innovative clinical trial designs

Innovative Clinical Trial Designs: How to maximize the benefit?

Emad Shash, MBBCh., MSc., MD.

Medical Oncology Department

National Cancer Institute

Cairo University

What are we going to discuss today!Evidence

Based Medicine

Resources Utilization

Clinical Research

Innovation

• How are we used to perform clinical trials in Oncology?

• Does it fits in today’s needs?

• Integration of biology knowledge in shaping drug development

• New Clinical trial designs “Can they offer solution for accelerating drug development?”

• The supporting infrastructure role in clinical trial execution

Right PatientRight

Treatment

Right TimeCost

Effectiveness

Evolution Theory

Adaptation is always and should be according to Needs

Experimental design for Scurvy“James Lind 1716-1794”

12 classical SCURVY Sailors

Vinegar Diluted sulfuric acid Cider Sea Water Nutmeg & Garlic 2 Oranges & 1 Lemon

Normal diet + supplementation

(6 experimental groups)

Phases of Clinical Trials “what we are used to do”

Phase I

Drug given to 20-100 healthy volunteers (although patients in some cases)

Duration 1mth – 1 year

Cost $100K to $500K

Following studied here

• PK/PD

• Food interaction

• Safety

• Dose escalation/MTD

• Safety

• Early evidence of efficacy

Drug given to 100-500 patient volunteers

Duration 1 – 2 years

Cost $10M to $100M


• Efficacy

• Safety

• Establish dose for Phase III

Drug given to 1000-5000 patient volunteers

Duration 3 – 4 years

Cost $10M to $500M


• Confirmation of Efficacy

• Safety

Drug is launched in the market. 1000’s of patients

Many years

No specific amount

Additional post marketing testing of patients for drug

• Safety & Efficacy

• Support use of the approved indication

• Finding new therapeutic opportunities

• Extended use to different classes of patients

• 1000s of patients

Phase II Phase III Phase IV

Stages of drug development“Time & Money Consumption”

Source: “An Overview of the Drug Development Process”, by Ross Tonkens, M.D.

Phase I Phase IIIRESOURCES

≅15 Years≅30 M – 700 M

Continuous Decline in Healthcare & Research Spending

What are we going to discuss today!

Evidence Based

Medicine


Clinical Research

Innovation


• Does it fit our today’s needs?




Molecularly Targeted therapy Versus Conventional therapy

Patient

DrugBiomarker

Efficacy

Schwaederle M et al. JCO 2015

Better Biology Understanding & Treatment Outcome Optimization

Matching patients with drugs based on specific biomarkers

PubMed search

January 1, 2010, and December 31,

2012

570

phase II single-agent studies

32,149 patients

NSCLC Pathology: From Traditional View to more sub-molecular categorization

Advanced NSCLC: Evolution of Treatment

2000 - 2006 2006 - 2009 2010 2011 – 2017……..

EGFR mutation

ALK rearrangement

K-ras mutation

B-raf, HER2 mutation

ROS1, RET

Immunotherapy

Non-Squamous

Squamous

Targeting an Oncogenic Driver

EGFR mutation

Non-Squamous

Squamous

Non-Squamous

Squamous

NSCLC

Targeting EGFRTreating according histologyNSCLC

Time elapsed from discovery to practice change

The biomarker and drug development cycle

Patients-industry-Drug developers-

Translational researchers

Regulators

Payers

Analytical validation

Clinical validation

Clinical utility

Market access

Health care

delivery TR

Drug developers

Patients-Payers-Regulators-Industry

Time & Money Consumption while patients are waiting!!

Can we accelerate time? &

Still get the maximal benefit!


Evidence Based

Medicine


Clinical Research

Innovation


• Does it fit in today’s needs?




Umbrella Trial

• Different targeted agents investigated in parallel in the same tumor type and within independent cohorts of patients

• Defined by specific molecular aberrations that could predict sensitivity to the investigational agent under assessment

Histology based clinical trial designTo evaluate multiple molecular aberrations

Le Tourneau et al. Lancet Oncol 2015Paoletti et al. CCO 2015

Molecularly targeted therapy based on tumor molecular profiling versus conventional therapy for advanced cancer (SHIVA) Trial: Proof-of-Concept

Le Tourneau et al. Lancet Oncol 2015


Molecularly targeted agent group (n=99)

Treatment at physician's choice group (n=96)

Age (years) 61 (54–69) 63 (54–69)

Sex

Female 60 (61%) 69 (72%)

Male 39 (39%) 27 (28%)

Previous lines of treatment 3 (2–5) 3 (2–5)

Royal Marsden Hospital score

0 or 1 51 (52%) 48 (50%)

2 or 3 48 (48%) 48 (50%)

Molecular pathway altered

Hormone receptor pathway 40 (40%) 42 (44%)

PI3K/AKT/mTOR pathway 46 (46%) 43 (45%)

RAF/MEK pathway 13 (13%) 11 (11%)

Adapted from: Le Tourneau et al. Lancet Oncol 2015


0 5 10 15 20 25

Breast adenocarcinoma

Colorectal cancer

Sarcoma

Adenocarcinoma of unknown primary

Non-adenoid cystic carcinoma salivary gland tumour

Neuroendocrine tumour

Cutaneous melanoma

Ependymoma

Germline tumour

Distribution By Tumor Type

Treatment at Physican Choice Moleculary Targeted Group

0

5

10

15

20

25

30

35

40

45

50

Hormone receptor pathway PI3K/AKT/mTOR pathway RAF/MEK pathway

Distribution By Molecular Abberation

Moleculary Targeted Group Physician Choice Group

Distribution of molecular alterations in the PI3K/AKT/mTOR pathway

Distribution of molecular alterations in the RAF/MEK pathway



Progression-free survival Intent to treat population

PI3K/AKT/mTOR pathway

RAF/MEK pathway



Progression-free survival Intent to treat population

PI3K/AKT/mTOR pathway

RAF/MEK pathway

• It is the first to test, with a randomized control, the idea of whether off-label use of commercial drugs for matched molecular biomarkers confers a clinical benefit.

• The results suggest that off-label use of molecularly targeted agents in this manner should be restricted.

• Instead, patients should be encouraged to participate in well-designed next-generation clinical trials that use an iterative and scientific approach to build on findings from trials such as SHIVA

• Irrespective of these limitations, SHIVA offers robust evidence for deficiencies in assigning therapy based on the various loose associations between biomarkers and inhibitors that are often provided in commercial clinical diagnostic reports.

Basket Trial

• Histology-independent trial design

• Patients with cancers of different histology enrolled in the clinical trial based on the presence of a specific molecular aberration

Histology-independentaberration-specific clinical trial design

EXAMPLE: NCI MPACT BASKET TRIAL

KummarS, et al., ASCO Annual Meeting 2014 poster

CREATE EORTC TRIAL

• Six Cohorts of rare solid tumors and anaplastic large cell lymphoma• ALK and/or MET alterations are considered to play a role of the carcinogenesis process of these tumors

Clinical trial information: NCT01524926

EORTC 90101 MET Driven (PRCC1 Cohort)

Schoffski et al. LBA AACR 2016

Basket of trials

BASKET TRIAL: PROS AND CONS

• Pros • Determining potential tumor efficacy of a single targeted agent in different

cancer types with the same gene abnormality

• Cons • Risk of overlooking the impact of tumor histology type. In fact, different

tumor responses by targeting the same mutation in several cancer types could be observed. (e.g. BRAF in melanoma versus BRAF in colorectal cancer: RR 50%-60% versus <5%)

ADAPTIVE TRIALS (1)

The principle of this trial is based on modifying parameters (dose, sample size, drug, schedule …) of a clinical trial evaluating a treatment in accord with observed outcomes in participants.

ADAPTIVE TRIALS (2)

Deepak et al. New Eng J Med 2016

ADAPTIVE TRIALS (3)

Deepak et al. New Eng J Med 2016

Park et al. New Eng J Med 2016

I-SPY 2

I-SPY 2 trialMulticenter, adaptive phase 2 trial of neoadjuvant therapy for:

• High risk clinical stage II or III breast cancer evaluated multiple new agents added to standard chemotherapy To assess the effects on rates of pathological

complete response


Neratinib (HKI-272; Puma Biotechnology)• an irreversible small-molecule inhibitor of the ErbB and the human

epidermal Growth factor receptor (HER) kinase family (epidermal growth Factor receptor, HER2, and HER4)

• It has shown promising activity against HER2-positive metastatic breast cancer.

• There is also evidence of preclinical activity against HER2negative tumor cells

Probability Distributions for SelectedBiomarker Signatures


Eligible women were categorized according to • 8 biomarker Subtypes on the basis of

• Human epidermal growth factor receptor 2 (HER2) status

• Hormone-receptor status• Risk according to a 70-geneprofile

Final Posterior and Predictive Probabilities of NeratinibEfficacy with Regard to 10 Biomarker Signatures

* The status of high-risk category 2 on the 70-gene profile was determined with the use of the MammaPrint assay


Final Posterior and Predictive Probabilities of NeratinibEfficacy with Regard to 10 Biomarker Signatures

* The status of high-risk category 2 on the 70-gene profile was determined with the use of the MammaPrint assay


• Neratinib reached the pre-specified efficacy threshold with regard to the HER2-positive, hormone-receptor–negative signature

• Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor–negative breast cancer.

ADAPTIVE TRIAL DESIGN: PROS AND CONS

• Pros• Faster evaluation of the drug

• Modification of drug, dosage and sample size during the trial according to the observed results

• Cons• Practical difficulties during the performance of the trial

• The clinicians are not familiar with the essential statistical part of this approach

• Active and dynamic follow-up of the trial is needed

WHAT ARE THE CHALLENGES OF THE NEW CLINICAL TRIAL DESIGNS?

• To show significant benefit in overall survival

• Rapidly evolving and not validated technics in use for tumor sequencing (NGS, circulating tumors cells, circulating tumor DNA…)

• High number of screened patients is needed

A strong infrastructure behind is needed to execute such trials with quality assurance


Evidence Based

Medicine


Clinical Research

Innovation


• Does it fit our today’s needs?




The current fragmented approach of Drug & Biomarker related Development

Screening patients

Enrolling patients

Collecting tissue

Analyzing tissue

Collecting real-life data

Screening patients

Enrolling patients

Collecting tissue

Analyzing tissue


Screening patients

Enrolling patients

Collecting tissue

Analyzing tissue


Company A Company B Company C

QA/QC validated platforms & services

Collected data

Towards data-driven healthcare

Faster access to effective care

Business risk reduction

Innovative trial designs /

Trial access

Regulatory pathway /

Market accesssupported by

adaptivelicensing

Biomarker analytical and

clinical validation

Treatment guideline development

• Clinical infrastructure

• Quality Assurance in RT(QART)

• Imaging• Translational Research Unit

• BiobankSample tool KEOSYS

platform

ORTA, VISTA, Safe,

PRISMA

QART

VODCA platform

EORTC Infrastructure as an “Example” supporting new generation clinical trials

Conclusion

• We need to adapt in our trials according to the accelerating needs

• Networking between institutions to render molecular tumor boardaccessible to the majority of centers and consequently to clinical trials and new drugs

• More collaboration with pharmaceutical companies due to the need of drugs (including off label drugs) with the different mechanisms of action to be used in precision medicine at the right time for the patient

• Validation Role of biomarkers and/or molecular imaging in determining mainly the negative predictive value of an evaluated drug

• We need the infrastructure that can support such complex trials

“In the long history of humankind (and animal kind, too) those who learned to collaborate and improvise most effectively have prevailed.”

Charles Darwin 1809-1882

Thank You

innovative clinical trial designs

Health & Medicine