 6 months prior to

inclusion for treatment, such as myocardial infarction, unstable angina,

cerebrovascular accident or transient ischemic attack;

− Disease requiring anticoagulation with warfarin (coumarin);


Study drug: IBI308

− Uncontrolled hypercalcemia (calcium ion > 1.5 mmol/L or calcium greater

than 12 mg/dL or corrected serum calcium > ULN), or symptomatic

hypercalcemia requiring continued bisphosphonate therapy;

− Other malignant tumors (excluding cancer that has been cured, such as

cervical carcinoma in situ, non-melanoma skin cancer, etc.);

9. Other acute or chronic diseases, psychiatric disorders or abnormal laboratory

values, which may result in an increased risk associated with study participation

or use of the study drug, or interfere with the interpretation of study results and

render the patient ineligible for the study in the investigator’s judgment;

10. Pregnant or breastfeeding women.

Study Drug, Strength

and Route of

Administration

IBI308

− Strength: 100 mg/10 ml

− Route of administration: 200 mg intravenous infusion (IV) Q3W for 2 cycles

Evaluation Criteria Efficacy evaluation:

ORR: total of complete response (CR) and partial response (PR)

MPR: defined as < 10% visible tumor cells by microscopy

DFS: Percentage of patients without disease recurrence or death at 1 and 2 years

RR: Percentage of patients with 1-year and 2-year disease recurrence

Overall survival (OS): 2-year overall survival

Safety evaluation:

Incidence rates of all adverse events (AEs), adverse events of special interest

(AESI) and serious adverse events (SAEs), treatment-related adverse events

(TRAEs) and severity, etc.

Changes in vital signs, physical examination findings, and laboratory findings

before, during, and after study treatment

Biomarker evaluation:



Study drug: IBI308

efficacy.

To evaluate the relationship of biomarkers in tumor tissues and peripheral blood

with the efficacy


Study drug: IBI308

Table 1. Visit Schedule

Period Screening

Neoadjuvant therapy Radical

operationSafety follow-up17

Recurrence-free survival follow-up18

Cycle 1 Cycle 2

Visits 1 2 3 4 5 6 7~N

Days -28 - -1 1 22 (±3)29 - 43 30 (± 7) days after

radical operation90 (± 7) days after the last dose

Every 90 (± 7) days after operation

General Study ProceduresWritten ICF1 XInclusion & exclusion criteria XDemographics/past medical history/past medications2

X

Vital signs3 X X X X X XBody weight/height4 XPhysical examination X X X X XECOG score X12-lead ECG5 X X X X XHematology/blood biochemistry/urinalysis6

X X X X X

Pregnancy test7 X X


Study drug: IBI308

Period ScreeningNeoadjuvant

therapy Radical operation

Safety follow-up17Recurrence-free survival

follow-up18

Cycle 1 Cycle 2Visits 1 2 3 4 5 6 7~N

Days -28 - -1 1 22 (±3)29 - 43 30 (± 7) days after

radical operation90 (± 7) days after the last dose

Every 90 (± 7) days after operation

Thyroid function8 X X X XHIV, HBV and HCV9 XEGFR mutation status10 XAE evaluation11 X X X X X XConcomitant medications X X X X X X XSurvival status X X X X XSubsequent anti-tumor treatment

X X X

Efficacy EvaluationTumor imaging evaluation12 X X X X

Study Drug InfusionIBI30813 X X

Biomarker Evaluation

Fresh tumor tissue samples14 X X

Blood samples15 X X X XImmunogenicity16 X X X

Notes:1. The signing of the ICF should precede any protocol-specified procedures.


Study drug: IBI308

2. Past medication includes treatment for initial diagnosis, including chemotherapy, radiation therapy and surgical treatment.3. Vital signs include body temperature, pulse rate, respiratory rate, and blood pressure.4. Height and weight measurements are only performed during the screening period.5. 12-lead ECG is scheduled at screening, prior to the second dose, prior to operation, Day 30 post-operation, and Day 90 after the last dose.6. Hematology includes: red blood cell count (RBC), HGB, white blood cell count (WBC), PLT, WBC differential [lymphocyte count (LYM), ANC]. Blood

biochemistry includes: liver function [TBIL, ALT, AST, γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), albumin (ALB), total protein (TP), lactate dehydrogenase (LDH)], renal function [blood urea nitrogen (BUN), Cr], blood electrolytes (Na, K, Cl, Mg, Ca, P), lipase, amylase and fasting blood glucose (FBG). Urinalysis includes pH, urine albumin (UALB), urine protein (UPRO), urine RBC (URBC) and urine glucose (UGLU). Hematology, blood biochemistry and urinalysis are performed within 7 days prior to the first dose, within 3 days prior to the second dose, before surgery, within 3 days prior to and on Day 30 post-operation and Day 90 after the last dose, respectively.

7. For women of child-bearing potential, urine or serum pregnancy test will be performed within 3 days prior to the first dose and on Day 90 after the last dose. If negative cannot be confirmed with the result of urine pregnancy test, serum pregnancy test is required and the result of serum pregnancy test should prevail.

8. T3, T4, FT3, FT4 and TSH tests are performed at screening, prior to the second dose, and on Day 30 post-operation and Day 90 after the last dose.9. HIV antibody, hepatitis B (HBsAg, HBsAb, HBcAb, HBeAg and HBeAb) and HCV antibody tests are performed during the screening period. For hepatitis B

virus carriers, regular monitoring of virus activity is recommended throughout this study.10. Tissue biopsy is preformed at baseline for the detection of EGFR mutations.11. AE and laboratory safety evaluations will be performed according to NCI CTCAE 4.03 (For the definitions, documentation, relevance judgment, severity

judgment, reporting time limit and handling of AEs and SAEs, please refer to the protocol).12. Tumor assessment is performed based on RECIST v1.1, through PET-CT and enhanced CT at baseline and prior to operation (after the second IBI308 dose but

within 1 week prior to operation), and through CT or enhanced CT on Day 30 post-operation and every 3 months after operation, until 2 years after operation, disease recurrence, or death. Enhanced MRI is required at screening to rule out brain metastasis. The results of imaging examination performed before the signing of the ICF can be used at screening.

13. IBI308 200 mg IV, 2 cycle, is administered on Days 1 and 22, respectively. 14. Subjects are required to undergo a tissue biopsy during the screening period to provide tumor tissue samples for detection of EGFR mutations, and those

subjects meeting the inclusion criteria are also required to assent the provision of biopsy tumor samples left after clinical examination for biomarker analysis; subjects are also required to agree to provide surgically removed tumor tissues left after completion of pathological diagnosis for a comparative study of biomarkers before and after the study treatment.


Study drug: IBI308

15. At baseline and each imaging evaluation, 10 ml of whole blood will be provided for relevant studies of peripheral blood biomarkers.16. Immunogenicity testing is performed before administration of each IBI308 dose and on Day 90 after the last dose.17. Safety follow-up takes place on Day 30 post-operation and Day 90 after the last dose. If these two follow-ups are expected to occur at an interval of less than 2

weeks, they can be combined as one follow-up (whichever occurs later).18. Imaging evaluation and recurrence-free survival follow-up are performed every 90 days (± 7 days) after surgery.


Study drug: IBI308

Table of Contents

Protocol Synopsis..........................................................................................................................................3

Table of Contents........................................................................................................................................13

Abbreviations and Definitions of Terms...................................................................................................18

1 STUDY BACKGROUND........................................................................................................................21

1.1 Disease Background..........................................................................................................................21

1.2 Study Drug (IBI308).........................................................................................................................22

1.3 Risk/BenefitAssessment....................................................................................................................25

2 Objectives of Study..................................................................................................................................26

2.1 Primary..............................................................................................................................................26

2.2 Secondary..........................................................................................................................................26

2.3 Exploratory:......................................................................................................................................26

2.4 Overall Design...................................................................................................................................27

3 STUDY POPULATION..........................................................................................................................29

3.1 Inclusion Criteria..............................................................................................................................29

3.2 Exclusion Criteria.............................................................................................................................30

3.3 Restrictions throughout Study.........................................................................................................31

3.4 Discontinuation of Treatment/Withdrawal of Subjects from Study.............................................31

3.4.1 Discontinuation of any study drug for subjects....................................................................................31

4 STUDY DRUG AND OTHER TREATMENTS....................................................................................33

4.1 Dosing regimen..................................................................................................................................33

4.1.1 Dosing regimen....................................................................................................................................33

4.2 Study Drug (IBI308).........................................................................................................................33

4.2.1 Description...........................................................................................................................................33

4.2.2 Labeling................................................................................................................................................34

4.2.3 Storage conditions...............................................................................................................................34

4.2.4 Preparation and infusion......................................................................................................................34

4.3 Dose Modifications............................................................................................................................35

4.4 Principles for Management of Toxicities Associated with Immune Checkpoint Inhibitors........37

4.5 Concomitant Treatment....................................................................................................................38


Study drug: IBI308

4.5.1 Prohibited medications........................................................................................................................38

4.5.2 Permitted medications.........................................................................................................................38

5 STUDY EVALUATIONS AND PROCEDURES..................................................................................39

5.1 Subject Enrollment Process..............................................................................................................39

5.1.1 Subject inclusion criteria......................................................................................................................39

5.2 Study Plan and Schedule..................................................................................................................40

5.2.1 Screening.............................................................................................................................................40

5.2.2 Baseline (prior to dosing on Day 1/Cycle 1..........................................................................................41

5.2.3 Visits during therapy period.................................................................................................................41

5.2.4 Safety Follow-up...................................................................................................................................41

5.2.5 Recurrence-free survival follow-up......................................................................................................42

5.3 Safety Evaluation..............................................................................................................................42

5.3.1 Routine Laboratory Safety evaluations................................................................................................42

5.3.2 Physical examination............................................................................................................................43

5.3.3 12-lead ECG..........................................................................................................................................43

5.4 Immunogenicity.................................................................................................................................45

5.5 Biomarker Analysis...........................................................................................................................45

5.6 Storage and Destruction of Biological Samples..............................................................................46

6 SAFETY REPORT AND AE MANAGEMENT...................................................................................46

6.1 Definition of Adverse Event.............................................................................................................46

6.2 Definition of Serious Adverse Event................................................................................................46

6.3 Criteria for AE Severity Judgment..................................................................................................47

6.4 Judgment on correlation between AE and study drug...................................................................48

6.5 Recording of AEs...............................................................................................................................49

6.6 Expedited reporting of SAEs and pregnancies...............................................................................53

7 STATISTICAL CONSIDERATIONS....................................................................................................56

7.1 Statistical analysis plan.....................................................................................................................56

7.2 Hypothesis Test..................................................................................................................................56

7.3 Statistical Analysis Population.........................................................................................................56

7.4 Methods of Statistical Analysis........................................................................................................57

7.4.1 General methods forstatistical analysis...............................................................................................57


Study drug: IBI308

7.4.2 Analysis of primary endpoint...............................................................................................................57

7.4.3 Analysis of efficacy outcome measures...............................................................................................57

7.4.4 Biomarker Analysis...............................................................................................................................58

7.4.5 Drug exposure......................................................................................................................................58

7.4.6 Analysis of safety outcome measures..................................................................................................58

7.5 Sample size determination................................................................................................................60

8 QUALITY ASSURANCE AND QUALITY CONTROL.....................................................................61

8.1 Clinical Monitoring...........................................................................................................................61

8.2 Data Management/Coding...............................................................................................................61

8.3 Quality Assurance Audit...................................................................................................................63

9 ETHICS....................................................................................................................................................63

9.1 Ethics Committee..............................................................................................................................63

9.2 Ethics in the Study............................................................................................................................64

9.3 Subject Information and Informed Consent..................................................................................64

9.4 Protection of Subject Data................................................................................................................65

10 STUDY MANAGEMENT.....................................................................................................................65

10.1 Data Processing and Record Retention.........................................................................................65

10.2 Source Data/Document Access.......................................................................................................66

10.3 Protocol Amendments.....................................................................................................................66

10.4 Responsibilities of Investigator......................................................................................................66

10.5 Publication Policy............................................................................................................................67

10.6 Finance and Insurance....................................................................................................................67

11 References...............................................................................................................................................68

12 Appendixes.............................................................................................................................................69

Appendix 1: ECOG PS scoring system.....................................................................................................70

Appendix 2: Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)................................71

Appendix 3: Guidance for IBI308 dose modification and toxicity management...................................87


Study drug: IBI308

Listing of Tables

Table 1. Visit Schedule...........................................................................................................................9

Table 2. Dose and dosing regimen.......................................................................................................33

Table 3. Dose adjustment scheme of IBI308........................................................................................35

Table 4. Routine Laboratory safety evaluations...................................................................................42

Table 5. Judgment on correlation between AE and study drug............................................................48

Table 6. Contact information for SAE reporting..................................................................................54


Study drug: IBI308

Listing of Figures

FIGURE 1. SCHEMATIC DIAGRAM OF STUDY DESIGN AND DOSING REGIMEN OF CIBI308Y002..................28


Study drug: IBI308

Abbreviations and Definitions of Terms

ADA Anti-drug antibodyAE Adverse eventAESI Adverse event of special interestALB AlbuminALK Anaplastic lymphoma kinaseALP Alkaline phosphataseALT Alanine aminotransferaseANC Absolute neutrophil countAST Aspartate aminotransferaseAUC Drug exposureBUN Urea nitrogenCCr Creatinine clearanceCFDA China Food and Drug AdministrationCI Confidence intervalCmax Observed maximum concentration Cr Serum creatinineCR Complete responseCRO Contract Research OrganizationCSR Clinical Study ReportCT Computed tomographyCTC Circulating tumor cellsCTCAE Common Terminology Criteria for Adverse EventsCTLA-4 Cytotoxic T lymphocyte antigen-4DCR Disease control rateDLT Dose-limiting toxicityDoR Duration of responseECG ElectrocardiogramECOG PS Eastern Cooperative Oncology Group Performance StatuseCRF Electronic Case Report FormEGFR Epidermal growth factor receptor

EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30

EORTC QLQ-LC13 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13

FAS Full analysis setFBG Fasting blood glucoseFDA Food and Drug AdministrationFFPE Formalin-fixed paraffin-embeddedFT3 Free triiodothyronineFT4 Free thyroxineGCP Good Clinical PracticeHBV Hepatitis B virusHCT Hematocrit


Study drug: IBI308

HCV Hepatitis CHGB Hemoglobin contentHR Hazard ratioHIV Human immunodeficiency virusICF Informed consent formIHC ImmunohistochemistryiDMC Independent Data Monitoring CommitteeIgG Immunoglobulin GirAE Immune-related adverse eventIRR Infusion-related reactionirRECIST Immune-Related Response Evaluation Criteria in Solid TumorsIV Intravenous IWRS Interactive web response systemLDH Lactic dehydrogenaseLYM Lymphocyte countMedDRA Medical Dictionary for Regulatory ActivitiesmOS Median overall survivalmRNA Messenger ribonucleic acidMRI Magnetic resonance imagingMTD Maximum tolerated doseNAb Neutralizing antibodyNCI National Cancer InstituteNOAEL No-observed-adverse-effect levelNOEL No-observed-effect levelNSCLC Non-small-cell lung cancerORR Objective response rateOS Overall survivalPBMC Peripheral blood mononuclear cellPD Progressive diseasePD-1 Programmed death 1PD-L1 Programmed death-ligand 1DFS Disease-free survivalPH pHPK/PD Pharmacokinetics/PharmacodynamicsPLT Platelet countPR Partial responsePV PharmacovigilanceQ2W every 2 weeksQ3W every 3 weeksRBC Red blood cell countRECIST Response Evaluation Criteria in Solid TumorsSAE Serious adverse eventSAP Statistical analysis planSD Stable diseasesqNSCLC Squamous NSCLCSS Safety Analysis Set


Study drug: IBI308

t½ Half-lifeT3 TriiodothyronineT4 ThyroxineTBIL Total bilirubinTEAE Treatment-emergent adverse eventTP Total proteinTPS Tumor proportion scoreTRAE Treatment-related adverse eventTSH Thyroid-stimulating hormoneUALB Urine albuminUGLU Urine glucoseULN Upper limit of normalUPRO Urine proteinURBC Urine RBCWBC White blood cellγ-GT Gamma-glutamyl transferase


Study drug: IBI308

1　STUDY BACKGROUND

1.1　Disease Background

With the increase in human average life span and changes in lifestyle, malignant

tumor has become a major life-threatening disease that poses a serious threat to the

health of Chinese people. According to the 2015 statistics, the morbidity and mortality

of lung cancer in China are 733,000 and 600,000, respectively, ranking first in the

world[1]. Non-small-cell lung cancer (NSCLC) is a systemic disease and has a potential

for micrometastases even in Stage I. Reactionary hemorrhage during a surgical

procedure can promote local transplantation of cancer cells or their metastases through

blood/lymph circulation, and immunity decrease of the patient after surgery further

promotes the metastasis of cancer. Therefore, how to design and reasonably arrange the

comprehensive therapy before and after surgery to reduce the recurrence and cancer

metastasis has emerged as an important research topic. Immune checkpoint inhibitors

(PD-1/PD-L1 inhibitors) not merely have the potential to kill invisible submicroscopic

lesions to reduce post-operative recurrence by activating the immune system, but

produce less adverse effects than traditional chemotherapy, thereby providing a new

approach for the clinical treatment of NSCLC.

In January 2015, the phase III clinical trial of Opdivo (Nivolumab), a PD-1

inhibitor developed by Bristol-Myers Squibb (BMS), in the treatment of squamous cell

carcinoma of the lung was prematurely terminated[2]. In this head-to-head study

comparing Nivolumab and docetaxel second-line therapy, the Independent Data

Monitoring Committee (IDMC) evaluated the overall survival (OS) in the Nivolumab

treatment group as significantly better compared with the docetaxel control group

(median 9.2 vs 6.0 months; HR 0.59, 95% CI 0.44 - 0.79; P < 0.001), with a longer

PFS (median 3.5 vs 2.8 months; HR 0.62, 95% CI 0.47-0.81; p < 0.001) and a higher

ORR (20% vs 9%; P = 0.008)[2]. In March of the same year, Nivolumab was approved

by the US FDA for advanced squamous cell carcinoma of the lung that failed second-

line therapy.


Study drug: IBI308

Based on the results of Keynote-010 study, the PD-1 inhibitor Keytruda

(Pembrolizumab) developed by Merck Sharp & Dohme Ltd (MSD) was also approved

by US FDA for second-line treatment of PD-L1-positive NSCLC in 2015. In

Keynote010 where a total of 1034 subjects were enrolled and randomized at 1:1: 1

ratio to receive Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg and Docetaxel 75

mg/m2, and the OS was 10.4, 12.7, and 8.5 months respectively in the three groups,

showing that both Pembrolizumab treatment groups had a significantly improved OS

compared with the Docetaxel[3] group. The indications of Pembrolizumab as

monotherapy and in combination with chemotherapy for first-line treatment of NSCLC

were approved by the FDA in September 2016 and May 2017, respectively [4-5].

Based on the results of POPLAR study and OAK study, the PD-L1 antibody

Tecentriq (Atezolizumab) of Roche was approved by US FDA in 2016 under the

indication for second-line treatment of NSCLC. Both studies were randomized

controlled studies comparing Atezolizumab and docetaxel in the second-line and above

treatment of NSCLC, with an OS of 12.6 months vs 9.7 months [6] and 13.8 months vs

9.6 months [7], respectively.

To sum up, immunotherapy blocking the PD-1/PD-L1 axis in the treatment of

advanced NSCLC has shown encouraging results, but clinical studies are yet required

for confirmation as to whether immunotherapy can be used as neoadjuvant therapy in

operable NSCLC to overcome recurrence and metastasis resulting from surgical

trauma-associated low immunity, kill subclinical lesions that are invisible to the naked

eye, and control tumor activity.

1.2　Study Drug (IBI308)

1.2.1　Mechanism of action of IBI308

Immune checkpoints can regulate or balance the intensity and extent of immune

response to avoid damage to the normal cells or tissues through the mechanism of

immune suppression. However, it is found that tumor cells will manipulate immune

checkpoints to escape the body's immune surveillance and refrain themselves from

being eliminated. With respect to multiple immune checkpoints that have been

identified so far, inhibitors of CTLA-4 and PD-1/PD-L1 are already available for


Study drug: IBI308

clinical practice. PD-1/PD-L1 inhibitors have a profile of good safety and broad

indications, with a promising future for clinical application.

PD-1 is mainly expressed on the surface of activated T cells and has two ligands:

PD-L1 and PD-L2, of which PD-L1 is its main ligand and is expressed in activated T

cells, antigen-presenting cells, and tumor cells[4]. PD-1/PD-L1 binding plays an

important role in regulating T cell activation and maintaining peripheral immune

tolerance. When T cells do not express PD-1, T cells interact with antigen-presenting

cells to induce the activation and proliferation of T cells, with the secretion of activated

cytokines that act on tumor cells to kill tumor cells; the activated T cells begin to

express PD-1, and when they bind to ligand PD-L1 on antigen-presenting cells or

tumor cells, the inhibitory signals in the downstream of PD-1 will inhibit the

proliferation of T cells and the secretion of activated cytokines, thereby decrease the

function of T cells. Most tumor cells escape from immune surveillance through this

mechanism. However, if the interaction between PD-1 and PD-L1 is blocked by drugs,

the activity of T cells and their ability to kill cancer cells can be restored [8].

Up to date, three PD-1/PD-L1 products have been approved for marketing by the

US FDA, i.e., anti-PD-1 monoclonal antibody Nivolumab (trade name: OPDIVO) of

BMS, anti-PD-1 monoclonal antibody Pembrolizumab (trade name: KEYTRUDA) of

MSD, and anti-PD-L1 monoclonal antibody Atezolizumab (trade name: TECENTRIQ)

of Roche, under the indications for advanced melanoma, advanced NSCLC, advanced

classical Hodgkin lymphoma, advanced renal cell carcinoma, advanced urothelial

carcinoma, and advanced head and neck tumors. In addition, many indications are

currently under phase III clinical studies or NDA submissions. The marketing of the

above drugs has determined the important role of PD-1/PD-L1 immune checkpoint

inhibitors in cancer immunotherapy. For the moment, there is no PD-1/PD-L1 immune

checkpoint inhibitor marketed in China. Therefore, it is of great significance to actively

develop such inhibitors to provide better treatment options for Chinese patients.

Recombinant fully human anti-PD-1 monoclonal antibody injection (R&D code:

IBI308) is a recombinant fully human IgG4 monoclonal antibody. The effect of

blocking PD-1 pathway with IBI308 has been verified in various preclinical in vitro


Study drug: IBI308

tests, and the anti-tumor activity of the murine analogue of IBI308 has been

demonstrated in several non-immunocompromised mouse tumor models (refer to the

Investigator's Brochure for detailed study results). The results of preclinical studies

suggested a promising future for the development of IBI308 for PD-1 blockade.

1.2.2　Results of IBI308 Clinical Study

In September 2016, a phase Ia dose-escalation trial of IBI308 was initiated. The

phase Ia was planned to enroll approximately 12 to 24 subjects with advanced solid

tumors who had failed standard of care, to evaluate IBI308 at four dose levels (1

mg/kg, 3 mg/kg, 200 mg, and 10 mg/kg), with the dose escalation decision based on

the classic “3+3” design. After completion of the 1 mg/kg dose group, subjects were

randomized to the 3 mg/kg and 200 mg dose groups at a 1:1 ratio for independent

evaluation. There was a 28-day DLT observation period for the two dose groups each

after initial dosing, and only subjects who completed the DLT observation period could

enter the subsequent treatment period to receive IBI308 Q2W (1 mg/kg, 3 mg/kg and

10 mg/kg) or Q3W (200 mg), until disease progression, intolerable toxicity, withdrawal

of consent, or occurrence of other conditions that require discontinuation of study

treatment, whichever occurs first.

Within the dose range studied (1 mg/kg - 10 mg/kg), the elimination half-life of

IBI308 was about 14 days, with a clearance of about 12 mL/h, a steady-state volume of

distribution of approximately 5 L and an apparent volume of distribution of about 84

mL/kg. The exposure (Cmax, AUC0-28, AUC0-inf) of IBI308 in the cancer patients

increased with dose across the dose range of 1 mg/kg - 10 mg/kg. For the doses 1

mg/kg, 3 mg/kg and 10 mg/kg, the geometric mean Cmax (µg/mL) of unit dose was

21.9, 23.2 and 21.6, respectively. The geometric mean AUC0-28 (μg*d/mL) of unit dose

was 199.8, 170.9 and 173.0, respectively. The geometric mean AUC0-inf (μg*d/mL) of

unit dose was 291.1, 215.7 and 213.7, respectively. The dose 1 mg/kg, 3 mg/kg and 10

mg/kg, presented similar profiles of clearance in the body, suggesting that IBI308

presented a linear pharmacokinetic (PK) profile mg/kg in the dose range of 1 - 10

mg/kg.


Study drug: IBI308

At the dose of 1 mg/kg: the geometric mean Cmax values of IBI308, Nivolumab [1]and Pembolizumab [2] were 21.9 µg/mL, 16 µg/mL, and 16.4 µg/mL, respectively, and

their geometric mean t1/2 was 17.0 days, 17 days, and 14.1 days, respectively. The three

drugs had similar profiles of disposition and clearance. The exposure parameters (Cmax,

AUC0-28) of IBI308 were positively correlated with the dose across the dose range of 1

- 10 mg/kg, and this characteristic was also similar to that observed for Nivolumab and

Pembolizumab. IBI308 preliminarily showed similar human PK profiles to Nivolumab

and Pembolizumab.

The results of PD-1 receptor occupancy assay showed that single-dose

administration of IBI308 1 mg/kg achieved saturated PD-1 receptor occupancy (mean

> 95%) in peripheral blood rapidly (24h) and could maintain the PD-1 occupancy level

during the study period (28 days) when the drug concentration decreased continuously.

The results of PD-1 receptor occupancy in the 3 mg/kg, 200 mg/kg and 10 mg/kg dose

groups were similar to that in the 1 mg/kg group. The pharmacodynamic results

suggest that IBI308 has an excellent ability to target PD-1 and good affinity in cancer

patients.

Based on the previous PK/ PD results and acceptable safety events, and taking into

account potential individual differences, the recommended dose of IBI308 for further

clinical study is 200 mg Q3W.

1.3　Risk/BenefitAssessment

Based on the pharmacological mechanism of this product of this product and on

the clinical safety information from products with the same mechanism, the possibly

adverse events of this product are mainly various immune-mediated inflammations

caused by immune activation, such as pneumonia, colitis, hepatitis, renal insufficiency

and inflammation of the endocrine system. According to available clinical data of anti-

PD-1 monoclonal antibody drugs, although the incidence of adverse reactions is high,

the drugs were well tolerated, and only a small portion of subjects discontinued

treatment due to adverse reactions, most of which were resolved after appropriate

treatment. As the early symptoms of immune-related adverse reactions are variable, the

investigator(s) should pay special attention to the early symptoms and signs of various August 12, 2017 Version 1.0 Confidential 25 / 116

Study drug: IBI308

immune-related reactions in the clinical study, make appropriate judgment in a timely

fashion, and perform dose adjustment and appropriate effective treatment as described

in Section 5.4.1 of the protocol to reduce the risks of drug use for the patients. In

addition, the investigator(s) should exclude patients with autoimmune diseases during

the clinical trial to avoid worsening of pre-existing diseases as a result of immune

system activation.

The phase Ia clinical pharmacology and safety data for IBI308 show that IBI308

has clear pharmacological activity and is well tolerated in patients with advanced

tumors.

The above data have preliminarily demonstrated the good safety and

pharmacological activity of IBI308, supporting the conduct of clinical studies of

IBI308 in patients with NSCLC.

2　Objectives of Study

2.1　Primary

To evaluate the disease-free survival (DFS) after IBI308 monotherapy as

neoadjuvant/adjuvant therapy for resectable non-small cell lung cancer (NSCLC)

To evaluate the study-related adverse events (90 days after the first dosing of IBI308

or 30 days after surgery, whichever occurs later)

To evaluate the incidence of surgical complications (both intraoperative and

perioperative)

To evaluate the rate of non-delayed surgery (surgical delay is defined as no

performance of surgery for more than 43 days from the day of the first dosing)

2.2　Secondary

To evaluate the objective response rate (ORR) and major pathologic response (MPR) after IBI308

monotherapy as neoadjuvant therapy for resectable NSCLC ;

To evaluate the 1-year and 2-year disease-free survival, the 1-year and 2-year

recurrence rate (RR) and the 2-year survival rate;


Study drug: IBI308

2.3　Exploratory:

To evaluate the relationship between pathological response and DFS and RR after

IBI308 monotherapy as neoadjuvant therapy


efficacy.

To evaluate the relationship of biomarkers in tumor tissue with efficacy, including but

not limited to the expression of PD-L1, tumor infiltrating lymphocytes (TIL), and

tumor mutational burden (TMB)

To evaluate the relationship of biomarkers in peripheral blood with efficacy, including

but not limited to the relationship between efficacy and dynamic changes in the

overall mutational burden of ctDNA

2.4　Overall Design

It is a phase Ib single-center study to evaluate IBI308 monotherapy as neoadjuvant

therapy for resectable NSCLC. A safety run-in study of 6 patients will be conducted

first, and if no major safety event occurs, the study will be expanded to a total of 30

patients.

After the signing of the informed consent form (ICF), patients with treatment-

naïve operable NSCLC who are confirmed eligible for the inclusion/exclusion criteria

after screening will be administered IBI308 200 mg IV Q3W for 2 cycles, and will

receive radical operation for NSCLC within 29 to 43 days following the first dose of

IBI308, as well as adjuvant treatment according to invergator’s discretion and patients’

status.

Imaging assessment will be conducted per RECIST v1.1 in this study, with PET

and enhanced CT performed at baseline and prior to radical operation (after the second

dose of IBI308 but within 1 week prior to operation), as well as CT or enhanced CT on

Day 30 post-operation and every 3 months post-operation, until 2 years after the

operation, disease recurrence or death. Enhanced CT/MRI is required at baseline to

rule out brain metastases.


Study drug: IBI308

The subjects will be followed for safety (90 days after the first dose of IBI308 or

30 days post-operation, whichever occurs later) and post-operative recurrence-free

survival (every 90 ± 7 days until 2 years post-operation).


Study drug: IBI308

Figure 1. Schematic diagram of study design and dosing regimen of CIBI308Y002


Postoperative conventional adjuvant therapy

Recurrence-free survival follow-up: every 90 days after operation

Safety follow-up:1. 90 days after the last dose of IBI308

2. 30 days post-operation

Radical resection + lymph node dissection (After 2 cycles of IBI308

200 mg IV Q3W treatment and within 29 to 43 days after the first dose of

IBI308)

IBI308 Group: 200 mg IV Q3W*2 cycles

D1, D22

Patients with pathologically confirmed, untreated, operable NSCLC

of tumor size > 2 cm

Study drug: IBI308

3　STUDY POPULATION

3.1　Inclusion Criteria

The subjects are required to meet the following inclusion criteria:

1　Cytologically or histologically confirmed NSCLC;

2　Assent to the collection of tumor histological specimens required for this study for

relevant studies;

3　Presence of treatment-naïve, surgically resectable NSCLC, with a tumor diameter of > 2

cm;

4　Consent to receive radical operation;

5　No surgical contraindications in the judgment of a thoracic surgeon;

6　Presence of at least one measurable lesion (RECIST v1.1);

7　Male or female, at an age ≥ 18 years and ≤ 75 years;

8　An ECOG score of 0;

9　Adequate functions of vital organs and bone marrow that meet the following

requirements:

- Hematology: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelets (PLT) ≥ 100 ×

109/L, hemoglobin (HGB) ≥ 9 g/dL;

- Liver function: serum total bilirubin (TBIL) ≤ 1.5 × ULN (upper limit of normal),

alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × ULN,

serum albumin (ALB) ≥ 2.8 g/dL;

- Renal function: Serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance ≥ 40

mL/min (calculated using the standard Cockcroft -Gault formula):

Females: CrCl = (140-age) x body weight (kg) x 0.85


Males: CrCl = (140-age) x body weight (kg) x 1.00



Study drug: IBI308

10　Provide signed the written ICF and could follow the visit schedule and relevant

procedures specified in the study protocol.

3.2　Exclusion Criteria

A subject meeting any of the following exclusion criteria will be excluded from

this study:

1. Presence of EGFR-sensitive gene mutation in tumor tissue as revealed by aspiration

biopsy;

2. A past medical history of any anti-tumor therapy, including radiotherapy,

chemotherapy, immunotherapy and traditional Chinese medicine therapy (excluding

therapy for malignancies that were radically treated, without recurrence or metastasis

for a period of ≥5 years);

3. Use of immunosuppressive agents within 4 weeks prior to the first dose of the study

treatment, excluding topical glucocorticoids for intranasal, inhalation or other routes of

administration, or physiological doses of systemic glucocorticoids (i.e., no more than

10 mg/day prednisone or equivalent of other glucocorticoids);

4. Known or suspected active autoimmune diseases (congenital or acquired), such as

interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis,

thyroiditis, etc. (patients with vitiligo or complete remission of asthma in childhood,

without requiring any intervention after adulthood can be enrolled; patients with type I

diabetes well controlled by insulin can also be enrolled);

5. Known allotransplant (excluding corneal transplantation) or allogeneic hematopoietic

stem cell transplantation;

6. Allergy to any ingredient of the monoclonal antibody;

7. Current interstitial lung disease;

8. Presence of other uncontrolled serious medical conditions, including but not limited to:

− Active or clinically uncontrolled severe infection;

− HIV-infection (HIV antibody positive);


Study drug: IBI308

− Acute or chronic active hepatitis B (HBsAg positive and HBV DNA > 1*103/mL)

or acute or chronic active hepatitis C (HCV antibody positive and HCV RNA > 15

IU/mL);

− Active pulmonary tuberculosis;

− Class III-IV congestive heart failure (New York Heart Association classification),

poorly controlled and clinically significant arrhythmia;

− Uncontrolled arterial hypertension (systolic blood pressure ≥ 160 mmHg or

diastolic blood pressure ≥ 100 mmHg);

− Any arterial thrombosis, embolism or ischemia within 6 months prior to inclusion

for treatment, such as myocardial infarction, unstable angina, cerebrovascular

accident or transient ischemic attack;

− Disease requiring anticoagulation with warfarin (coumarin);

− Uncontrolled hypercalcemia (calcium ion > 1.5 mmol/L or calcium greater than 12

mg/dL or corrected serum calcium > ULN), or symptomatic hypercalcemia

requiring continued bisphosphonate therapy;

− Other malignant tumors (excluding cancer that has been cured, such as cervical

carcinoma in situ, non-melanoma skin cancer, etc.);

9. Other acute or chronic diseases, psychiatric disorders or abnormal laboratory values,

which may result in an increased risk associated with study participation or use of the

study drug, or interfere with the interpretation of study results and render the patient

ineligible for the study in the investigator’s judgment;

10. Pregnant or breastfeeding women.

3.3　Restrictions throughout Study

Male and female subjects of childbearing potential are required to use effective

methods of contraception from screening and must agree to maintain these precautions

until 90 days after the last dose of study drug; discontinuation of contraception should

be discussed with a responsible physician after this time point.


Study drug: IBI308

3.4　Discontinuation of Treatment/Withdrawal of Subjects from Study

3.4.1　Discontinuation of any study drug for subjects

Discontinuation of study drug "Must" be performed for a subject if any of the

following circumstances:

The subject requests discontinuation of study treatment

Occurrence of any clinical adverse event (AE), laboratory abnormality, or

intercurrent disease, in which case continued participation in the study is not in the

best interest of the subject based on the investigator’s judgment

Discontinuation criteria specified in the protocol are satisfied

Violation of inclusion/exclusion criteria, which may pose potential risks to the

patient’s safety or jeopardize the accuracy of trial data, rendering it unsuitable for

the subject to continue the study;

The subject has constituted a gross violation of the study protocol, rendering it

unsuitable for the subject to continue the study in the investigator’s judgment;

Participation of the subject in another interventional drug clinical trial at the same

time;

All subjects who discontinued the study drug should be followed up according to

the procedures specified in Table 1, unless a subject has withdrawn informed consent

to all study procedures (including study follow-up after treatment discontinuation).

If a subject discontinued the study drug before completing the study, the reason for

discontinuation must be documented in the subject's medical records and entered into

the appropriate page of the electronic medical records system (EDC).

3.4.2　Study follow-up after treatment discontinuation

For subjects who discontinued the study drug, follow-up must be continued to

collect outcome and/or recurrence-free survival follow-up data as required, until death

of the subject or the end of study as specified in Table 1.


Study drug: IBI308

For subjects who are lost to follow-up, the site should make all possible efforts to

contact the subject to determine the cause(s) of loss to follow-up, and re-schedule a

visit wherever possible. Meanwhile, the site should document the date of the subject to

be contacted and the contact information used in the study file.

3.4.3　Withdrawal of informed consent

A subject that requested discontinuation of study drug is still required to continue

in the study, and must be followed continuously according to the follow-up procedures

specified in the study protocol. However, there is one exceptional situation where the

subject himself or herself or the person previously authorized to provide this

information cannot be contacted again after the subject has clearly withdrawn the

informed consent. Where possible, the subjects should inform the investigator(s) of

their decision to withdraw consent to future follow-up in writing form. The

investigator(s) should provide a delineation of informed consent withdrawal in the

medical records, by clarifying whether it is only a decision not to use the study

treatment or a decision not to perform the study procedures and/or the study follow-up

after treatment discontinuation, and enter such information into the appropriate case

report form (CRF) page. If needed for evaluation of survival status survival (whether

the subject is living or dead), it can be performed only using the publicly available

information in accordance with corresponding provisions and with law.

4　STUDY DRUG AND OTHER TREATMENTS

4.1　Dosing regimen

4.1.1　Dosing regimen

For the purpose of this study, study drug refers to IBI308, and other medications

used during the study are collectively referred to as non-study drugs. The dosing

regimen is presented in the table below.

Table 2. Dose and dosing regimen

Group Dosing regimen Dosage time


Study drug: IBI308

IBI308 group200 mg IV infusion over approximately 1 hour, Q3W, for 2 cycles before surgery

D1 and D22 prior to operation;

4.2　Study Drug (IBI308)

4.2.1　Description

The study drug is recombinant fully human anti-programmed cell death receptor 1

monoclonal antibody injection, referred to as IBI308.

Its main active ingredient is recombinant fully human anti-programmed cell death

receptor 1 monoclonal antibody, with the finished product supplied in strength of 10

mL: 100 mg. IBI308 is at a concentration of 10 mg/mL, free of preservatives, and

contains the following excipients: mannitol 140 mmol/L, histidine 25 mmol/L, sodium

citrate dihydrate 20 mmol/L, sodium chloride 50 mmol/L, edetate disodium (disodium

edetate) 0.02 mmol/L, and polysorbate 80 0.2 mg/mL, with a pH value of 6.0.

This product is a clear, colorless liquid, free of foreign matters, floccules and

precipitates.

Manufacturer: Innovent Biologics (Suzhou) Co., Ltd (hereinafter referred to as

Innovent).

4.2.2　Labeling

IBI308 is supplied in the minimum packaging unit of boxes, with per box

containing 1 piece of IBI308 injection packaged in a vial. Printed on the packaging

boxes of IBI308 are drug name, drug number, dosage form, strength, drug code, lot

number, shelf life, storage conditions, usage and dosage, and precautions. The same

information is also printed on the labels for the vials and packaging boxes, except for

dosage form and precautions information, which is not provided on the vial labels. The

labels of all packaging boxes and vials are clearly indicated with "For clinical trial

only".


Study drug: IBI308

4.2.3　Storage conditions

Store at 2 to 8 , protect from light, shelf life of 24 months. If quality problems ℃such as turbidity and precipitation occur with the injection, seal up the product

immediately and notify Innovent.

4.2.4　Preparation and infusion

IBI308 is prepared and infused according to procedures as follows:

1. Draw the liquids of 2 vials of IBI308 injection completely into an IV infusion bag

containing 100 mL of 0.9% (weight/volume) sodium chloride sterile normal saline,

and record the start time of preparation.

2. Gently invert the infusion bag to mix, to ensure the homogeneity of drug in the

infusion bag and avoid shaking violently to produce bubbles.

3. Administer infusion via an IV pump installed with 0.2 - 1.2 μm in-line filters (it is

recommended that the infusion be completed over 60 minutes), and record the start

time and end time of infusion.

Notes: Prior to preparation, confirm that IBI308 injection is transparent without

turbidity, precipitates or other quality problems; ensure that the time from the puncture

of the first vial of IBI308 injection to the end of infusion does not exceed 24 hours (the

prepared mixture is refrigerated at 2 - 8 ); avoid mixing other drugs; avoid IV bolus.℃

4.3　Dose Modifications

4.3.1　General principle

The subjects must have adequate hematologic, hepatic, and renal functions prior to

dosing of study drug on Day 1, and all toxicities must have been resolved to NCI CTCAE

4.03 grade 0-1 or baseline (excluding alopecia, fatigue).

All dosage modifications should be documented, including the reason and the

method(s) used.


Study drug: IBI308

4.3.2　Dosage modifications for IBI308

No dose adjustment for IBI308 is allowed throughout the study. The dosage

modification scheme for IBI308 (only for AEs judged as IBI308-related by the

investigator) is presented in the table below.

Table 3. Dose adjustment scheme of IBI308

Adverse reactions Severity Dose modifications

Pneumonitis

Grade 2 pneumonitis Interruptiona

Grade 3 or 4 pneumonitis Permanent discontinuation

Diarrhea/enterocolitis

Grade 2 or 3 diarrhea or enterocolitis Interruptiona

Grade 4 diarrhea or enterocolitis Permanent discontinuation

Dermatitis

Grade 3 dermatitis Interruptiona

Grade 4 dermatitis Permanent discontinuation

Hepatitis

Grade 2 increased AST, ALT, or TBIL for subjects with normal ALT, AST, or TBIL at baseline; or AST, ALT, or TBIL elevations ≥ 50% and persisting < 7 days for subjects with AST, ALT, or TBIL > ULN at baseline

Interruptiona

Grade 3 or 4 increased AST, ALT, or TBIL for subjects with normal ALT, AST, or TBIL at baseline; or AST, ALT, or TBIL elevation ≥ 50% and lasting ≥ 7 days for subjects with AST, ALT, or TBIL > ULN at baseline

Permanent discontinuation

Hypophysitis

Grade 2 hypophysitis Interruptionb

Grade 3 or 4 hypophysitis Permanent discontinuation

Adrenal insufficiency Grade 2 adrenal insufficiency Interruptionb

Grade 3 or 4 adrenal insufficiency Permanent


Study drug: IBI308

Adverse reactions Severity Dose modifications

discontinuation

Hyperthyroidism Grade 3 or 4 hyperthyroidism Permanent discontinuation

Type 1 diabetes

Grade 3 hperglycaemia Interruptionb

Grade 4 hperglycaemia Permanent discontinuation

Renal insufficiency

Grade 2 or 3 elevated Cr Interruptiona

Grade 4 elevated Cr Permanent discontinuation

Neurotoxicity

Grade 2 neurotoxicity Interruptiona

Grade 3 or 4 neurotoxicity Permanent discontinuation

Transfusion reaction Grade 3/4 infusion reaction Permanent discontinuation

Other AEs

First occurrence of other grade 3 AE Interruptiona

Second occurrence of the same grade 3 AE Permanent discontinuation

Grade 3 AE that did not return to grade 0 - 2 or the baseline level within 7 days or was not resolved to grade 0/1 or the baseline level within 14 days


Grade 4 AE Permanent discontinuationc

a: The drug may be resumed after the symptoms are resolved to grade 0 - 1 or the

baseline level.

b: The drug may be resumed after hypophysitis, adrenal insufficiency, and/or type 1

diabetes mellitus is adequately controlled, only requiring physiological hormone

replacement therapy (HRT).


Study drug: IBI308

c: For grade 4 laboratory abnormalities, discontinuation of treatment should be based

on concomitant clinical symptoms/signs and the investigator’s clinical judgment.

The maximum interval between the first and second doses of IBI308 is 5 weeks. If the

abnormalities do not return to a status allowing for resumption of IBI308 within 5 weeks,

the subject will be discontinued from IBI308 permanently and proceed to the radical

surgery stage.

4.4　Principles for Management of Toxicities Associated with Immune Checkpoint

Inhibitors

IBI308 pharmacologically promotes the activation and proliferation of T cells to

cause immune hyperfunction, thereby leading to autoimmune disorders of multiple

systems. Immune-related adverse events were reported with clinical application of

other immune checkpoint inhibitors (Ipilimumab, Nivolumab, Pembrolizumab and

Atezolizumab), including immune-related pneumonia, diarrhea/enterocolitis, renal

insufficiency, rash, hepatitis, endocrine disorders, and peripheral or central neuritis. In

the event any of the above AEs occurs for a subject in this study, appropriate measures

should be taken for the subject, including monitoring of symptoms and signs, and

identification of cause(s). If no alternative causes (e.g., disease progression,

concomitant medication and infection) are identified and treatment with

glucocorticoids and/or other immunosuppressive agents is required (except for

endocrine events such as hyperthyroidism/hypothyroidism, hypophysitis, type 1

diabetes and adrenal insufficiency, which may not be treated with immunosuppressive

therapy but are still considered to be related to immune hyperfunction caused by

IBI308), the above AE should be considered related to hyperfunction of the immune

system caused by IBI308 and diagnosed as irAE.

Guidelines on dose adjustment and toxicity management for potential major irAEs,

potential other irAEs and infusion-related reactions are provided in Appendix 4.

4.5　Concomitant Treatment

4.5.1　Prohibited medications

Use of the following medications is prohibited during the preoperative treatment August 12, 2017 Version 1.0 Confidential 39 / 116

Study drug: IBI308

period of study drug:

Other chemotherapy, immunotherapy, targeted therapy and Chinese herbal

medicines with anti-tumor activity for anti - tumors.

Immunosuppressive agents and high-dose glucocorticoids (excluding those for

AEs).

Immunoglobulins.

Live attenuated vaccine.

4.5.2　Permitted medications

Use of the following medications is permitted during the preoperative treatment period

of study drug:

Medications that comply with the protocol requirements in the investigator’s

judgment (e.g., concomitant medications for disease-related symptoms and

treatment-related AEs).

Long-term medications that are required for management of underlying diseases

such as hypertension and diabetes.

Glucocorticoids that are intended for topical use, such as topical skin application,

eye application, nasal spray and inhalation.

4.6　Treatment Compliance

Study treatment is administered at the study site, and treatment compliance is

monitored using drug receipt & dispensing records, medical records and eCRFs.

4.7　Drug Recovery and Destruction

In this study, the used and partially used containers, bottles, infusion bags, and

syringes of the study drug may be destroyed on site according to the applicable

guidelines and operating procedures established by the study site and local authorities

after confirmation by the clinical research associate (CRA).


Study drug: IBI308

4.8　Documentation of Study Drug

The designated site personnel should keep a record of the receipt, dispensing, use,

inventory, loss, recovery and destruction of the study drugs in time according to the

requirements of relevant regulations and guidelines as well as the operating procedures

of this trial.

5　STUDY EVALUATIONS AND PROCEDURES

5.1　Subject Enrollment Process

5.1.1　Subject inclusion criteria

The investigator(s) will enroll subjects according to the following procedures:

1. Obtain signed ICF the subject prior to initiation of any study-related procedures.

2. The principal investigator (PI) or the appropriately trained designee formally

confirm the subject’s eligibility against the inclusion/exclusion criteria.

Re-screening may be performed for patients who do not meet the relevant criteria

for this study (screening failure). At re-screening, the patient must re-sign the ICF and

will be reassigned with an identification number.

5.2　Study Plan and Schedule

5.2.1　Screening

The following study procedures must be completed during the screening period

(Day -28 - -1) to ensure the subject’s eligibility for the study:

Sign ICF

Inclusion/exclusion criteria

Demographics, past medical history and previous medication

Vital signs, height and weight

Physical examination

ECOG PS score


Study drug: IBI308

12-lead ECG

Hematology/blood biochemistry/urinalysis (within 7 days prior to the first dosing)

Pregnancy test (within 3 days prior to the first dosing)

Thyroid function

HIV antibody, hepatitis B two and a half pairs (HBsAg, HBsAb, HBcAb, HBeAg,

HBeAb), HCV antibody

Adverse event assessment

Concomitant medications

Tumor imaging evaluation (the results of imaging examinations obtained before

signing of ICF can be used for the screening period)

Biopsy of fresh tumor tissue

EGFR testing

Biomarker blood sample collection

5.2.2　Baseline (prior to dosing on Day 1/Cycle 1

Vital signs



Immunogenicity

5.2.3　Visits during therapy period

Vital signs


12-lead ECG

Hematology/blood biochemistry/urinalysis

Thyroid function



Tumor imaging evaluation


Study drug: IBI308

Administration of study drug

Biomarker blood sample collection

The flow chart of study treatment visits is provided in Table 1.

5.2.4　Safety Follow-up

Safety follow-up takes place on Day 30 post-operation and Day 90 after the last

dose. If these two follow-ups are expected to occur at an interval of less than 2 weeks,

they can be combined as one follow-up (whichever occurs later).

Safety follow-up on Day 30 post-operation covers the following:

Vital signs


12-lead ECG


Thyroid function

Imaging evaluation



Subsequent anti-tumor treatment

Safety follow-up on Day 90 after the last dose covers the following:

Vital signs


12-lead ECG


Thyroid function



Subsequent anti-tumor treatment


Study drug: IBI308

Immunogenicity

Pregnancy test

5.2.5　Recurrence-free survival follow-up

At the time of imaging evaluation performed every 90 days (± 7 days) after

surgery, information regarding the subject's survival and information regarding any

subsequent systemic anticancer therapy and disease recurrence will be recorded until 2

years after surgery. After 2 years post-operation, the investigator may continue to

follow the patient for a long period of time until death of the subject.

5.3　Safety Evaluation

5.3.1　Routine Laboratory Safety evaluations

Table 4 Routine Laboratory safety evaluations

Hematology

RBC、HGB、WBC、PLT、LYM、ANC

Blood chemistry

TBIL, ALT, AST, γ-GT ALP, ALB, TP, LDH, BUN, Cr, Na, K, Cl, Mg, Ca, P, Lipase, Amylase and FBG

Urinalysis PH, UALB, UPRO, URBC, UGLU

5.3.2　Physical examination

Complete physical examination includes: general condition, respiratory,

cardiovascular, abdominal, skin, head and neck (including ears, eyes, nose and throat),

lymph nodes, thyroid, musculoskeletal (including spine and limbs), genital/anal and

neurological assessments.

Refer to Table 1 visit schedule for the specific time of physical examination. Refer

to Appendix 2 for ECOG PS scoring system.

5.3.3　12-lead ECG

Resting 12-lead ECG will be analyzed at a local laboratory according to Table 1

visit schedule.


Study drug: IBI308

A 12-lead ECG is performed for each subject after a rest of minimum 5 minutes in

recumbent position. All 12-lead ECGs should be recorded with the subject in a

recumbent position. Further ECG will be performed as clinically indicated, e.g., when

there is an occurrence of cardiac-related AE. The investigator completes ECG

assessment on the day of the examination and write down the results of assessment on

the electrocardiogram. The same assessment method(s) should be used throughout the

study.

The investigator should assess all ECGs according to the category of clinically

significant abnormality/not clinically significant abnormality. If the abnormality is

clinically significant, the investigator should record this result as an AE in the eCRF.

5.3.4　Vital signs

Vital signs examination will be performed as described in Table 1 study visit

schedule. Vital signs include body temperature, pulse rate, respiratory rate, and blood

pressure.

Additional monitoring of vital signs may be performed at the discretion of the

investigator based on standard clinical practice or as clinically indicated.

In the event of an AE/SAE, additional vital sign values may be collected from the

eCRF (if appropriate). The date(s) and time of collection and measurement will be

recorded in the appropriate section of the eCRF.

5.3.4.1　Pulse and blood pressure

Blood pressure (BP) and pulse rate are measured with the subject a supine position

after a rest of at least 5 minutes. Two ore more readings should be obtained with

measurement performed at intervals of two minutes, and the mean of the measurements

is calculated. If the first two systolic blood pressure readings differ by more than 5

mmHg, another measurement should be performed to calculate the mean value. The

date(s) and time of collection and measurement will be recorded in the appropriate

section of the eCRF.


Study drug: IBI308

Measurement of pulse and blood pressure measurements needs to be performed

prior to administration of the study drug.

5.3.4.2　Body temperatureand respiratory rate

Blood temperature and respiratory rate should be collected prior to infusion on the

scheduled dosing day(s).

5.3.5　Body weight and height

Body height is measured only during the screening period.

Body weight measurement needs to be performed prior to each scheduled dosing

throughout this study. If a subject's body weight fluctuations from baseline (the day of

the first dose of study treatment) are less than 10%, the baseline body weight will be

used to calculate the dose for the subject. Otherwise, the subject's body weight on the

scheduled dosing day will be used for calculating the actual dose.

5.3.6　Pregnancy test

For women of childbearing potential (see 4.3 for definition), a pregnancy test

using urine or serum human chorionic gonadotropin (hCG) samples should be

performed within 3 days prior to the first dose of study drug. If urine hCG test reports

positive or negative cannot be confirmed, a pregnancy test should be using serum β-

hCG samples, and the result of serum pregnancy test should prevail. If the pregnancy

test is positive, the subject is not eligible for enrollment/must be discontinued from the

study. In the event of suspected pregnancy during the study, a test should be repeated

for confirmation.

5.3.7　Other safety tests

HIV antibody

Hepatitis B: Two and a half pairs (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb).

Hepatitis C: HCV antibody.

Thyroid function: T3, T4, TSH, FT3 and FT4.


Study drug: IBI308

5.4　Immunogenicity

Immunogenicity testing will be performed before each IBI308 dose and on Day 90

after last dose. If a subject experienced an IBI308 infusion reaction, blood samples

should be collected as close as possible to the start and resolution of the event, and at

approximately 30 days after the end of the event for comparison of immunogenicity

before and after IBI308 infusion.

Testing on anti-drug antibody titer will be performed for each subject, and ADA-

positive serum specimens will be further tested for neutralizing antibodies (NAbs).

Four (4) mL of whole blood will be collected into a coagulation-promoting

vacuum tube, then separated serum, split and frozen for ADA and NAb analysis.

See the "Laboratory Manual" for details on the sample collection method and

sample preservation, transport & analysis.

5.5　Biomarker Analysis

Where permitted by the Ethics Committee, all subjects who meet the inclusion

criteria are required to provide tissue biopsy specimens at baseline for biomarker

analysis, including but not limited to PD-L1 expression, TIL, and TMB. See Specimen

Collection Manual for specific requirements regarding the amounts of specimens to be

collected, specimen preservation and transportation. Subjects are required to provide

10 ml of whole blood specimens at the following time points: during the screening

period and at each efficacy evaluation, until 2 years after surgery. See Specimen

Collection Manual for specific requirements.

5.6　Storage and Destruction of Biological Samples

Samples will be anonymized and pooled. In addition, they will be disposed of or

destroyed appropriately. Additional analyses may be performed for the anonymized,

pooled samples to further assess and validate the analytical methods. Any results

obtained from these analyses may be reported separately from the CSR.


Study drug: IBI308

Sample reproducibility analysis (if performed) will be performed in parallel with

the bioanalysis of the test samples. The assessment results will be separately reported

in a bioanalysis report rather than in the clinical study report.

6　SAFETY REPORT AND AE MANAGEMENT

6.1　Definition of Adverse Event

An adverse event (AE) is defined as any untoward medical occurrence in a clinical

trial subject from the signing of the ICF through 90 days after administration of the last

study treatment, irrespective of a causal relationship with the drug. Therefore, AEs

include but are not limited to the following:

Worsening of preexisting medical conditions/diseases (including worsening of

symptoms, signs and laboratory abnormalities);

Any new adverse medical conditions (including symptoms, signs and newly

diagnosed diseases);

Clinically significant abnormal laboratory values or findings.

6.2　Definition of Serious Adverse Event

A serious adverse event (SAE) is defined as the AE that meets at least one of the

following criteria:

Results in death, excluding deaths due to disease progression from the studied

indication.

Is life-threatening ("life-threatening"in the definition refers to an AE that

places the subject at immediate risk of death as it occurred, and therefore it does

not include an AE that might have caused death had it occurred in more severe

form).

Requires inpatient hospitalization or prolongation of existing hospitalization,

with the exception of the following:

- Admission to a rehabilitation facility;

- Admission to nursing homes;


Study drug: IBI308

- Routine admission to the emergency room

- Same-day surgery (e.g. outpatient/same-day/ambulatory surgery)

- Inpatient hospitalization that is not related to worsening of AE, or

prolongation of hospitalization which itself is not an SAE. For example,

hospitalization due to preexisting diseases, without occurrence of new adverse

events or worsening of preexisting diseases (for example, in order to examine the

laboratory abnormalities that have already existed before initiation of the trial and

been persisting throughout the study); administrative hospitalization (for example,

routine annual physical examination); hospitalization specified in the trial protocol

during the clinical trial (for example, operations performed according to the

requirements of the trial protocol); elective hospitalization unrelated to worsening

of an adverse event (for example, selective operation); scheduled treatment or

surgery, which should be recorded in the whole trial protocol and/or the subject’s

baseline data; hospitalization only due to the use of blood products.

Results in persistent or significant disability/incapacity.

Is a congenital anomaly/birth defect.

Other important medical events: defined as events that jeopardize the subject

or require medical intervention to prevent any of the above consequences.

6.3　Criteria for AE Severity Judgment

The investigator(s) will assess the severity of AEs according to the five-grade

judgment criteria as established in NCI CTCAE v4.03.

AEs that are not included in CTCAE v4.03 will be graded according to the

following CTCAE principles:

Grade 1- Mild; asymptomatic or minimal signs; clinical or diagnostic

observations only; intervention not indicated.

Grade 2 - Moderate; minimal, local or non-invasive intervention indicated;

limiting age-appropriate instrumental activities of daily living (ADL, e.g.,


Study drug: IBI308

preparing meals, shopping for groceries, using the telephone, managing money,

etc.).

Grade 3 - Severe or clinically significant but not immediately life-threatening;

hospitalization or prolongation of hospitalization indicated; disabling; limiting

self-care ADL (e.g., bathing, dressing and undressing, feeding self, using the

toilet, and taking medications), but not bedridden.

Grade 4 - Life-threatening consequences; urgent intervention indicated.

Grade 5 - Death related to AE

6.4　Judgment on correlation between AE and study drug

The relationship of the study drug with the AE or the role it plays in the occurrence

of AE can be judged using the following classification and criteria:

Table 5. Judgment on correlation between AE and study drug

Correlation Criteria

Definitely

related

- There exists a reasonable temporal consequence in use of the study

drug with occurrence of the AE;

- The AE can be more reasonably explained by the investigational drug

than other causes (e.g., the subject's preexisting disease,

environmental or toxic factors or other treatments the subject

received, etc.);

- The AE disappeared or is mitigated after treatment discontinuation or

dose reduction;

- It falls into the known AE types of the suspected drug or similar

drugs;

- The adverse event appears again after resumption of the drug;

Possibly

related

- There exists a reasonable temporal consequence in use of the study

drug with occurrence of the AE;

- The AE can be reasonably explained by the investigational drug as

well as by other causes (e.g., the subject's preexisting disease,

environmental or toxic factors or other treatments the subject


Study drug: IBI308

Correlation Criteria

received, etc.);

- The AE disappeared or is mitigated after treatment discontinuation or

dose reduction (if applicable).

Possibly

unrelated

- The AE can be more reasonably explained by other reasons (e.g., the

subject's preexisting disease, environmental or toxic factors or other

treatments the subject received, etc.) than the investigational drug;

- It is unknown whether the AE disappeared or is mitigated after

treatment discontinuation or dose reduction (if applicable);

- It is unknown whether the AE appeared again or not after resumption

of the drug.

Definitely

unrelated

- There does not exist a reasonable temporal consequence in use of the

drug with occurrence of the AE, or

- There are other obvious explanations for the AE (e.g., the subject's

preexisting disease, environmental or toxic factors or other treatments

the subject received, etc.).

Unable to

judge

- The above information is unknown; the investigator considers it

impossible to judge based on available information and is unable to

obtain further follow-up information.

6.5　Recording of AEs

The investigator(s) should record AEs or SAEs using medical

terminology/concepts. Use of colloquialisms and abbreviations should be avoided. All

AEs (including SAEs) should be recorded on the adverse event form of the eCRF.

6.5.1　Collection of AEs and time period

The investigator is aware of AEs by asking the subjects non-inductive questions.

All AEs (including SAEs), whether observed by the investigator or spontaneously

reported by the subjects, should be collected from the signing of the ICF through 90

days after the last dose.


Study drug: IBI308

After 90 days after the last dose, the investigator should report SAEs that are

considered related to the study drug or procedures.

6.5.2　Follow-up of AEs

All AEs should be followed up until they are resolved to baseline or grade 0 - 1 or

the investigator consider further follow-up unnecessary for good justification (e.g, the

AE cannot be resolved or has improved). If the AE cannot be resolved, the reasonable

explanation(s) should be recorded on the eCRF. The outcomes of AEs or SAEs in the

subjects and their dates should be documented on the eCRF and medical records,

irrespective of their relationship with the study drug.

6.5.3　AE records

The investigator should keep a complete record of any adverse event, including

diagnosis (if no diagnosis, record the symptoms and signs including abnormal

laboratory findings), start and end dates and time (if applicable), CTCAE severity

grade and change (Grade 3 events and above), whether it is an SAE, whether it is an

AESI, actions taken for the study drug, treatment administered due to AE and the

outcome of the event, and the relationship of AE with the study drug.

For an SAE, the investigator should also provide the following details: the date

on which the AE is judged to meet the criteria for an SAE, the date the investigator

became aware of the SAE, rationale for the determining the AE as an SAE, the date of

hospitalization, the date of discharge, the possible cause(s) of death, the date of death,

whether an autopsy was performed, the assessment of causality with the study

procedures, assessment of causality with other drugs, and other possible explanations

for the SAE. The investigator should also provide the rationale for correlation

judgment and a description of the SAE. The description of SAE needs to address the

following: the subject's number, age, gender, height and weight; the subject’s

indication for the investigational treatment, disease stage and general conditions;

clinical course of the SAE, including occurrence, development, outcome and

consequence; laboratory findings related to the SAE (the time of laboratory test, unit

and normal range must be provided); past medical history/ concomitant diseases


Study drug: IBI308

related to the SAE, and their occurrence time and duration; medication history and

concomitant medications related to the SAE, and their start date, duration and dosage;

details about the investigational treatment, including the start time, duration and

dosage.

The items of AE records are described as follows:

Diagnosis, symptoms and signs

If a diagnosis has been made, the diagnosis should be recorded in the eCRF rather

than the individual signs and symptoms (e.g., record liver failure other than jaundice,

elevated transaminases, and asterixis). If symptoms and signs cannot be determined to

be a result of the diagnosis at the time of reporting, they should be recorded as a

separate AE/SAE. If the symptoms and signs are determined to be a result of the

diagnosis, only the diagnosis is reported separately, with the symptoms and signs

included in the diagnosis. For an AE, the records of signs and symptoms need to be

deleted; for an SAE, the updated follow-up report needs to be sent.

AEs secondary to other events

For adverse events secondary to other events (e.g. caused by other events or

clinical sequelae), their primary events should be documented in general, unless such a

secondary event is of high severity or an SAE. However, a secondary event of great

clinical significance should be recorded as a separate AE in the eCRF provided it

occurred at different time from the primary event. If the correlation between the events

is unclear, the events should be recorded separately in the eCRF.

Persistent or recurred AE

A persistent AE refers to an AE that is not resolved between two evaluations for

the subject and persists. Such AEs should be recorded only once on the eCRF. The

initial severity of the event should be recorded, and should be updated to the greatest

severity when there is a worsening of the event.

A recurred AE refers to an AE that was already resolved between two evaluations

but occurs later again. The occurrence of such events should be recorded separately on

the eCRF.


Study drug: IBI308

Abnormal laboratory findings

Clinically significant abnormal laboratory findings should be reported as AEs. It is

the responsibility of the investigator to review all abnormal laboratory findings and

make medical judgment on each abnormal laboratory finding as to whether they should

be reported as an AE.

Death

All deaths that occurred throughout the trial, including the 90-day follow-up

period that begins following the last dose, should be recorded on the death report form

on the eCRF and reported to the sponsor in a timely manner, irrespective of

relationship with the study drug.

When recording a death event, if the cause of death is identified, the cause of death

should be recorded as an AE, with its outcome recorded as death, and the event should

be reported as SAE (it should not be recorded and reported as an AE/SAE if death is

due to tumor progression, but the investigator should record the death on the death

report form on eCRF and inform the sponsor in a timely fashion); if the cause of death

is unknown at the time of reporting, it should be recorded as "Unexplained death" on

the adverse event form on the eCRF, and then reported as SAE, followed by further

investigation into the exact cause(s) of death.

If the death is clearly due to tumor progression, it will not be recorded and

reported as AE/SAE, but the investigator should keep a record of the death on the death

report form on the eCRF and inform the sponsor timely.

Preexisting medical conditions

The preexisting symptoms/signs a subject has already presented in the screening

period of the trial should be recorded and reported as AE only when there is worsening

in severity, frequency and nature (excluding worsening of the medical condition

studied) after entry into the trial. Changes from the previous state should be reflected in

the record, e.g., “increased frequency of headache”.

Progressive disease


Study drug: IBI308

Progressive disease (PD) is defined as worsening of a subject’s condition due to

the primary tumor the investigational drug is targeted on. Appearance of new lesions

relative to the primary tumor or progression of the original lesions is considered as PD.

PD is not reported as an AE. Death due to signs and symptoms of disease progression,

events that were life-threatening, required inpatient hospitalization or prolongation of

existing hospitalization, resulted in persistent or significant disability/incapacity, or

were a congenital anomaly/birth defect, and other important medical events warrant

expedited reporting as SAE.

Overdosage

Overdose is defined as use beyond the protocol-specified dose. Overdose with AE

should be recorded as AE. Expedited reporting per SAE procedures is required when

overdose is accompanied by an SAE.

6.6　Expedited reporting of SAEs and pregnancies

Reporting of SAEs:

The time limit of SAE reporting is from signing of the ICF to 90 days (including

90 days) after the last dose. In case of an SAE during this period of time, the

investigator must immediately fill out, sign and date "CFDA Serious Adverse Event

Report Form", and submit the completed form to China Food and Drug Administration

(CFDA), Cancer Hospital CAMS and Innovent no later than 24 hours after awareness,

whether it is an initial report or a follow-up report. Detailed contact information on

SAE reporting is provided in the Table below.

If an SAE occurring during the above time limit is considered related to the study

drug, it should also be reported to the Cancer Hospital CAMS and Innovent.

The investigator must submit the completed SAE report form to Cancer Hospital

CAMS and Innovent as soon as possible within 24 hours after awareness of the SAE.

For deaths and life-threatening SAEs, the investigator should conduct an emergency

follow-up to obtain the missing information and provide a complete SAE report.

When reporting SAEs by email, the investigator is advised to encrypt the report

file and send the report file and its cryptogram via different emails.


Study drug: IBI308

Meanwhile, the investigator should report to the drug regulatory authority, the

health administration, Cancer Hospital CAMS and Innovent in accordance with the

regulatory requirements of the country

Table 6 Contact information for SAE reporting

Organizations Contact persons Fax/Phone/Address

Cancer Hospital Chinese

Academy of Medical

Sciences

Ethics Committee Fax/Phone

Division of Drug Research

Supervision, Department of

Drug and Cosmetics

Registration, CFDA

Address: Building 2, No.26

Xuanwumen West Street, Xicheng

District, Beijing. P.R. China

Postcode: 100053

Tel.: 010-88330732

Fax: 010-88363228

The Bureau of Health

Administration, the

National Health

Commission

Address: No. A38 Lishi Road,

Xicheng District, Beijing, P.R.

China

Tel.: 010-68792001

Fax: 010-68792734

Innovent Biologics

(Suzhou) Co., LtdFax number: 021-31652800

Email: [email protected]

Pregnancy

Considering embryotoxicity risks are reported for similar drugs, all clinical trial

participants of childbearing potential must take effective contraceptive measures.

If a female subject becomes pregnant during the clinical trial, the subject should be

removed from the study, and the investigator should report to Cancer Hospital CAMS

and Innovent within 24 hours after awareness of the pregnancy, and fill out Innovent

Clinical Trial Pregnancy Report/Follow-up Form.


Study drug: IBI308

If the partner of a male subject becomes pregnant during the clinical trial, the

subject can continue participating in the clinical trial, and the investigator should report

to Cancer Hospital CAMS and Innovent within 24 hours after being informed of the

pregnancy, and complete Innovent Clinical Trial Pregnancy Report/Follow-up Form.

The investigator should follow up the pregnancy outcome until 8 weeks after

delivery of baby by the mother, and report the outcome to Cancer Hospital CAMS and

Innovent.

If the outcome of pregnancy is still birth, spontaneous abortion, fetal malformation

(any congenital anomaly/birth defect), or induced abortion for medical reasons, it

should be considered as SAE and reported according to the procedures and time limit

for SAE reporting.

If a subject experienced a concurrent SAE during pregnancy, CFDA Serious

Adverse Event Report Form should also be completed for reporting according to the

SAE reporting procedures.

6.6.1　Immune-related adverse event

Given that IBI308 pharmacologically acts to cause activation and proliferation of

T cells, immune-related adverse events (irAEs) may be observed during this study. The

definition of irAE is provided in Section 4.4 of the protocol. Subjects should be

monitored for signs and symptoms of irAEs.

The principles for IBI308 dose modifications and AE handling are detailed in

Sections 4.3 and 6 of the protocol. Guidelines for the handling of irAEs are provided in

Appendix 4 (Tables 1 - 2).

6.6.2　Adverse events of special interest

An adverse event of special interest (AESI) refers to an AE that needs to be closely

monitored to better understand the safety profile of the investigational drug, and

therefore AESI can be non-serious events.

AESI includes:

≥ grade 3 infusion reactionsAugust 12, 2017 Version 1.0 Confidential 57 / 116

Study drug: IBI308

≥ grade 2 diarrhea, colitis, uveitis, interstitial pneumonia

≥ grade 3 other irAEs

7　STATISTICAL CONSIDERATIONS

7.1　Statistical analysis plan

A detailed statistical analysis plan (SAP) will be written after enrollment of the

first subject and finalized before database lock. The SAP will provide a full

presentation of all statistical analyses and their results.

7.2　 Hypothesis Test

As this study is a single-arm, exploratory study, rigorous hypothesis testing will

not be performed.

7.3　Statistical Analysis Population

The analysis population includes safety analysis set (SS), full analysis set (FAS),

and per-protocol set (PPS):

1） SS: the population of subjects who received at least one dose of the study

drug.

2） FAS: the population of subjects who received at least one dose of the study

drug and completed the radical surgery.

3） PPS: a subset of the FAS, defined as the population of subjects with good

compliance who constituted no gross protocol violations, without major protocol

violations and used no concomitant medications prohibited by the protocol.

7.4　Methods of Statistical Analysis

7.4.1　General methods forstatistical analysis

Measurement data will be presented by mean, standard deviation (SD), median,

maximum and minimum, and count data will be described by frequency and

percentage.

All statistical analyses will be completed using SAS 9.2 (or a higher version).


Study drug: IBI308

7.4.2　Analysis of primary endpoint

Safety analysis is performed on the SS, and the primary safety outcome measures

include:

Study-related adverse events (90 days after the first dose of IBI308 or 30 days

after surgery, whichever occurs later): ≥ grade 3 adverse events related to the

study drug

Incidence of surgical complications: defined as ≥ grade 3 or severe intraoperative

and perioperative complications

Rate of no-delayed surgery (surgical delay is defined as no performance of

surgery for more than 43 days from the day of the first dosing).

Other safety analysis include adverse event, laboratory examination, vital signs,

electrocardiogram, etc..

7.4.3　Analysis of efficacy outcome measures

Efficacy analysis is mainly based on FAS and PPS, and the primary efficacy

endpoint is Overall response rate (ORR)

ORR=Number of subjects achieving CR+PRTotal number of subjects

∗100%, with its 95% CI calculated

using binomial distribution.

Major pathologic response (MPR), which is defined as < 10% visible tumor cells

under a microscope.

MPR=Number of subjectsachieving MRPTotalnumber of subjects

∗100 %, with its 95% CI calculated

using binomial distribution.

Disease-free survival (DFS): the time from the first dose of study drug to the

occurrence of death or recurrence.

The 1-year and 2-year DFS will be calculated using Kaplan-Meier estimator.

1-year and 2-year recurrence rate (RR): the 1-year and 2-year RR in the patients

will be calculated.

Overall survival (OS): The time from the first dose of study drug to the date of the

subject's death.


Study drug: IBI308

The 2-year survival rate will be calculated using Kaplan-Meier estimator.

7.4.4　Biomarker Analysis

Tumor tissue specimens will be collected to analyze the relationship between

biomarkers and efficacy, including but not limited to the expression of PD-L1,

tumor infiltrating lymphocytes (TIL), tumor mutational burden (TMB)

Peripheral blood samples will be collected to analyze the relationship between

biomarkers and efficacy, including but not limited to the relationship between

efficacy and dynamic changes in overall mutational burden of ctDNA

7.4.5　Drug exposure

The exposure and use duration (cycles) of the study drug in the subjects during the

study period will be summarized.

7.4.6　Analysis of safety outcome measures

Safety analysis is performed on the SS, and the primary safety outcome measures

include:

Study-related adverse events (90 days after the first dose of IBI308 or 30 days

after surgery, whichever occurs later): ≥ grade 3 adverse events related to the

study drug

Incidence of surgical complications: defined as ≥ grade 3 or severe intraoperative

and perioperative complications

Rate of no-delayed surgery (surgical delay is defined as no performance of

surgery for more than 43 days from the day of the first dosing).

7.4.6.1　Adverse events

All AEs will be coded using MedDRA.

The incidence rates (frequency of occurrence) of AEs, TEAEs, ADRs,Immune-

related adverse events (irAEs), adverse events of special interest (AESI), SAE, and

AEs that resulted in study terminationwill be summarized, respectively; the distribution


Study drug: IBI308

of severity will be summarized for TEAEs, ADRs, irAEs and AESI by SOC and PT in

MedDRA coding, respectively.

Subjects who discontinued treatment due to AE, subjects who experienced SAEs

and subjects who died will be tabulated (at least including the start date, end date and

severity of AE, relationship with drug, actions taken, and outcome).

7.4.6.2　Laboratory tests

For hematology and blood biochemistry, the measured values and values of change

before and after treatment will be described using mean ± SD, maximum, minimum

and median, and cross classification table will be employed for describing normal and

abnormal changes before and after treatment.

Urinalysis: cross classification table will be used to describe the normal and

abnormal changes before and after treatment.

The percentage of subjects with abnormal changes evaluated as “abnormal and

clinically significant” will be described. The investigator judges whether the

abnormality is clinically significant or not.

A list of subjects with abnormal changes (clinically significant or not clinically

significant) after treatment will be provided.

7.4.6.3　ECG examination

The changes of ECG indicators from baseline will be descriptively described.

Cross-classification table will be used to describe the normal and abnormal changes

before and after treatment, and a data list will be provided.

7.4.6.4　Vital signs, physical examination and other safety-related examinations

The results of vital signs examination and changes from baseline will be summarized

descriptively.

Subjects with abnormal changes from baseline in physical examination will be

summarized by tabulation.


Study drug: IBI308

7.4.7　Compliance analysis

The following will be summarized: the percentage and number of subjects with a

violation of the intended dosing regimen;

Percentage of subjects who used the study drug at 80% - 120% of the dose specified in

the protocol;

Percentage of subjects having completed the study, and percentage of subjects having

completed different treatment cycles.

7.4.8　Baseline characteristics of subjects

The following baseline characteristics of the subjects will be descriptively

summarized: demographic characteristics (gender, age); tumor diagnosis and treatment

information (pathological diagnosis, clinical stage, previous treatment); baseline tumor

detection (number of target lesions and non-target lesions, their location and total long

diameter, etc.); other baseline information: height and weight (body mass index, body

surface area), vital signs, laboratory findings, previous/concomitant/new combination

medications, etc.

7.4.9　Interim analysis

No interim analysis is planned for this study.

7.4.10　Subgroup analysis

Subgroup analyses are based on the baseline characteristics of the subjects and

other potential clinically significant factors.

Subgroup analyses will be defined in detail in the SAP.

7.5　Sample size determination

As this study is a single-arm study, no rigorous statistical assumptions were made.

Six patients will be enrolled first for safety run-in of this study, and then up to 30

subjects can be enrolled after comprehensive risk assessment by the study team.


Study drug: IBI308

8　QUALITY ASSURANCE AND QUALITY CONTROL

Pursuant to GCP guidelines, the sponsor has the responsibility to implement and

maintain the quality and quality control systems for this study according to

corresponding standard operating procedures (SOPs) to ensure proper conduct of the

clinical trial and the authenticity of data generated, and that the data are collected,

documented and reported in compliance with the requirements of the protocol, GCP

and corresponding regulations.

8.1　Clinical Monitoring

The sponsor or the sponsor-authorized CRO conducts clinical monitoring of the

study. The clinical research associate (CRA) should conduct monitoring according to

the standard operating procedures of the sponsor or CRO, and have the same rights and

responsibilities as the sponsor's monitor. The monitor (CRA) should hold regular

communications with the investigator, the authorized study personnel and the sponsor.

Prior to the initiation of the study, the monitor will assess the competence of each

study site and report problems regarding facilities, technical equipment, and/or medical

personnel to the sponsor. During the study, the monitor will be responsible for

monitoring whether the investigator has obtained the signed written ICFs from all

subjects and whether the data records are correct and complete. Meanwhile, the

monitor will also check the data entries in the eCRF against the original data and

inform the investigator of any errors or omissions. The monitor will also control the

site compliance with the protocol and trial procedures, arrange for supplies of the

investigational drug and the clinical trial supplies, and ensure that the drugs are stored

under the specified conditions.

Monitoring visits will be conducted in accordance with applicable laws and

regulations. Each site will receive regular monitoring visits from the start of subject

enrollment. After each site visit, the monitor will submit a written report to the sponsor.

8.2　Data Management/Coding

An electronic data capture (EDC) system will be used for this study and study data

will be entered into the eCRF by the investigator or the authorized study personnel.


Study drug: IBI308

Prior to site initiation or data entry, appropriate training will be provided to the

investigators and the authorized study personnel, and appropriate security measures

will be taken for equipment used in the study, e.g., computers.

Data entry into the eCRF should be completed during or as soon as possible after a

visit and updated promptly to ensure that it reflects the latest status of the subjects

participating in the study. To avoid differences in the assessment of the results by

different evaluators, it is recommended that the baseline and all subsequent efficacy

and safety evaluations be completed by the same evaluator. The investigator must

review the data to ensure the accuracy and correctness of all data entered into the

eCRF. In the event some evaluations were not performed or some information is

unavailable, not applicable, or unknown on study, the investigator should record it in

the eCRF. The investigator should electronically sign the verified data.

The monitor (CRA) will review the eCRFs and assess their completeness and

consistency. In addition, the CRA will check the eCRFs against the source documents

to ensure consistency of key data. The entry, correction and modification of all data

will be completed by the investigator or the designee. The data in the eCRF are

submitted to the data server, and any changes to the data will be recorded in the audit

trail, i.e. the reason for the change, the name of the operator, the time and date of the

change will all be recorded. The roles and authorities of the site staff responsible for

data entry will be determined in advance. If any data query, the CRA or the data

manager will send a query in the EDC system and the site staff is responsible for

answering the query. The EDC system will document the audit trails of the queries,

including investigator’s name, time and date.

Unless otherwise specified, the eCRF will be used only as a form for collecting

data rather than as source data. Source documents, which are used by the investigators

and related to the subjects, refer to all records that can prove the subjects’ existence and

their eligibility per the inclusion and exclusion criteria as well as participation in this

study, including laboratory records, ECG results, pharmacy dispensing records, subject

folder, etc.


Study drug: IBI308

The investigator is responsible for maintaining all source documents and providing

them to the CRA for monitoring at each visit. In addition, the investigator must submit

a complete eCRF for each enrolled subject, regardless of the duration of study

participation. The protocol number and subject number on all supporting documents

(e.g., laboratory records or hospital records) submitted together with the eCRF should

be carefully verified, and all personal privacy information (including the subject's

name) in these documents should be removed or made illegible to protect the subject's

privacy. The investigator uses electronic signature to testify that he or she has reviewed

the record, and assures the accuracy of the data recorded. The electronic signature will

be completed through the investigator’s user ID and password, with the data and time

of signature generated by the system automatically. The Investigator shall not share the

user ID and password with other personnel. Any changes to the data in the eCRF, if

necessarily required, should be made according to the work procedures as defined in

the EDC system. All changes and the reasons for change will be documented on the

audit trails.

AEs and concomitant diseases/medical history will be coded. The dictionary used

for coding will be described in the final Clinical Study Report (CSR).

8.3　Quality Assurance Audit

During the process of the study, the sponsor or its authorized representative may

perform quality assurance audits of the study site, the study database and related study

documents. Moreover, the appropriate regulatory authorities may conduct inspections

of the study site, the study database and related study documents at their discretion.

The investigator should notify the sponsor immediately upon receipt of an inspection

notification from the regulatory authority.

9　ETHICS

9.1　Ethics Committee

The sponsor or its authorized representative will prepare the relevant documents

that need to be submitted to the corresponding site Ethics Committee (EC) for review,

including the trial protocol, ICF, Investigator's Brochure (IB), subject recruitment


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materials or advertisements and other documents required by laws and regulations.

Written approval of the site EC must be obtained and provided to the sponsor prior to

initiation of the study. The EC approval letter must specify the name, number and

version number of the study protocol, as well as the version number and approval date

of other documents (e.g., ICF). The investigator should inform the sponsor of the EC’s

written comments of delay, suspension and re-approval.

The site must observe the requirements of the site EC. Such documents may

include possible protocol amendments, ICF amendments and amendments to subject

recruitment materials, all of which should be submitted to the EC for review and

approval. Safety reports should be submitted and updated periodically per local

requirements and the provisions of the EC, and the final report should be submitted. All

of the above documents and EC approval letters must be provided to the sponsor or its

designee.

9.2　Ethics in the Study

The conduct of this study and the process of obtaining informed consent should be

in compliance with Declaration of Helsinki, relevant GCP requirements and applicable

laws and regulations of China on drug and data protection.

GCP provides scientifically and ethically sound global quality standards for the

design, conduct, recording and reporting of clinical research involving human subjects.

This study will be conducted according to GCP and relevant national regulations and in

compliance with the relevant ethical principles that have their origins in the

Declaration of Helsinki to protect the rights, safety and health of the subjects.

The investigator should follow the procedures specified in this trial protocol and

should not change the procedures without permission of the sponsor. Any protocol

violations will be reported to the EC, the sponsor, and/or the regulatory authorities.

9.3　Subject Information and Informed Consent

Prior to initiation of any study procedures, the possible risks and benefits of this

study will be explained to potential study participants using the informed consent form

(ICF), which should be written in plain language. The ICF statement should clarify that


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signing the ICF is voluntary, the possible risks and benefits associated with

participation in this study, and that the subjects are free to withdraw from the study at

any time. The investigator should not enroll a subject until written consent has been

obtained from the subject or their legal representative, who should be provided with

adequate explanations about details of this study and with adequate time to think over,

and have their questions answered satisfactorily. All signed ICFs must be kept in the

investigator study file or subject folder.

The investigator is responsible for explaining the contents of the ICF to the

subjects and obtaining the signed and dated ICFs from the subjects or their legal

representatives prior to the initiation of the study. After signing the ICF, the

investigator should provide each subject with a copy of the signed ICF. The

investigator should record the informed consent process in the study source documents.

9.4　Protection of Subject Data

The ICF will contain (or in some cases, together with the use of separate files)

information on data protection and privacy protection.

Precautions are taken to ensure the confidentiality of the documents and prevent

the identification of the subjects. However, under special circumstances, the genetic

data and personal identification code of a certain subject may be accessed by some

persons. For example, in the event of a medical emergency, the sponsor, its

representative physician or the investigator will be aware of a subject’s identification

code and have access to the genetic data of this subject. In addition, relevant regulatory

authorities require access to relevant documents.

10　STUDY MANAGEMENT

10.1　Data Processing and Record Retention

Documents (protocol and protocol amendments, completed eCRF, signed ICF,

etc.) in the clinical trial should be retained and managed according to the GCP

requirements. These documents should be retained at the study site until 5 years after

the end of study.


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Study files should be properly kept for access or data traceability in the future. File

retention should security and environmental risk issues into account.

No study files may be destroyed without the written permission of the sponsor and

the investigator. The investigator/study site may transfer the study files to another party

that observes the file retention requirements or to another location that meets the

specified requirements for storage only after having notified the sponsor and obtained

its written permission.

10.2　Source Data/Document Access

The investigator agrees that the sponsor, the CRO and relevant authorized

regulatory authorities will have direct access to all study-related documents, including

the medical records of the subjects.

10.3　Protocol Amendments

Any possible appropriate amendments to the protocol during the conduct of the

study will be communicated and agreed by the sponsor to the investigator. The sponsor

should ensure that protocol amendments are submitted to regulatory authorities in a

timely manner.

All amendments to the protocol should be maintained as addenda to the protocol.

Any amendments to the protocol should be submitted to the Ethics Committee for

approval or filing according to the provisions of the EC. If necessary, they should also

be submitted to the regulatory authority for review and approval, and can be

implemented only after approval by EC and the regulatory authority (if necessary)

(except for changes that were made to protocol to eliminate immediate hazards to trial

subjects).

10.4　Responsibilities of Investigator

The investigator should conduct this study in accordance with the protocol, ethical

principles that have their origins in Declaration of Helsinki, and GCP and

corresponding regulatory requirements of Chia.

The detailed responsibilities of relevant investigators are listed in Chapter 5

(Responsibilities of Investigators) of Chinese GCP (CFDA Order No. 3).August 12, 2017 Version 1.0 Confidential 68 / 116

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10.5　Publication Policy

All data generated from this study are confidential information of the sponsor. The

sponsor has the right to publish the study results. Information regarding the publication

policies between the sponsor and the investigator will be described in the clinical trial

agreement.

All information about this trial (not limited to the following documents: protocol,

IB) must be kept strictly confidential. The investigator must recognize that the

scientific or medical information derived from this trial may be of commercial value to

the sponsor. The investigator shall keep confidential the information and data related to

this trial. In order to publish the information related to this trial or the conclusions

drawn from this trial, the investigator should negotiate with the sponsor in advance and

obtain the written consent of the sponsor. In order to protect its own rights and

interests, the sponsor may require the investigator not to publish any information about

the trial until the investigational product is approved for marketing.

The sponsor has the right to reveal or publish the information or data related to this

trial or submit it to the drug regulatory authority. If the sponsor needs to include the

investigator's name in a published paper, publication or advertisement, the consent of

the investigator should be obtained.

10.6　Finance and Insurance

The sponsor will buy insurance for subjects participating in this study in

accordance with local regulations and minimum requirements. Relevant insurance

clauses will be kept in the study folder.


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11　References

1. Park S, Ko YH. Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders. J Dermatol 2014,41:29-39.2. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015,373:123-135.3. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016,387:1540-1550.4. Langer CJ1, Gadgeel SM2, Borghaei H3, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. 5. Carbone DP, Reck M, Paz-Ares L, Creelan B, et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Jun 22;376(25):2415-2426.6. Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000,18:2095-2103.7. Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000,18:2354-2362.8. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004,22:1589-1597.


Study drug: IBI308

12　Appendixes


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Appendix 1: ECOG PS scoring system

Score Activity level

0 Fully active, able to perform all normal activity without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours

3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair

5 Death

References

Oken MM，Creech RH，Tormey DC，Horton J，Davis TE，McFadden ET，and Carbone PP. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982；5：649-655.


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Appendix 2: Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)

The following is an excerpt from the RECIST v1.1.

1. Measurability of tumor at baseline

1.1 Definitions

At baseline, tumor lesions/lymph nodes will be categorized measurable or non-

measurable as follows

1.1.1 Measurable lesions

Tumor lesions: must be accurately measured in at least one dimension (longest

diameter in the plane of measurement is to be recorded), with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately

measured with calipers should be recorded as non-measurable)

20 mm by Chest X-ray

Malignant lymph nodes: To be considered pathologically enlarged and measurable, a

lymph node must be ≥ 15 mm in short axis when measured by CT scan (CT scan slice

thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the

short axis will be measured and followed.

1.1.2 Non-measurable lesions

All other lesions, including small lesions (longest diameter < 10 mm or pathological

lymph nodes with ≥ 10 mm to < 15 mm short axis) as well as truly non-measurable lesions.

Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural

or pericardial effusion, inflammatory breast cancer, lymphangitic involvement of skin or

lung, abdominal masses that cannot be diagnosed and followed by imaging techniques, as

well as cystic lesions.

1.1.3 Special considerations regarding lesion measurability

Bone lesions, cystic lesions, and lesions previously treated with local therapy require

particular comment:

Bone lesions:


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Bone scan, PET scan or plain films are not considered adequate imaging techniques to

measure bone lesions; however, these techniques can be used to confirm the presence or

disappearance of bone lesions;

Lytic bone lesions or mixed lytic/osteogenic lesions, with identifiable soft tissue

components, that can be evaluated by cross sectional imaging techniques such as CT or

MRI can be considered as measurable lesions if the soft tissue component meets the

definition of measurability described above.

Blastic bone lesions are non-measurable.

Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be

considered as malignant lesions (neither measurable nor non-measurable) since they are, by

definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered as measurable

lesions, if they meet the definition of measurability described above. However, if noncystic

lesions are present in the same patient, these are preferred for selection as target lesions

Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to other

loco-regional therapy, are usually not considered measurable unless there has been

demonstrated progression in the lesion. Study protocols should detail the conditions under

which such lesions would be considered measurable.

1.2 Specifications by methods of measurements

1.2.1 Measurement of lesions

All measurements should be recorded in metric notation, using calipers if clinically

assessed. All baseline evaluations should be performed as close as possible to the treatment

start and never more than 21 days (3 weeks) before the beginning of the treatment.

1.2.2 Method of assessment

The same method of assessment and the same technique should be used to characterize

each identified and reported lesion at baseline and during follow-up. Imaging-based

evaluation should always be done rather than clinical examination unless the lesion(s) being

followed cannot be imaged but are assessable by clinical exam.


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Clinical lesions: Clinical lesions will only be considered measurable when they are

superficial and ≥ 10mm diameter as assessed using calipers (e.g. skin nodules). For the case

of skin lesions, documentation by colour photography including a ruler to estimate the size

of the lesion is suggested. As noted above, when lesions can be evaluated by both clinical

exam and imaging, imaging evaluation should be undertaken since it is more objective and

may also be reviewed at the end of the study.

Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is

an important endpoint, since CT is more sensitive than X-ray, particularly in identifying

new lesions. However, lesions on chest X-ray may be considered measurable if they are

clearly defined and surrounded by aerated lung.

CT, MRI: CT is the best currently available and reproducible method to measure

lesions selected for response assessment. This guideline has defined measurability of

lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. when

CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion

should be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for

whole body scan).

Ultrasound: Ultrasound should not be used as a method of measurement. Ultrasound

examinations cannot be reproduced in their entirety for independent review at a later date

and, because they are operator dependent, it cannot be guaranteed that the same technique

and measurements will be taken from one assessment to the next. If new lesions are

identified by ultrasound in the course of the study, confirmation by CT or MRI is advised.

If there is concern about radiation exposure at CT, MRI may be used instead of CT in

selected instances.

Endoscopy, laparoscopy: The utilization of these techniques for objective tumor

evaluation is not advised. However, they can be useful to confirm CR when biopsies are

obtained or to determine relapse in trials where recurrence following CR or surgical

resection is an endpoint.

Tumor markers: tumor markers alone cannot be used to assess objective tumor

response. If markers are initially above the upper normal limit, however, they must

normalize for a patient to be considered in complete response. Because tumor markers are

disease specific, instructions for their measurement should be incorporated into protocols


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on a disease specific basis. Specific guidelines for both CA-125 response (in recurrent

ovarian cancer) and PSA response (in recurrent prostate cancer), have been published. In

addition, the Gynecologic Cancer Intergroup has developed CA125 progression criteria

which are to be integrated with objective tumor assessment for use in first-line trials in

ovarian cancer.

Cytology, histology: These techniques can be used to differentiate between PR and CR

in rare cases if required by protocol (for example, residual lesions in tumor types such as

germ cell tumors, where known residual benign tumors can remain). When effusions are

known to be a potential adverse effect of treatment (e.g. with certain taxane compounds or

angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any

effusion that appears or worsens during treatment can be considered if the measurable

tumor has met criteria for response or stable disease (SD) in order to differentiate between

response (or SD) and progressive disease.

2 Tumor Response Evaluation

2.1 Assessment of overall tumor burden and measurable disease

To assess objective response or future progression, it is necessary to estimate the

overall tumor burden at baseline and use this as a comparator for subsequent measurements.

Only patients with measurable disease at baseline should be included in protocols where

objective tumor response is the primary endpoint. Measurable disease is defined by the

presence of at least one measurable lesion. In studies where the primary endpoint is tumor

progression (either time to progression or proportion with progression at a fixed date), the

protocol must specify if entry is restricted to those with measurable disease or whether

patients having non-measurable disease only are also eligible.

2.2 Baseline documentation of target lesions and non-target lesions

When more than one measurable lesion is present at the baseline, all lesions up to a

maximum of 5 lesions total (and a maximum of two lesions per organ) representative all

involved organs should be identified as target lesions (this means in instances where

patients have only one or two organ sites involved a maximum of two and four lesions

respectively will be recorded).

Target lesions must be selected on the basis of their size (lesions with the longest

diameter), be representative of all involved organs, but in addition should be those that lend


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themselves to reproducible repeated measurements. It may be the case that, on occasion, the

largest lesion does not lend itself to reproducible measurement, in which circumstance the

next largest lesion which can be measured reproducibly should be selected.

Lymph nodes merit special mention since they are normal anatomical structures which

may be visible by imaging even if not involved by tumor. Pathological nodes which are

defined as measurable and may be identified as target lesions must meet the criterion of a

short axis of P15 mm by CT scan. Only the short axis of these nodes will contribute to the

baseline sum. The short axis of the node is the diameter normally used by radiologists to

judge if a node is involved by solid tumor. Nodal size is normally reported as two

dimensions in the plane in which the image is obtained (for CT scan this is almost always

the axial plane; for MRI the plane of acquisition may be axial, saggital or coronal). The

smallest of these measures is the short axis. For example, an abdominal node which is

reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant,

measurable node. In this example, 20 mm should be recorded as the node measurement. All

other pathological nodes with short axis ≥ 10 mm but <15 mm should be considered non-

target lesions. Nodes that have a short axis <10 mm are considered non-pathological and

should not be recorded or followed.

A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for

all target lesions will be calculated and reported as the baseline sum diameters. If lymph

nodes are to be included in the sum, then as noted above, only the short axis is added into

the sum. The baseline sum diameters will be used as reference for baseline disease level.

All other lesions including pathological lymph nodes should be identified as non-

target lesions and require no measurements but should also be recorded at baseline. These

lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’

In addition, it is possible to record multiple non-target lesions involving the same organ as a

single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or

‘multiple liver metastases’).

2.3 Response Criteria

2.3.1 Evaluation of target lesions

Complete response (CR): Disappearance of all target lesions, all pathological lymph

nodes (whether target or non-target) must have reduction in short axis to < 10 mm.


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Partial response (PR): At least a 30% decrease in the sum of the diameters of target

lesions compared with baseline.

Progressive disease (PD): At least a 20% increase in the sum of the diameters of target

lesions, taking as reference the smallest sum on study (this includes the baseline sum if that

is the smallest on study); in addition to the relative increase of 20%, the sum must also

demonstrate an absolute increase of at least 5 mm. (the appearance of one or more new

lesions is also considered progression).

Stable disease (SD): Neither sufficient shrinkage of target lesions to qualify for PR,

nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters

while on study.

2.3.2 Special notes on the assessment of target lesions

Lymph nodes: lymph nodes identified as target lesions should always have the actual

short axis measurement recorded (measured in the same anatomical plane as the baseline

examination), even if the nodes regress to below 10 mm on study. This means that when

lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if

complete response criteria are met, since a normal lymph node is defined as having a short

axis of <10 mm. eCRF or other data collection methods may therefore be designed to have

target nodal lesions recorded in a separate section where, in order to qualify for CR, each

node must achieve a short axis <10 mm. For PR, SD and PD, the actual short axis

measurement of the nodes is to be included in the sum of target lesions.

Target lesions that become ‘too small to measure’: while on study, all lesions (nodal

and non-nodal) recorded at baseline should have their actual measurements recorded at

each subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes

lesions or lymph nodes which are recorded as target lesions at baseline become so faint on

CT scan that the radiologist may not feel comfortable assigning an exact measure and may

report them as being ‘too small to measure’. When this occurs it is important that a value be

recorded on the eCRF. If it is the opinion of the radiologist that the lesion has likely

disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be

present and is faintly seen but too small to measure, a default value of 5 mm should be

assigned (Note: It is less likely that this rule will be used for lymph nodes since they

usually have a definable size when normal and are frequently surrounded by fat such as in


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the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen

but too small to measure, a default value of 5 mm should be assigned in this circumstance

as well). This default value is derived from the 5 mm CT slice thickness (but should not be

changed with varying slice thickness on CT scans). The measurement of these lesions is

potentially non-reproducible, and therefore providing this default value will prevent false

responses or progressions based upon measurement error. To reiterate, however, if the

radiologist is able to provide an actual measure, that should be recorded, even if it is below

5 mm.

Lesions that split or coalesce on treatment: when non-nodal lesions ‘fragment’, the

longest diameters of the fragmented portions should be added together to calculate the

target lesion sum. Similarly, as lesions coalesce, a plane between them may be maintained

that would aid in obtaining maximal diameter measurements of each individual lesion. If

the lesions have truly coalesced such that they are no longer separable, the vector of the

longest diameter in this instance should be the maximal longest diameter for the coalesced

lesion.

2.3.3 Evaluation of non-target lesions

This section provides the definitions of the criteria used to determine the tumor

response for the group of non-target lesions. While some non-target lesions may actually be

measurable, they need not be measured and instead should be assessed only qualitatively at

the time points specified in the protocol.

Complete response (CR): disappearance of all non-target lesions and normalization of

tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short

axis).

Non-CR/non-progressive disease: presence of one or more non-target lesions and/or

maintenance of tumor marker level above normal limits.

Progressive disease (PD): unequivocal progression of existing non-target lesions.

(Note: appearance of one or more new lesions is also considered progression).

2.3.4 Special notes on assessment of progression of non-target disease

The concept of progression of non-target disease requires additional explanation as

follows: When the patient also has measurable disease, to achieve ‘unequivocal

progression’ on the basis of the non-target disease, there must be an overall level of


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substantial worsening in non-target disease such that, even in presence of SD or PR in

target disease, the overall tumor burden has increased sufficiently to merit discontinuation

of therapy. A modest increase in the size of one or more non-target lesions is usually not

sufficient to quality for unequivocal progression status. The designation of overall

progression solely on the basis of change in non-target disease in the face of SD or PR of

target disease will therefore be extremely rare.

When the patient has only non-measurable disease: This circumstance arises in some

phase III trials when it is not a criterion of study entry to have measurable disease. The

same general concepts apply here as noted above, however, in this instance there is no

measurable disease assessment. Because worsening in non-target disease cannot be easily

quantified (by definition: if all lesions are truly non-measurable), a useful test that can be

applied when assessing patients for unequivocal progression is to consider if the increase in

overall disease burden based on the change in non-measurable disease is comparable in

magnitude to the increase that would be required to declare PD for measurable disease : i.e.,

an increase in tumor burden representing an additional 73% increase in ‘volume’ (which is

equivalent to a 20% increase diameter in a measurable lesion). Examples include an

increase in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease

from ‘localized’ to ‘widespread’, or may be described in protocols as ‘sufficient to require a

change in therapy’. Some illustrative examples include pleural effusions from trace to large,

lymphatic involvement spreading from the primary site to distant sites, or may be described

in the protocol as "a change necessarily required in terms of treatment". If ‘unequivocal

progression’ is seen, the patient should be considered to have had overall PD at that point.

While it would be ideal to have objective criteria to apply to non-measurable disease, the

very nature of that disease makes it impossible to do so, therefore the increase must be

substantial.

2.3.5 New lesions

The appearance of new malignant lesions denotes disease progression; therefore some

comments on detection of new lesions are important. There are no specific criteria for the

identification of new radiographic lesions; however, the finding of a new lesion should be

unequivocal: i.e. not attributable to differences in scanning technique, change in imaging

modality or findings thought to represent something other than tumor (for example, some


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‘new’ bone lesions may be simply healing or flare of preexisting lesions). This is

particularly important when the patient’s baseline lesions show partial or complete

response. For example, necrosis of a liver lesion may be reported on a CT scan report as a

‘new’ cystic lesion, which it is not.

A lesion identified on a follow-up study in an anatomical location that was not scanned

at baseline is considered a new lesion and will indicate disease progression. An example of

this is the patient who has visceral disease at baseline and while on study has a CT or MRI

brain ordered which reveals metastases. The patient’s brain metastases are considered to be

evidence of PD even if he/she did not have brain imaging at baseline.

If a new lesion is equivocal, for example because of its small size, continued therapy

and follow-up evaluation will clarify if it represents truly new disease. If repeat scans

confirm there is definitely a new lesion, then progression should be declared using the date

of the initial scan.

While FDG-PET response assessments need additional study, it is sometimes

reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in

assessment of progression (particularly possible ‘new’ disease). New lesions on the basis of

FDG-PET imaging can be identified according to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD

based on a new lesion.

No FDG-PET at baseline and a positive FDG-PET at follow-up:

If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed

by CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT,

additional follow-up CT scans are needed to determine if there is truly progression

occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET

scan).

If the positive FDG-PET at follow-up corresponds to a preexisting site of disease on

CT that is not progressing on the basis of the anatomic images, this is not PD.

2.4 Evaluation of Best Overall Response

The best overall response is the best response recorded from the start of the study

treatment until the end of treatment taking into account any requirement for confirmation.


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On occasion a response may not be documented until after the end of therapy so protocols

should be clear if post-treatment assessments are to be considered in determination of best

overall response. Protocols must specify how any new therapy introduced before

progression will affect best response designation. The patient’s best overall response

assignment will depend on the findings of both target and non-target disease and will also

take into consideration the appearance of new lesions. Furthermore, depending on the

nature of the study and the protocol requirements, it may also require confirmatory

measurement. Specifically, in non-randomized trials where response is the primary

endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall

response’.

2.4.1 Time point response

It is assumed that at each protocol-specified time point, a response assessment occurs.

Table 1 provides a summary of the overall response status calculation at each time point for

patients who have measurable disease at baseline.

When patients have non-measurable (therefore non-target) disease only, Table 2 is to

be used.

2.4.2 Missing assessments and unevaluable designation

When no imaging/measurement is done at all at a particular time point, the patient is

not evaluable (NE) at that time point. If only a subset of lesion measurements is made at an

assessment, usually the case is also considered NE at that time point, unless a convincing

argument can be made that the contribution of the individual missing lesion(s) would not

change the assigned time point response. This would be most likely to happen in the case of

PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions and

at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient

will have achieved PD status, regardless of the contribution of the missing lesion.

2.4.3 Best overall response: all time points

The best overall response can be determined once all the data for the subject are

known.

Best response determination in trials where confirmation of complete or partial

response is NOT required: Best response in these trials is defined as the best response

across all time points (for example, a patient who has SD at first assessment, PR at second


Study drug: IBI308

assessment, and PD on last assessment has a best overall response of PR). When SD is

believed to be best response, it must also meet the protocol-specified minimum time from

baseline. If the minimum time is not met when SD is otherwise the best time point

response, the patient’s best response depends on the subsequent assessments. For example,

a patient who has SD at first assessment, PD at second and does not meet minimum

duration for SD, will have a best response of PD. The same patient lost to follow-up after

the first SD assessment would be considered unevaluable.

Best response determination in trials where confirmation of complete or partial

response is required: Complete or partial responses may be claimed only if the criteria for

each are met at a subsequent time point as specified in the protocol (generally 4 weeks

later). In this circumstance, the best overall response can be interpreted as in Table 3.

2.4.4 Special notes on response assessment

When nodal disease is included in the sum of target lesions and the nodes decrease to

‘normal’ size (< 10 mm), they may still have a measurement reported on scans. This

measurement should be recorded even though the nodes are normal in order not to overstate

progression should it be based on increase in size of the nodes. As noted earlier, this means

that patients with CR may not have a total sum of ‘zero’ on the eCRF.

In trials where confirmation of response is required, repeated ‘NE’ time point

assessments may complicate best response determination. The analysis plan for the trial

must address how missing data/assessments will be addressed in determination of response

and progression. For example, in most trials it is reasonable to consider a patient with time

point responses of PR-NE-PR as a confirmed response.

Patients with a global deterioration of health status requiring discontinuation of

treatment without objective evidence of disease progression at that time should be reported

as ‘symptomatic deterioration’. Every effort should be made to assess objective progression

even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an

objective response: it is the reason for stopping study therapy. The objective response status

of such patients is to be determined by evaluation of target and non-target disease as shown

in Tables 1–3.


Study drug: IBI308

Conditions that define early progression, early death and unevaluability are study

specific and should be clearly described in each protocol (depending on treatment duration,

treatment periodicity).

In some circumstances it may be difficult to distinguish local disease from normal

tissue. When the evaluation of complete response depends upon this determination, it is

recommended that biopsy be performed to investigate the local disease before assigning a

status of complete response. FDG-PET may be used to confirm a response to a CR in a

manner similar to a biopsy in cases where a local radiographic abnormality is thought to

represent fibrosis or scarring. The use of FDG-PET in this circumstance should be

prospectively described in the protocol and supported by disease-specific medical literature

for the indication. However, it must be acknowledged that both approaches may lead to

false positive CR due to limitations of FDG-PET and biopsy (resolution/sensitivity).

Table 1 Time point response: patients with target (+/- non-target) disease

Target lesionsNon-target

lesionsNew lesions Overall response

CR CR No CR

CRNon-CR/non-

PDNo PR

CR Not evaluated No PR

PRNon-PD or not

all evaluatedNo PR

SDNon-PD or not

all evaluatedNo SD

Not all

evaluatedNon-PD No NE

PD Any Yes or No PD

Any PD Yes or No PD

Any Any Yes PD

CR = complete

response

PR = partial

response

SD = stable

disease

PD = progressive disease

NE = in evaluable


Study drug: IBI308

Table 2 Time point response: patients with non-target lesions only

Non-target lesions New lesions Overall response

CR No CR

Non-CR/non-PD No Non-CR/non-PD

Not all evaluated No NE

Unequivocal PD Yes or No PD

Any Yes PD

Note: ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since

SD is increasingly used as endpoint for assessment of efficacy in some trials so to assign

this category when no lesions can be measured.

For equivocal findings of progression (e.g. very small and uncertain new lesions;

cystic changes or necrosis in existing lesions), treatment may continue until the next

scheduled assessment. If progression is confirmed at the next scheduled assessment, the

date of progression should be the earlier date when progression was suspected.

Table 3 Best overall response when confirmation of CR and PR required

Overall

response -

First time

point

Overall response -

Subsequent time

pointBest overall response

CR CR CR

CR PR SD, PD or PRa

CR SD SD provided minimum criteria for SD

duration met, otherwise, PD

CR PD SD provided minimum criteria for SD


CR NE SD provided minimum criteria for SD

duration met, otherwise NE

PR CR PR

PR PR PR

PR SD SD

PR PD SD provided minimum criteria for SD


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PR NE SD provided minimum criteria for SD

duration met, otherwise NE

NE NE NE

Notes: CR = complete response; PR = partial response; SD = stable disease; PD =

progressive disease; and NE = unevaluable. Superscript "a": If a CR is truly met at first

time point, then any disease seen at a subsequent time point, even disease meeting PR

criteria relative to baseline, makes the disease PD at that point (since disease must have

reappeared after CR). Best response would depend on whether minimum duration for SD

was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small

lesions were likely still present and in fact the patient had PR, not CR at the first time point.

Under these circumstances, the original CR should be changed to PR and the best response

is PR.

2.5. Frequency of tumor re-evaluation

Frequency of tumor re-evaluation while on treatment should be protocol-specific and

adapted to the type and schedule of treatment. However, in the context of phase II studies,

follow-up every 6 - 9 weeks (timed to coincide with the end of a cycle) is reasonable, and

smaller or greater time intervals than these could be justified in specific regimens or

circumstances. The protocol should specify which organ sites are to be evaluated at

baseline (usually those most likely to be involved with metastatic disease for the tumor type

under study) and how often evaluations are repeated. Normally, target and non-target

lesions are evaluated at each assessment. In selected circumstances, certain non-target

organs may be evaluated less frequently. For example, bone scans may need to repeated

only when CR is identified in target disease is or when progression in bone is suspected.

After the end of the treatment, the need for repetitive tumor evaluations depends on

whether the trial has as a goal the response rate or the time to an event (progression/death).

If ‘time to an event’ (e.g. TTP/DFS1/PFS) is the main endpoint of the study, then routine

scheduled re-evaluation of protocol specified sites of disease is warranted. In randomized

comparative trials in particular, the scheduled assessments should be performed as

identified on a calendar schedule (for example: every 6 - 8 weeks on treatment or every 3 -

4 months after treatment) and should not be affected by delays in therapy, drug holidays or


Study drug: IBI308

any other events that might lead to imbalance in a treatment arm in the timing of disease

assessment.

2.6. Confirmatory measurement/duration of response

2.6.1. Confirmation

In non-randomized clinical studies where response is the primary endpoint,

confirmation of PR and CR is required to ensure responses identified are not the result of

measurement error. This will also permit appropriate interpretation of results in the context

of historical data where response has traditionally required confirmation in such trials.

However, in all other circumstances, i.e. in randomized trials (phase II or III) or studies

where stable disease or progression is the primary endpoint, confirmation of response is not

required since it will not add value to the interpretation of trial results. However,

elimination of the requirement for response confirmation may increase the importance of

central review to protect against bias, in particular in studies which are not blinded.

In the case of SD, measurements must have met the SD criteria at least once after

study entry at a minimum interval (in general not less than 6 - 8 weeks) that is defined in

the study protocol.

2.6.2 Duration of overall response

The duration of overall response is measured from the time measurement criteria are

first met for CR/PR (whichever is first recorded) until the first date that recurrent or

progressive disease is objectively documented (taking as reference for progressive disease

the smallest measurements recorded on study). The duration of overall complete response is

measured from the time measurement criteria are first met for CR until the first date that

recurrent disease is objectively documented.

2.6.3. Duration of stable disease

Stable disease is measured from the start of the treatment (in randomized trials, from

date of randomization) until the criteria for progression are met, taking as reference the

smallest sum on study (if the baseline sum is the smallest, this is the reference for

calculation of PD). The clinical relevance of the duration of stable disease varies in

different studies and diseases. If the proportion of patients achieving stable disease for a

minimum period of time is an endpoint of importance in a particular trial, the protocol


Study drug: IBI308

should specify the minimal time interval required between two measurements for

determination of stable disease.

Note: The duration of response and stable disease as well as PFS are influenced by the

frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to

define a standard follow-up frequency. The frequency should take into account many

parameters including disease types and stages, treatment periodicity and standard practice.

However, these limitations of the precision of the measured endpoint should be taken into

account if comparisons between trials are to be made.

2.7. PFS/TTP

2.7.1. Phase II clinical trials

This guideline is focused primarily on the use of objective response endpoints for

phase II trials. In some circumstances, ‘response rate’ may not be the optimal method to

assess the potential anticancer activity of new agents/regimens. In such cases, PFS or the

proportion progression-free (PPF) at landmark time points, might be considered appropriate

alternatives to provide an initial signal of biologic effect of new agents. It is clear, however,

that in an uncontrolled trial, these measures are subject to criticism since an apparently

promising observation may be related to biological factors such as patient selection and not

the impact of the intervention. Thus, phase II screening trials utilizing these endpoints are

best designed with a randomized control. Exceptions may exist where the behavior patterns

of certain cancers are so consistent (and usually consistently poor), that non-randomized

trial is justifiable. However, in these cases it will be essential to document with care the

basis for estimating the expected PFS or PPF in the absence of an active control.


Study drug: IBI308

Appendix 3: Guidance for IBI308 dose modification and toxicity management

Table 1. Guidelines on dose modification and toxicity management for potentially major irAEs

AE grading/dose adjustment Toxicity management

General AEs are graded according to NCI CTCAE v4.03, and should be handled in reference to the guidelines if identified as irAE

It is recommended that irAEs be handled according to the guidelines presented in this table

- Thorough assessment should be performed for the subject to rule out any alternative causes (e.g., progression, concomitant medications and infection)

- In the absence of a clear alternative cause and if treatment with corticosteroids is required, it should be considered an irAE

- For low-grade events (Grade 1 or 2, unless otherwise specified), symptomatic and local treatments should be considered

- For persisting low-grade events (Grade 1 - 2) or severe (≥ grade 3) events, systemic corticosteroid therapy should be considered

- If relapse or worsening occurs during corticosteroid tapering, dose increase should be performed for the corticosteroid until stabilization or improvement of symptoms, followed with corticosteroid dose reduction at a low rate

Grade 1

Dose modification not indicated

Grade 2

Interruption

• Handle according to grade 3 or 4 if worsening

• If improvement to grade 0 - 1 or baseline, continue on the next scheduled treatment day

Grade 3

Interruption or permanent discontinuation

Grade 4



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- Once sustained clinical improvement is observed, subjects receiving intravenous corticosteroids may be switched to equivalent of oral corticosteroids at the start of dose tapering or sooner (the issue of lower oral corticosteroid bioavailability should be taken into account)

- For events that did not respond to systemic corticosteroids, more potent immunosuppressive

Pneumonitis Any grade

- Perform monitoring on the patient for signs and symptoms of pneumonia or interstitial lung disease (e.g., new shortness of breath, cough, chest pain, or worsening of existing symptoms and signs), and perform assessment on the patient using imaging, lung function test and other tests

- Initial examination may include clinical assessment, arterial oxygen saturation, laboratory tests, and high-resolution CT scan


Study drug: IBI308


Grade 1

Dose modification not indicated However, interruption of treatment should be considered based on clinical need and during diagnostic workup for other etiologies

For grade 1:

- Perform monitoring of symptoms & signs and arterial oxygen saturation for 2-4 days

- Perform other laboratory tests as clinically indicated

- Consider consultation with the pneumology department and the infection department

Grade 2

Interruption



For grade 2

- Perform monitoring of symptoms and signs every day, consider inpatient hospitalization

- Consider systemic corticosteroids

- Repeat a radiologic examination as clinically indicated

- If no improvement is noted within 3 - 5 days, consider additional tests and increase corticosteroid dose

- If no improvement is noted within 3 - 5 days, a more potent immunosuppressive agent (e.g. infliximab) should be considered

- Once improved, have the glucocorticoid dose reduced gradually over ≥ 4 weeks and consider administering prophylactic antibiotics



Study drug: IBI308


Grade 3

or 4


For grade 3 - 4


- Inpatient hospitalization

- Supportive care (oxygen inhalation, etc.)

- Initiate systemic corticosteroids empirically

- If no improvement is noted within 3 - 5 days, consider additional tests and additional immunosuppressants (e.g. infliximab)



Study drug: IBI308


Diarrhea or enterocolitis

Any grade

- Monitor for signs and symptoms that may be associated with diarrhea/enterocolitis, e.g., abdominal pain, cramps, change in bowel habits, melena, mucous stool, bloody stool, and muscle guarding

- Thorough assessment should be performed for the subject to rule out any alternative causes (e.g., progression and infection)

- In the event no alternative cause is identified, corticosteroid therapy should also be considered for low-grade events to prevent progression to a higher grade

- Use painkillers with care (for they may mask the symptoms of perforation and peritonitis)

Grade 1


For grade 1

- Initiate close monitoring on worsening of symptoms

- Consider symptomatic treatment, including hydration, electrolyte replacement, dietary modification, and loperamide


Study drug: IBI308


Grade 2

or 3

Interruption



For grade 2-3

- Consider symptomatic treatment, including hydration, electrolyte replacement, modification of diet, and loperamide and/or budesonide

- Consider systemic corticosteroids if the event is persisting (for > 3 - 5 days) or has worsened

- If not resolved within 3 - 5 days or worsening, consider additional test and increasing the dose of corticosteroids

- If the event is NOT resolved within 3 - 5 days or has worsened, consider additional testing and administration of other immunosuppressive agents (e.g. infliximab)



Study drug: IBI308


Grade 4


For grade 4

- Monitor the frequency and volume of bowel movement and maintain hydration

- If applicable, perform emergency gastrointestinal consultation as well as lower gastrointestinal endoscopy and imaging to confirm whether there is a presence of intestinal perforation


- If improvement is NOT noted within 3 - 5 days, consider increasing the systemic corticosteroid dose

- If improvement is not noted within 3 - 5 days, consider other immunosuppressive agents (such as infliximab, but not in the of perforation or sepsis)



Study drug: IBI308


Hepatitis (ALT, AST, or TBIL elevations)

Any grade

Pay close attention to hepatitis-related symptoms and signs (e.g., jaundice, tea-colored urine, nausea, vomiting, decreased appetite, hepatalgia, bleeding and tendency)

Perform monitoring and assessment of liver function

Perform evaluation for identification of alternative cause(s), e.g., viral hepatitis, disease progression, concomitant medications

The guidelines for dose modification and dose adjustment and toxicity management suggested in this table apply to subjects with normal baseline ALT, AST, and TB; for subjects with baseline ALT, AST, or TB > ULN, dose interruption is required when ALT, AST, or TB elevations ≥ 50% and lasting < 7 days; for subjects with baseline ALT, AST, or TB > ULN, permanent discontinuation is required when ALT, AST, or TB elevations ≥ 50% and lasting ≥ 7 days ; toxicity management is at the discretion of the investigator

Grade 1


For grade 1

- Continue liver function monitoring per protocol


Study drug: IBI308


Grade 2

Interruption



For grade 2

- If ALT, AST, or TBIL is elevated, repeat a liver function test in the next 3 - 4 days and increase the frequency of monitoring

- Consider systemic corticosteroids if the event is persisting (for > 3 - 5 days) or has worsened


- If no improvement is noted within 3 - 5 days, a more potent immunosuppressant (e.g., mycophenolate mofetil) should be considered



Study drug: IBI308


Grade 3

or 4


For grade 3 - 4


- If no improvement is noted within 3 - 5 days, a more potent immunosuppressant (e.g., mycophenolate mofetil) should be considered

- If further improvement is Note noted within 3 - 5 days, consider treatment with other immunosuppressive agents according to local guidelines

- Perform gastroenterology consultation, abdominal examination and imaging if appropriate


Dermatitis Any grade

- Perform monitoring on signs and symptoms of dermatitis, such as rash, exudation, hypopigmentation, photosensitivity, and pruritus

- Consider dermatology consultation

- Perform skin biopsy if necessary


Study drug: IBI308


Grade 1

Dose modification note indicated

For grade 1

- Consider symptomatic treatment including oral antipruritics (e.g., diphenhydramine or hydroxyzine) and topical treatment (e.g., urea ointment or topical corticosteroid ointment)

Grade 2


• For refractory grade 2 events (which are persisting for > 1 - 2 weeks), interrupt the treatment until resolution to grade 0-1 or baseline and continue the treatment on next scheduled treatment day

For grade 2:

- Consider symptomatic treatment including oral antipruritics and topical therapy

- Consider moderate-intensity topical corticosteroids

- If the event is not improved within 3 - 5 days or has worsened, consider systemic corticosteroids

- Consider dermatology consultation

- Consider skin biopsy if a duration > 1 - 2 weeks duration or recurrence



Study drug: IBI308


Grade 3

Interruption

• Handle according to grade 4 if worsening

• Discontinue the treatment permanently if grade 3 rash has not resolved to grade 0-1 or baseline within 30 days

For grade 3-4:

- Consider inpatient hospitalization

- Monitor the extent of rash (nine-point scale)

- Dermatology consultation

- Consider skin biopsy (preferably more than one) if clinically feasible




Grade 4



Study drug: IBI308


Hypopituitarism All grades

- Performing monitoring on the patient for symptoms and signs of endocrine disorders, including weakness, fatigue, lethargy, nausea, vomiting, cold intolerance, abnormal bowel habits, behavioral changes, altered mental status, hypotension, hypoglycemia, vertigo, headache, visual field impairment, low libido in men, and irregular menstruation in women

- Thorough assessment should be performed for the subject to rule out any alternative causes (e.g., progression, brain metastasis and infection)

- Perform monitoring and evaluation of pituitary function: TSH, FT3, FT4, adrenocorticotropic hormone, cortisol, luteinizing hormone, follicle-stimulating hormone, growth hormone, prolactin, Na+, blood glucose, estradiol, testosterone and other endocrine laboratory parameters suspected to be related to endocrine disorders, and if necessary, perform function tests (including adrenocorticotropic hormone stimulation test and hypoglycemia stimulation test)

- Consider pituitary MRI scan

- Consider endocrinology consultation

- Consider submitting a blood sample for appropriate autoimmune antibody testing


Study drug: IBI308


Grade 1


For grade 1:

- Perform appropriate monitoring on the patient’s pituitary function

- Thorough assessment for the patient to rule out any alternative causes

- Consider endocrinology consultation as clinically indicated

Grade 2

Interruption

• Discontinue permanently if worsening to grade 3-4

• If resolution to grade 0-1 or baseline, continue on next scheduled treatment day

For grade 2-4:

Endocrinology consultation

Hospitalization if necessarily required

Perform endocrine function assessment, and consider a pituitary MRI scan as clinically indicated


Study drug: IBI308


Initiate hormone replacement therapy as needed (replacement therapy with cortisone should begin one week prior to levothyroxine therapy)

Initiate immunosuppression empirically and consider systemic corticosteroids

Once improved, have the dose of glucocorticoids reduced gradually over ≥ 4 weeks (cortisone used for replacement therapy is adjusted on the basis of recovery of endocrine function, and should be maintained chronically in a patient who failed to recover); consider prophylactic antibiotics to prevent opportunistic infections during dose reduction

Grade 3

or 4



Study drug: IBI308


Adrenal insufficiency

Any grade

- Perform monitoring on the patient for signs and symptoms of endocrine disorder, including fatigue, hyperpigmentation, annorexia, hypotension, and weakness

- Thorough assessment should be performed for the subject to rule out any alternative causes

- Perform monitoring and assessment of adrenocortical function: cortisol, adrenocorticotropic hormone, serum sodium, serum potassium, blood glucose, and other endocrine laboratory parameters suspected to be related to adrenocortical function, and if necessary, perform adrenocorticotropic hormone stimulation test

- Immunosuppressive therapy if necessary

- Hormone replacement therapy (cortisone) if necessary


- Consider submitting a blood sample for appropriate autoimmune antibody testing

Grade 1


For grade 1

Perform appropriate monitoring on the patient’s adrenal function

Consider endocrinology consultation as clinically indicated


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Grade 2

Interruption

• Discontinue permanently if worsening to grade 3 or 4

• If resolution to grade 0 - 1 or baseline, continue on next scheduled treatment day

For grade 2

Perform assessment of adrenal cortical function, and initiate hormone replacement therapy as needed

Grade 3


For grade 3 - 4:

Endocrinology consultation

Consider systemic corticosteroids

Intravenous corticosteroids with mineralocorticoid activity should be initiated immediately for adrenal crisis, severe dehydration, hypotension, or shock

Once improved, have the dose of glucocorticoids reduced gradually over ≥ 4 weeks (cortisone used for replacement therapy is adjusted on the basis of recovery of endocrine function, and should be maintained chronically in a patient who failed to recover); consider prophylactic antibiotics to prevent opportunistic infections during dose reduction

Grade 4


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Hyperthyroidism or hypothyroidism

Any grade

- Performing monitoring on the patient for symptoms and signs related to thyroid dysfunction, including hyperthyroidism-related (palpitations, sweating, increased food uptake and bowel movements, and weight loss) and hypothyroidism-related (generalized weakness, fatigue, cold intolerance, memory loss, andconstipation.)


- Monitoring and assessment of thyroid function


- Consider submitting a blood sample for testing of thyroid autoantibodies (anti-thyroglobulin antibody, anti-thyroid peroxidase antibody, thyroid stimulating hormone receptor antibody)

Grade 1

or 2


For grade 1 - 2:

- Perform regular monitoring of thyroid function and thyroid autoantibodies

- Initiate levothyroxine replacement therapy or hyperthyroidism medications if necessarily required


Study drug: IBI308


Grade 3

or 4

Hyperthyroidism

• Permanent discontinuation

Hypothyroidism

• Dose modification not indicated

For grade 3 - 4:

- Monitoring of thyroid function and thyroid autoantibodies

- Consultation with endocrinologist

Hyperthyroidism

- Hyperthyroidism medications

- Consider beta-blockers if tachycardia

Hypothyroidism

- Levothyroxine replacement therapy

Type 1 diabetes Any grade

- Pay close attention to relevant symptoms and signs, such as polyuria, polydipsia, polyphagia, fatigue, weakness and weight loss


- Monitoring and evaluation of islet function: blood glucose, insulin, C-peptide, pancreatic β-cell autoantibodies, blood ketone, and other endocrine laboratory parameters suspected to be associated with type 1 diabetes

Grade 1

or 2


For grade 1 - 2

Monitoring and assessment of islet function

Insulin treatment if necessarily required


Study drug: IBI308


Grade 3

Interruption

• Continue after blood glucose is brought under control

For grade 3 - 4

Monitoring and assessment of islet function

Consider endocrinology consultation

Insulin for controlling blood glucose, and adjust insulin dosage on the basis of blood glucose control

Inpatient hospitalization for insulin therapy, hydration and alakaline supplements if ketoacidosis occurs

Grade 4


Renal insufficiency (increased serum creatinine)

Any grade

Pay close attention to relevant symptoms and signs (e.g., decreased urine volume, dark urine color, anemia, fatigue and weakness, and weight loss)

Thorough assessment should be performed for the subject to rule out any alternative causes

Monitoring and assessment of renal function

Consider nephrology consultation

Consider renal biopsy to distinguish between inflammatory and non-inflammatory causes if necessary

Grade 1


For grade 1

- Monitor creatinine levels weekly

- Resume routine creatinine monitoring per protocol if return to baseline


Study drug: IBI308


Grade 2

or 3

Interruption

• If improvement to grade 0 - 1, continue on the next scheduled treatment day

• Handle according to grade 4 if persisting > 7 days or worsening

For grade 2 - 3

- Monitor creatinine levels every 2 - 3 days


- If improved to grade 1, have the corticosteroid dose reduced over at least 1 month, and consider prophylactic antibiotics to prevent opportunistic infections

- Consider renal biopsy

- Consult a nephrologist

Grade 4


For grade 4

- Monitor creatinine levels daily


- If improved to grade 1, have the corticosteroid dose reduced over at least 1 month, and consider prophylactic antibiotics to prevent opportunistic infections

- Consult a nephrologist

- Consider renal biopsy


Study drug: IBI308


Immune-related neurotoxicity (excluding myasthenia gravis and Guillain-Barre syndrome)

Any grade

- Monitor the patient’s systemic symptoms (headache, nausea, dizziness, behavioral changes, or weakness)

- Thorough assessment should be performed for the subject to rule out any alternative causes (e.g., progression, infection, metabolic syndrome and medications)

- Consider appropriate diagnostic tests (e.g., electromyography and nerve conduction study)

- Perform symptomatic treatment and neurology consultation if applicable

Grade 1


- Follow the patient closely for symptoms and signs

Grade 2

Interruption


• Handle according to grade 3 if worsened

For grade 2 - 4

- Consider neurology consultation

- Hospitalization if necessarily required

- Appropriate agents (e.g., gabapentin, duloxetine) may be used to treat sensory neuropathy and neuropathic pain

- Consider systemic corticosteroids

- If improvement is Not noted within 3 - 5 days, consider additional tests and other immunosuppressive agents (e.g., intravenous immunoglobulin G (IVIgG))

- Once stabilized, have the corticosteroid dose reduced gradually over ≥ 4 weeks

Grade 3


Grade 4


Study drug: IBI308


Immune-related peripheral nerve syndromes, such as Guillain-Barré syndrome and myasthenia gravis

Any grade

- Pay close attention to the relevant symptoms and signs (myasthenia gravis: sore and swollen eyelids or limbs, blurred vision, and fatigue easily, and characterized by being mild in the morning and severe in the evening; Guillain-Barre syndrome: sudden severe nerve root pain, flaccid paralysis of extremities, paresthesia in limbs (such as numbness, tingling or burning sensation)

- Because the patient is likely to experience unpredictable acute decompensation, which results in a severe disease or death, it is very important that a diagnosis of immune-related peripheral neuropathy be made in a timely manner. Attention should be particularly paid to certain symptoms or signs that may denote serious consequences, such as marked dysphagia, rapidly progressive weakness, respiratory insufficiency, or autonomic instability.

- Electrophysiology and other appropriate examinations should be performed to rule out any alternative causes (e.g., disease progression, infection, metabolic syndrome, and impact of medications). It is worth noting that the diagnosis of immune-related peripheral neuropathy is difficult due to impact of both the patient’s disease itself and treatment that neurology consultation should be sought.


Study drug: IBI308


Grade 1


For grade 1

- Discuss with study physician

- Monitoringof symptoms and signs

- Consider neurology consultation

Grade 2

Interruption


• Handle according to grade 3 - 4 if worsening

For grade 2 - 4

- Monitoring of symptoms and signs

- Neurology consultation

- Hospitalization if necessarily required


Study drug: IBI308


- Appropriate agents may be used to manage sensory neuropathy/neuropathic pain, such as gabapentin, duloxetine, etc.

Myasthenia Gravis

- Corticosteroids may be used to treat myasthenia gravis (since glucocorticoid therapy, especially at high doses, may lead to transient worsening of muscle weakness and therefore should be used under the supervision of a neurologist)

- Plasma exchange or IVIgG may be used for subjects who do not tolerate glucocorticoids

- In the presence of myasthenia gravis-like neurotoxicity, acetylcholinesterase inhibitors should be considered in addition to glucocorticoids

Guillain-Barre syndrome

- Plasma exchange or IVIgG therapy should be considered in Guillain-Barre syndrome (glucocorticoid therapy is usually ineffective)

Grade 3

or 4



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Table 2. Guidelines on dose modification and toxicity management for other potential irAEs

CTD classification/dose modification

Toxicity management

Any grade

No dose modification is required for adverse events considered unrelated to study treatment or for abnormal laboratory findings considered not clinically significant (i.e., events due to underlying disease)

Handle according to local clinical practice

Grade 1 Dose modification not indicated

Grade 2 Consider drug interruption until recovery to grade 0 - 1 or baseline

Grade 3 • First occurrence, discontinue study drug until recovery to grade 0 - 1 or baseline

• If a second occurrence of the same grade 3 AE, withdraw the drug permanently

• For an AE that decreased to grade 0 - 2 within 7 days or recovered to grade 0 - 1 or baseline within 14 days, interrupt the treatment and resume at the next scheduled treatment day Otherwise, withdraw the drug permanently

Grade 4 Permanent discontinuation (Note: For grade 4 laboratory abnormalities, discontinuation should be based on concomitant clinical symptoms/signs and the investigator’s clinical judgment)


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Table 3. Guidelines on dose modification and toxicity management for infusion reactions

CTD

classification

Dose Modifications Toxicity management

Any grade - Handle according to local clinical

practice

- Monitor the patient for any infusion-

related reactions (e.g., fever or

chills, flushing and/or pruritus,

variations of heart rate and blood

pressure, dyspnea, chest discomfort,

and rashes) and allergic reactions

(e.g., generalized urticaria,

angioedema, asthma, hypotension,

and tachycardia)

Grade 1 Reduce the infusion rate by

50% or interrupt the infusion,

until the infusion reaction is

resolved

For grade 1 or 2:

- Acetaminophen and/or

antihistamines may be administered

at the discretion of the investigator

according to local clinical practice

- Consider prophylaxis prior to

subsequent courses according to

local clinical practice

Grade 2 Reduce the infusion rate by

50% or interrupt the infusion,

until the infusion reaction is

resolved, after which the

subsequent infusion can be

resumed at 50% of the initial

rate


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Grade 3/4 Permanent discontinuation For grade 3 or 4:

- Manage severe infusion-related

reactions according to local clinical

practice (e.g., administration of

epinephrine, diphenhydramine,

ranitidine, and glucocorticoids)
