Clinical trial NCT03310619: A Safety and Efficacy Trial of JCAR017 Combinations in Subjects With Relapsed/Refractory B-cell Malignancies
Official title: An Exploratory Phase 1/2 Trial To Evaluate The Safety And Efficacy Of JCAR017 Combinations In Subjects With Relapsed/Refractory B-Cell Malignancies (PLATFORM)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Lymphoma, Non-Hodgkin
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Follicular
Keywords: JCAR017
B-Cell Malignancies
NHL
non-Hodgkin lymphoma
CAR T cells
chimeric antigen receptor
CC-220
Ibrutinib
relatlimab
nivolumab
CC-99282
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2017-10-16
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a global, open-label, multi-arm, parallel multi-cohort, multi-center, Phase 1/2 study to determine the safety, tolerability, PK, efficacy and patient-reported quality of life of JCAR017 in combination with various agents. This protocol is intended to evaluate various drug combinations with JCAR017, as separate arms, over the life of the protocol, using the same objectives. Each combination will be evaluated separately (ie, the intention is not to compare between combinations) for the purposes of the objectives, trial design, and statistical analysis. The following combinations will be tested:

Arm A: JCAR017 in combination with durvalumab Arm B: JCAR017 in combination with CC-122 (avadomide) Arm C: JCAR017 in combination with CC-220 (iberdomide) Arm D: JCAR017 in combination with ibrutinib Arm E: JCAR017 in combination with relatlimab and/or nivolumab Arm F: JCAR017 in combination with CC-99282 Additional arms will be added by way of amendment once combination agents have been selected.

The study will consist of 2 parts: dose finding (Phase 1) and dose expansion (Phase 2). Dose expansion may occur in one or more arms.

Detailed description: During Phase 1, different arms may be opened to test JCAR017 in combination with combination agent(s) in adult subjects with R/R aggressive B-cell NHL. Within each arm, different doses and schedules of JCAR017 and the combination agent(s) may be tested in several cohorts and subcohorts per arm. During Phase 2 of the study, the expansion of any dose level and schedule for any arm that has been shown to be safe may occur.

Arm A will test JCAR017 in combination with Durvalumab Arm B will test JCAR017 in combination with CC-122 Arm C will test JCAR017 in combination with CC-220 (iberdomide ) Arm D will test JCAR017 in combination with ibrutinib. Arm E will test JCAR017 in combination with relatlimab and/or nivolumab Arm F will test JCAR017 in combination with CC-99282 All subjects from Phase 1 and Phase 2 will be followed for 24 months following JCAR017 infusion. Post-study follow-up for survival, relapse, long-term toxicity (including new malignancies), and viral vector safety will continue under a separate long-term follow-up (LTFU) protocol for up to 15 years after the JCAR017 dose as per health authority regulatory guidelines.

Eligibility criteria: Inclusion Criteria:

1. Subject is ≥ 18 years of age at the time of signing the informed consent form ().
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
4. Subject must have aggressive B-cell NHL according to "the 2016 revision of the WHO classification of lymphoid neoplasms", histologically confirmed at last relapse by the treating institution, defined as:

   1. Diffuse large B-cell lymphoma (DLBCL) Not otherwise specified (NOS) including transformed indolent Non-Hodgkin lymphoma (NHL)
   2. Follicular lymphoma Grade 3B
   3. T cell/histiocyte-rich large B-cell lymphoma
   4. Epstein-Barr virus (EBV) positive DLBCL, NOS
   5. Primary mediastinal (thymic) large B-cell lymphoma
   6. High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma)
5. Subjects disease must have relapsed or be refractory to at least 2 prior lines of therapy. Previous therapy must have included a CD20-targeted agent and an anthracycline.
6. Subject must have

   1. Positron emission tomography (PET)-positive (Deauville score 4 or 5) and computed tomography (CT) measurable disease as per Lugano Classification
   2. Sum of product of perpendicular diameters (SPD) of up to 6 index lesions ≥ 25 cm2 by CT scan (not applicable to Arm A or B or subjects with Richter's transformation)
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 at screening
8. Adequate organ function
9. Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals
10. Participants must agree to use effective contraception

Exclusion Criteria:

1. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study based on investigator´s judgment.
2. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study based on investigator´s judgment.
3. Subject has any condition that confounds the ability to interpret data from the study based on investigator´s judgment.
4. Subjects with prior history of malignancies, other than aggressive R/R NHL, unless the subject has been free of the disease for ≥ 2 years with the exception of the following non-invasive malignancies:

   1. Basal cell carcinoma of the skin
   2. Squamous cell carcinoma of the skin
   3. Carcinoma in situ of the cervix
   4. Carcinoma in situ of the breast
   5. Incidental histologic finding of prostate cancer (T1a or T1b using the TNM \[tumor, nodes, metastasis\] clinical staging system) or prostate cancer that is curative.
   6. Other completely resected stage 1 solid tumor with low risk for recurrence
5. Prior treatment with any prior gene therap y product
6. Prior treatment with any adoptive T cell therapy; prior hematopoietic stem cell transplant (HSCT) is allowed
7. Allogeneic HSCT within 90 days of leukapheresis
8. Prior treatment with the combination agent from the assigned arm:

   1. Anti PD-1 or PD-L1 (Arm A and E)
   2. CC-122 (Arm B)
   3. CC-220 (Arm C)
   4. Prior treatment with ibrutinib is not exclusionary for subjects on any study arm
   5. Anti LAG-3 targeted agent (Arm E)
   6. CC-99282 (Arm F)
9. Presence of acute or chronic graft-versus-host disease (GVHD)
10. Presence of the following:

    1. Active hepatitis B or active hepatitis C infection
    2. History of or active human immunodeficiency virus (HIV) infection
11. Uncontrolled bacterial, viral or fungal infection at the time of leukapheresis, lymphodepleting chemotherapy or JCAR017 infusion
12. Any history of myocarditis (Arm E); history of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease (all arms)
13. History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
14. Subjects with active CNS or cerebrospinal fluid (CSF) involvement by malignancy
15. Pregnant or nursing (lactating) women.
16. Subjects with active auto immune disorders/processes or active neurological or inflammatory disorders
17. For subjects to receive oral combination therapy (Arms B, C, D or F): History of a gastrointestinal (GI) condition or procedure that in the opinion of the investigator may affect oral drug absorption.
18. Progressive tumor invasion of venous or arterial vessels.
19. Deep venous thrombosis (DVT)/pulmonary embolism (PE) not managed on a stable regimen of anticoagulation.

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicity (DLT)
timeFrame: From first dose of the combination agent until 1 month (28 days) after JCAR017 infusion (pre- JCAR017 cohort) or from JCAR017 infusion until 1 month (28 days) after the first dose of combination agent (post-JCAR017 cohort)
measure: Complete Response Rate (CRR)
timeFrame: At 3 and 6 months post-JCAR017 infusion.
Secondary outcomes:
measure: European Organisation for Research and Treatment of Cancer - Quality of Life C30 Questionnaire (EORTC QLQ-C30) Scores - Phase 2
timeFrame: At baseline and 29 days and 57 days post JCAR017 dose
measure: EuroQol- 5 Dimensions of Health Visual Analogue Scale (EQ-5D VAS) Scores - Phase 2
timeFrame: At baseline and 1, 29, 57, 85, 180, 270, 365, 545, and 730 days post JCAR017 dose
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Up to 3 months after the dose of JCAR017 or after the last dose of the combination agent, whichever occurred last (an average of 6.5 months up until a max of 9.5 months)
measure: Number of Participants With Severe Adverse Events (SAEs)
timeFrame: Up to 3 months after the dose of JCAR017 or after the last dose of the combination agent, whichever occurred last (an average of 6.5 months up until a max of 9.5 months)
measure: Change From Baseline in White Blood Cell and Platelet Numbers
timeFrame: 85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
measure: Change From Baseline in Percent of White Blood Cells
timeFrame: 85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
measure: Change From Baseline Erythrocyte Numbers
timeFrame: 85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
measure: Change From Baseline Hematocrit Ratio
timeFrame: 85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
measure: Change From Baseline in Hemoglobin Levels
timeFrame: 85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
measure: Change From Baseline in Specific Liver Serum Enzyme Levels
timeFrame: 85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
measure: Change From Baseline in Specific Serum Protein Levels
timeFrame: 85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
measure: Change From Baseline in Serum Beta-2-Microglobulin Levels
timeFrame: 85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
measure: Change From Baseline in Serum Bicarbonate Levels
timeFrame: 85 days after the dose of JCAR017 for Arms A, B, D, E, and F; 57 days after the dose of JCAR017 for Arm C
measure: Change From Baseline in Coagulation Times
timeFrame: 57 days after the dose of JCAR017
measure: Change From Baseline in D-Dimer Levels
timeFrame: 57 days after the dose of JCAR017
measure: Change From Baseline in Fibrinogen Levels
timeFrame: 57 days after the dose of JCAR017
measure: Change From Baseline in Prothrombin International Normalized Ratio
timeFrame: 57 days after the dose of JCAR017
measure: Progression-Free Survival (PFS)
timeFrame: From JCAR017 infusion to disease progression or death from any cause (up to approximately 62 months)
measure: Overall Survival (OS)
timeFrame: From start of JCAR017 to time of death from any cause, or data cut-off date, whichever occurred first (up to approximately 62 months)
measure: Overall Response Rate (ORR)
timeFrame: At 1, 3, 6, 9, 12, 18 and 24 months post-JCAR017 infusion
measure: Duration of Response (DOR)
timeFrame: From JCAR017 infusion to disease progression or death from any cause (up to approximately 62 months)
measure: Event-Free Survival (EFS)
timeFrame: From JCAR017 infusion to disease progression or death from any cause (up to approximately 62 months)
measure: Maximum Concentration (Cmax) of JCAR017 by qPCR
timeFrame: Up to 24 months post- JCAR017 infusion
measure: Time to Maximum Concentration (Tmax) of JCAR017 by qPCR
timeFrame: Up to 24 months post- JCAR017 infusion
measure: Total Exposure to JCAR017 as Measured by the Area Under the Curve (AUC) by qPCR
timeFrame: Up to 24 months post- JCAR017 infusion
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Local Institution - 011
state: California
city: Atlanta
country: United States
facility: Local Institution - 022
state: Georgia
city: Chicago
country: United States
facility: Local Institution - 014
state: Illinois
city: Boston
country: United States
facility: Local Institution - 012
state: Massachusetts
city: Boston
country: United States
facility: Local Institution - 021
state: Massachusetts
city: Omaha
country: United States
facility: Local Institution - 015
state: Nebraska
city: Philadelphia
country: United States
facility: Local Institution - 016
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Local Institution - 020
state: Pennsylvania
city: Houston
country: United States
facility: Local Institution - 013
state: Texas
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.