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Clinical Trials on Multiple Myeloma in China

Wenming Chen

Beijing Chaoyang Hospital

Capital Medical University

Multiple Myeloma Research Center of Beijing

Current situation of anti-myeloma drugs

Available Reimbursement Indication

Melphalan oral：x iv: x Transplant

Bortezomib NDMM, RRMM

Ixazomib RRMM

Carfilzomib Trail closed, will be approved on 2020

Thalidomide off-label

Lenalidomide NDMM,RRMM, Mainten

Pomalidomide will be approved on 2019

Daratumumib will be approved on 2019

Isatuximab on trial

Selinexor on trial

CAR-T Ongoing Phase I-II trial: 3 IIS: >10

TRAIL Phase III on goning

Circularly Permuted TNF-Related Apoptosis-Inducing Ligand

(TRAIL，CPT) for the treatment of RRMM

Recombinant human TRAIL-induced apoptosis

TRAIL: TNF-Related Apoptosis-Inducing LigandDR: death receptor DcR: Decoy receptor OPG: osteoprotegerin

Modified CPT monomer structureWild type TRAIL monomer structure

Structure of CPT

CPT—Circularly Permuted TRAIL

N-terC-ter

N-ter

C-ter

Flexible linker

Advantages of CPT

⚫ more potent anti-tumor activity in preclinical studies compared with wild type

TRAIL

⚫ longer half-life than recombinant human Apo2L/TRAIL in human

Nude mice with established RPMI-8226(left) or NCI-H460(right) xenografts were

given CPT or wtTRAIL as an i.p. bolus for 10 consecutive days (n=6-8/group).

Results shown(plot) are mean values.

Anti-myeloma activity of CPT

in vivo: more potent anti-myeloma tumor activity in mouse xenograftmodels compared with wild type TRAIL (wtTRAIL)

0 5 10 15 20 25

0

500

1000

1500

2000

2500

3000

3500

4000

Tum

or si

ze (m

m3 )

Days

control

CPT15mg/kg

CPT3mg/kg

wtTRAIL15mg/kg

CPT/TRAIL

CPT for RRMM: Phase I Trial

Study design

−Open-label, single agent, dose escalation studies

−Observe overall safety, PK, Preliminary efficacy studies

2.5mg /kg/d×14d

1.7mg /kg/d×14d

1.0mg /kg/d×14d

Phase Ia: Advanced solid tumor and

hematologic cancers (N=28)

15mg /kg/d×5d

10mg /kg/d×5d

8.0mg /kg/d×5d

6.5mg /kg/d×5d

5.0mg /kg/d×5d

Phase Ib: Refractory/Relapsed Multiple

Myeloma (N=29)

Am J Hematol, 2014, 89: 1037-42

Phase Ib：Efficacy Results In RRMM patients

*Efficacy evaluable patients

Response Rates: assessments were based EBMT criteria.

Response

Rate

5,6.5mg/kg

（n=9）8, 10mg/kg

（n=12）15mg/kg

（n=6）Total*

（n=27）

CR & nCR, n（%） 0 0 1（16.67） 1（3.70）

PR, n（%） 0 3 (25) 1（16.67） 4（14.81）

MR, n（%） 3 (33.33) 0 1 (16.67) 4（14.81）

CR+PR, n（%) 0 3 (25) 2 (33.33) 5（18.52）

CR+PR+MR, n（%） 3 (33.33) 3 (25) 3 (50) 9（33.33）

Am J Hematol, 2014, 89: 1037-42

Phase Ⅰ：Treatment-related Adverse Events

Well tolerated, No DLT were found

AE, %Phase I

(N=28+29)

ALT 24.56%

AST 22.80%

Fever 17.54%

Fatigue 12.28%

Nausea 7.02%

Vomiting 10.53%

Leukopenia 12.28%

Anorexia 5.26%

Rash 3.51%

Tumor Lysis Syndrome 1.75%

Am J Hematol, 2014, 89: 1037-42

Phase II

Trial-1:

CPT monotherapy for

RRMM (N=27)

Trial-2:

CPT plus Thalidomide for

RRMM(N=43)

Objectives: safety, efficacy

Patients: Refractory or Relapsed MM

Trial-3:

CPT plus Thalidomide

and Dexamethasone (TD)

for RRMM (N=71)

CPT FOR RRMM: Phase II Trial

Cancer Chemother Pharmacol. 2017,79(6):1141-1149Am J Clin Oncol. 2018,41(10):1008-1014

Trial-3: CPT in combination with Thalidomide and Dexamethasone (TD) for RRMM (N=71)

− Design: multi-center, open-Label, Randomized and Controlled

− Inclusion criteria: relapsed and/or refractory multiple myeloma , received at least 2

prior anti-MM therapy.

− Intervention: CPT+TD vs TD

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19 – 28

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19 - 28

CPT 10mg/kg

Thalidomide 150mg

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19 – 28

Dexamethasone 40mg

Phase II: Trial-3 (CPT+TD vs TD)

Cancer Chemother Pharmacol. 2017,79(6):1141-1149

Efficacy results


Best Response（EBMT）（n=71）

CPT+TD

（n=47)

TD

(n=24)

Efficacy-evaluable patients 41 23

nCR, n(%) 7（17.1） 0（0）

PR, n(%) 11（26.8） 6（26.1）

MR, n(%) 7（17.1） 1（4.3）

nCR+PR, n(%) 18（43.9） 6（26.1）

nCR+PR+MR, n(%) 25（61.0） 7（30.4）

PFS (n=71), Median(95% CI) 6.7(3.3~10.1) 3.1(1.7~4.5)


Kaplan-Meier curves of progression-free survival (PFS)



Safe and well tolerated of CPT in combination with TD therapies

Table 1. Incidences of adverse events (Safety population)Adverse events (AEs), n (%)b CPT+TD (N=47) TD (N=24)

Any grades Grade 3 or 4 Any grades Grade 3or 4

Hematologic AEsNeutropenia 22 (46.8) 7 (14.9) 12 (50.0) 6 (25.0)Leukopenia 18 (38.3) 3 (6.4) 9 (37.5) 3 (12.5)Decreased Haemoglobin 13 (27.7) 3 (6.4) 11 (45.8) 8 (33.3)Thrombocytopenia 9 (19.1) 5 (10.6) 5 (20.8) 5 (20.8)

Non-hematologic AEsIncreased ALT 22 (46.8) 4 (8.5) 2 (8.3) 0Increased AST 13 (27.7) 5 (10.6) 0 0Hypocalcaemia 12 (25.5) 3 (6.4) 0 0Lung infection 11 (23.4) 4 (8.5) 6 (25.0) 4 (16.7)Fever 11 (23.4) 0 4 (16.7) 1 (4.2)Hypokalemia 9 (19.1) 3 (6.4) 1 (4.2) 0Increased LDH 8 (17.0) 2 (4.3) 1 (4.2) 0

Serious adverse events (SAEs), n (%)c

Any event 8 (17.0) 6 (25.0)aAEs were evaluated independent of the relation to the treatment. bAEs with an incidence ≥15% among

patients in either study group were listed. cAll SAEs were listed.



Summary

1. CPT showed more potent activity and longer half life compared

with wtTRAIL

2. Safe and well tolerated

3. Definite efficacy for refractory/relapsed MM as mono-therapy.

4. Definite Dose-Response Relationship.

5. CPT+TD, show superior efficacy compared with TD

Study of CPT or Placebo plus Thalidomide and Dexamethasone

in Relapsed and/or Refractory Multiple Myeloma

Phase III trial

− A Multicenter, Randomized, Double-Blind, Controlled Phase 3 study

− Enrollment: 417 patients, received at least 2 prior line therapy

− Study start date: March 2017

Study completion date: Q2 2019

− Primary endpoint: PFS

Ongoing trial

PublicationsNo. Time Journal Title

1 2018Hematology

2018,23(9):620-625.

Synergistic effects of rmhTRAIL and 17-AAG on

the proliferation and apoptosis of multiple myeloma cells

2 2017Cancer Lett

2017 Mar 28;389:70-77.

Rocaglamide breaks TRAIL-resistance in human multiple myeloma and

acute T-cell leukemia in vivo in a mouse xenogtraft model.

3 2018Med Sci Monit

2018;24:2550-2561.

Effects of Recombinant Circularly Permuted Tumor Necrosis Factor (TNF)-

Related Apoptosis-Inducing Ligand (TRAIL) (Recombinant Mutant Human

TRAIL) in Combination with 5-Fluorouracil in Human Colorectal Cancer

Cell Lines HCT116 and SW480

4 2016 Exp HematolEffects and mechanism of arsenic trioxide in combination with rmhTRAIL

in multiple myeloma

5 2015 Onco Targets TherGefitinib upregulates death receptor 5 expression to mediate rmhTRAIL-

induced apoptosis in Gefitinib-sensitive NSCLC cell line

6 2015 Clin LabNovel Molecular Regulators of Tumor Necrosis Factor-Related Apoptosis-

Inducing Ligand (TRAIL)-Induced Apoptosis in NSCLC Cells

7 2019 On submitEffects and mechanism of Bortezomib in combination with rmhTRAIL in

refractory multiple myeloma

CAR-T cell from Legend: LCAR-B38M

Zhao WH, J Hematol Oncol. 2018 Dec 20;11(1):141


LCAR-B38M was composed of a human CD8 alpha signal peptide (CD8α SP),

BCMA-targeting domain consisting of two different VHHs (single-domain antibody,

clones VHH1 and VHH2), human CD8 alpha hinge and transmembrane domain

(CD8α hinge + TM), human 4-1BB cytoplasmic domain, and a human CD3 zeta

cytoplasmic domain (CD3ζ)


Legend (LCAR-B38M) Study in XiAn

• Prior lines of therapy: 3±2

• ECOG: ≥2: 16%

• Cyclophosphamide: 300mg/m2

• Dose: 0.5×10e6/kg

• 57 patients treated

• ORR 88%

• sCR：68%

• CRS： 90%； ≥3= 7%

• mPFS : 15m

NCT03090659



Legend (LCAR-B38M)

hydrothorax

Exploratory trial of a biepitopic CAR T-targeting B cell

maturation antigen in relapsed/refractory multiple

myeloma

Jie Xua,1, Li-Juan Chenb,1, Shuang-Shuang Yanga,1, Yan Suna,1, Wen Wua, Yuan-Fang Liua, Ji Xu b, Yan Zhuangc, Wu Zhanga,

Xiang-Qin Wenga, Jing Wua, Yan Wanga, Jin Wanga, Hua Yana, Wen-Bin Xua, Hua Jiangc, Juan Duc, Xiao-Yi Dingd, Biao Lid,

Jun-Min Lia, Wei-Jun Fuc, Jiang Zhua, Li Zhue, Zhu Chena,2, Xiao-Hu (Frank) Fane,2, Jian Houc,2, Jian-Yong Lib,2, Jian-Qing

Mia,2, and Sai-Juan Chena,2

aState Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital

affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China; bDepartment of Hematology, Jiangsu Province Hospital, First

Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China; cDepartment of Hematology, Changzheng Hospital, The Second Military

Medical University, 200003 Shanghai, China; dDepartment of Radiology and Nuclear Medicine, Ruijin Hospital affiliatedwithShanghai JiaoTong

University School of Medicine, 200025 Shanghai, China; and eNanjing Legend Biotech, 210008 Nanjing, China

Contributed by Zhu Chen, December 17, 2018 (sent for review November 19, 2018; review

Xu J, et al. PNAS, 2019 Apr 15

Legend (LCAR-B38M)

(A) LCAR-B38M was composed of a human CD8 alpha signal peptide (CD8α SP), BCMA-targeting domain consisting of two

different VHHs (single-domain antibody, clones VHH1 and VHH2), human CD8 alpha hinge and transmembrane domain

(CD8α hinge + TM), human 4-1BB cytoplasmic domain, and a human CD3 zeta cytoplasmic domain (CD3ζ) (see Materials

and Methods for details).

(B and C) Measurements of LCAR-B38M gene-modified T cells assessed by means of qPCR assay in peripheral blood of

patients treated with cyclophosphamide/fludarabine combination conditioning and three-infusion CAR T delivery (B) or

cyclophosphamide conditioning and one-infusion CAR T delivery (C).




Legend (LCAR-B38M)

17 patients

treated

Prior lines of

therapy: 4.6

15/17 response

--13 CR

--4/5 EM disease

progressed

• Progression-free survival (PFS) rates of 82.4% at 6 mo and 52.9% at 12 mo (Fig. 2F)

• The 1-y overall survival (OS) rate was 82.3% (Fig. 2G) Xu J, et al. PNAS, 2019 Apr 15

Research on the safety, tolerability, pharmacokinetics and

efficacy of autologous CAR-BCMA T cells (CT053) for relapsed

and/or refractory multiple myeloma

Unpublished data, only for academic communication

CT053: Fully-human BCMA CAR-T Therapy

Size exclusion chromatograms of anti-BCMA antibodies in scFv_Fcform

High Percentage of Monomer Ratio of CT053 scFv

Potent in vivo Antitumor Activities of CT053 CAR T

CT053 CAR-BCMA T Study Design

Screening

Lymphodepletion

CAR-BCMA T manufacturing ( ~14 Day）

Infusion

F: fludarabine

C: cyclophosphamide

W: week

M: Month

Apheresis

Baseline

ICF

F+C

D-5 ~ -3

D0

W2 W4 W8 W12 M4 M5 M6 M9 M12 M18 M24W1

Main follow-up period Follow-up period

Treatment

Key Eligibility Criteria

• 18 -79 years of age

• Relapsed and/or refractory myeloma after at least 2 prior standard lines of therapy

• Subjects must be positive for BCMA per flow cytometry analysis or pathological exam.

• Estimated survival time > 12 weeks

• Have measurable disease on study entry

• ECOG performance status of 0-2

• WBC ≥ 1.5×109/L and PLT ≥ 45×109/L; serum creatinine ≤ 1.5 ULN; ALT ≤ 2.5 ULN，and AST ≤ 2.5 ULN

CT053 CAR-BCMA-T Cell Infusion

◼ Cell infusion dose in 24 patients: 0.5 – 1.8 ×108 transduced T-cells

✓ 1st patient: 0.5 ×108 cells (0.86 ×106/kg)

✓ 2nd patient: 1.8 ×108 cells (1.98 ×106/kg)

✓ 17th patient: 1.0×108 cell (2.04×106/kg)

✓ 21 patients: 1.5 ×108 (1.94-3.57×106/kg)

◼ Infusion was finished within 2 – 20 min

◼ No infusion related reactions were reported

◼ Second infusion:

✓ Pt 2 received the 2nd dose infusion 2.0×108 cell



Subjects（N=24） Without EM infiltration（N=13） With EM infiltration（N=11)Age (year)* 60.2 (38.5-70.0) 56.3 (39.5-67.2) 63.4 (38.5-70.0)Male/Female 13/11 7/6 6/5

Body Surface Area (m2)* 1.7 (1.3-2.1) 1.7 (1.4-1.9) 1.6 (1.3-2.1)

Time since diagnosis (year)* 3.5 (0.3-10.8) 4.3 (1.1-10.8) 2.9 (0.3-5.9)

IgG λ/IgA κ/λ light chains/IgA λ/IgG κ 12/6/2/2/2 7/3/1/1/1 5/3/1/1/1

ECOG

0-1 16 (66.7%) 10 (76.9%) 6 (54.5%)

2 6 (25.0%) 3 (23.1%) 3 (27.3%)

3 2 (8.3%) 0 (0.0%) 2 (18.2%)

ISS

I 4 (16.7%) 2 (15.4%) 2 (18.2%)

II 11 (45.8%) 4 (30.8%) 7 (63.6%)

III 9 (37.5%) 7 (53.8%) 2 (18.2%)

BCMA positivity (%)* 91.3 (30.4-99.8) 90.5 (58.5-99.8) 95.7 (30.4-99.5)No. of prior regimens excluding bridging therapy 4.5 (2.0-12.0) 6.0 (3.0-12.0) 4.0 (2.0-8.0)

PIs 24(100%) 13(100%) 11(100%)

IMiDs 22(91.7%) 13(100%) 9(81.8%)

PIs and IMiDs 22(91.7%) 13(100%) 9(81.8%)

Monoclonal antibody 5(20.8%) 4(30.8%) 1(9.1%)

Stem cell transplantation 10(41.7%) 7(53.8%) 3(27.3%)

Patient’s Characteristics

Treatment related AE

Number of

subjects （%） Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Cytokine release syndrome(CRS) 15(62.5%) 4 11 0 0 0

Fever 15(62.5%) 4 5 5 1 0

Neurologic toxicity*(NTX) 2(8.3%) 1 0 1 0 0

Infections and infestations 6(25%) 1 0 5 0 1

Hematological toxicity 23(95.8%) 5 9 24 46 1

Lymphocyte count decreased 18(75%) 0 0 1 17 0

White blood cell count

decreased 21(87.5%) 0 1 7 13 0

Platelet count decreased 13(54.2%) 4 3 2 4 0

Neutrophil count decreased 19(79.2%) 0 3 5 11 0

Full blood count decreased 1(4.2%) 0 0 0 1 0

Anaemia 9(37.5%) 1 1 7 0 0

Coagulopathy 2(8.3%) 0 1 1 0 0

Bone depression 2(8.3%) 0 0 1 0 1

Adverse Events of Special Interest

& Death resulting by neutropenic infections, myelosuppression and disease progression at Day 25th after infusion

*Treatment related AEs include lymphodepletion-related AEs or CAR-BCMA T-cell infusion-related AEs.

# One subject experienced both grade 3 NTX and grade 2 CRS

Efficacy Assessment

• Efficacy follow-up: 295 days (119 – 509)

• ORR is 87.5% in 24 pts who received cell infusion

• Outstanding efficacy was observed even with low dose: 0.5×108 (VGPR) persisting 378+ days, and

achieved CR on day 437, sCR on day 502.

• CR/sCR: 70.8% (17/24); VGPR and above: 83.3%（20/24）

CG6002-01001: 0.5×108 CG6002-01002: 1.8×108 CGZ001-61007: 1.0×108

• 5/6 PD subjects had baseline EM disease.

Data cut-off: 28Feb2019

Expansion and Persistence of CAR-T cells

• Detectable 1~7 days after infusion

• Peaked on 7~21 days, with the

lowest peak value at 1.5×104

copies/µg gDNA and the highest at

4.5×105 copies/µg gDNA

• Persistence at least 21~375 days

CAR T copies in subjects who experienced PD and received the second dose

Clinical Efficacy on Extramedullary Plasmacytoma

Day 1 after CT053 treatment Day 5 after CT053 treatment Day 6 after CT053 treatment

Pt8: Male, 65yrs. MM(λ type).

Achieved CR at week 4.

lesion 2

lesion 1

lesion 2 lesion 1

lesion 2lesion 1

Lesion 1

Lesion 2

New Lesion（no neoplasm exist at base line and on week10, appear in M4, disappeared 2w thereafter）

Summary

The patients had worse clinical condition (ECOG 2/3 in 33.3% patients; 46%

with EM disease) when compared to patients in other BCMA-CAR T studies

24 subjects with R/R MM infused 0.5 - 1.8×108 CT053 cells, the dose in the 1st, 2nd

and 17th cases was 0.5×108, 1.8×108 and 1.0×108 CAR T-cells, respectively and the

other 21 subjects received a dose of 1.5×108 transduced T cells.

➢ CT053 CAR BCMA T cells conferred tolerable safety profiles (No grade 3

or higher CRS was observed)

➢ Sufficient CAR T-cell expansion and persistence observed

➢ 87.5% ORR; 83.3% of VGPR and above; 70.8% CR/sCR

Data cut-off: 28Feb2019

The safety and efficacy of autologous CAR-BCMA T cells

(CT053) for relapsed and refractory multiple myeloma

Phase I & II trial

PI: Wenming Chen

Approved by CFDA

Thank you!

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