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A Safety and Efficacy Trial of JCAR017 Combinations in Subjects With Relapsed/Refractory B-cell Malignancies (PLATFORM)

  • Clinicaltrials.gov identifier

    NCT03310619

  • Recruitment Status

    Recruiting

  • First Posted

    October 16, 2017

  • Last update posted

    May 3, 2021

Study Description

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.

  • Condition or Disease:Lymphoma, Non-Hodgkin
    Lymphoma, Large B-Cell, Diffuse
    Lymphoma, Follicular
  • Intervention/Treatment: Biological: JCAR017
    Drug: Durvalumab
    Drug: CC-122
    Drug: Ibrutinib
    Drug: CC-220
    Drug: Relatlimab
    Drug: Nivolumab
    Drug: CC-99282
  • Phase: Phase 1/Phase 2

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.

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 77 participants
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • 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)
  • Actual Study Start Date: November 2017
  • Estimated Primary Completion Date: October 2024
  • Estimated Study Completion Date: October 2024

Arms and interventions

Arm Intervention/treatment
Experimental: Arm A: JCAR017 in combination with Durvalumab
JCAR017 will be administered at a single flat dose of 50 x 10^6 CAR+T cells or 100 x 10^6 CAR+T cells. The combination agent will be administered at different doses and/ or schedules
Biological: JCAR017
Gene modified autologous T cells

Drug: Durvalumab
Anti-PD-L1
Experimental: Arm B: JCAR017 in combination with CC-122
This arm will test JCAR017 in combination with the CC-122. In adult subjects with R/R aggressive B-cell NHL. JCAR017 will be administered at a dose of 100 x 10^6 CAR+T cells. The combination agent will be administered at different doses
Biological: JCAR017
Gene modified autologous T cells

Drug: CC-122
Pleiotropic Pathway Modifier
Experimental: Arm C: JCAR017 in combination with CC-220
This arm will test JCAR017 in combination with CC-220. In adult subjects with R/R aggressive B-cell NHL. JCAR017 will be administered at a dose of 100 x 10^6 CAR+T cells. The combination agent will be administered at different doses
Biological: JCAR017
Gene modified autologous T cells

Drug: CC-220
CC-220
Experimental: Arm D: JCAR017 in combination with Ibrutinib
This arm will test JCAR017 in combination with ibrutinib. In adult subjects with R/R aggressive B-cell NHL. JCAR017 will be administered at a dose of 100 x 10^6 CAR+T cells. The combination agent will be administered at a fixed dose of 420 mg daily
Biological: JCAR017
Gene modified autologous T cells

Drug: Ibrutinib
Ibrutinib
Experimental: Arm E: JCAR017 in combination with relatlimab and/or nivolumab
This arm will test JCAR017 in combination with relatlimab and/or nivolumab in adult subjects with R/R aggressive B-cell NHL. JCAR017 will be administered at a dose of 100 x 10^6 CAR+T cells. The combination agent will be administered at different doses and/or schedules
Biological: JCAR017
Gene modified autologous T cells

Drug: Relatlimab
Relatlimab

Drug: Nivolumab
Nivolumab
Experimental: Arm F: JCAR017 in combination with CC-99282
This arm will test JCAR017 in combination with CC-99282 in adult subjects with R/R aggressive B-cell NHL. JCAR017 will be administered at a dose of 100 x 10^6 CAR+T cells. The combination agent will be administered at different doses and/or schedules.
Biological: JCAR017
Gene modified autologous T cells

Drug: CC-99282
CC-99282

Outcome Measures

  • Primary Outcome Measures: 1. Dose-limiting toxicity (DLT) rates [ Time Frame: From first dose of the combination agent until 1 month (28 days) after JCAR017 infusion or from JCAR017 infusion until 1 month (28 days) after the first dose of combination agent ]
    Percentage of participants experiencing DLTs
  • 2. Complete Response Rate [ Time Frame: Up to approximately 6 months post-JCAR017 infusion ]
    Is defined as the proportion of subjects achieving a CR according to the Lugano Classification.
  • Secondary Outcome Measures: 1. Adverse Events (AEs) [ Time Frame: Up to approximately 24 months ]
    Number of participants with adverse events, type of adverse events, severity of adverse events, and number of participants with laboratory abnormalities, type of laboratory abnormalities and severity of laboratory abnormalities.
  • 2. Progression-free survival (PFS) [ Time Frame: Up to approximately 24 months post-JCAR017 infusion ]
    Time from start of JCAR017, or start of combination agent, whichever occurs first, to progressive disease (PD) or death from any cause
  • 3. Overall survival (OS) [ Time Frame: Up to approximately 3.5 years ]
    Time from start of JCAR017, or start of combination agent, whichever occurs first, to death due to any cause
  • 4. Overall response rate (ORR) [ Time Frame: Up to approximately 24 months post-JCAR017 infusion ]
    Percentage of subjects achieving an objective response of partial response (PR) or better according to the Lugano Classification
  • 5. Duration of response (DOR) [ Time Frame: Up to approximately 24 months post-JCAR017 infusion ]
    Time from first response to disease progression or death from any cause
  • 6. Event-free survival (EFS) [ Time Frame: Up to approximately 24 months post-JCAR017 infusion ]
    Time from start of JCAR017, or start of combination agent, whichever occurs first, to death from any cause, disease progression, or starting a new antilymphoma therapy whichever occurs first
  • 7. Pharmacokinetic (PK)- Cmax [ Time Frame: Up to approximately 24 months post-JCAR017 infusion ]
    Maximum observed concentration in plasma
  • 8. Pharmacokinetic (PK)- Tmax [ Time Frame: Up to approximately 24 months post-JCAR017 infusion ]
    Time to maximum concentration
  • 9. Pharmacokinetic (PK)- AUC [ Time Frame: Up to approximately 24 months post-JCAR017 infusion ]
    Area under the plasma concentration vs time curve
  • 10. Health-related quality of life (HRQoL) [ Time Frame: Up to approximately 24 months post-JCAR017 infusion ]
    Is described as parameters assessed by European Organization for Research and Treatment of Cancer
  • 11. Quality of Life C30 questionnaire (EORTC-QLQ-C30) [ Time Frame: Up to approximately 24 months post-JCAR017 infusion, for Phase I of Arm A and Arm B. ]
    EORTC-QLQ-C30 is composed of both multi-item scales and single item measures. These include five functional scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea/vomiting, and pain), a global health status/health-related quality of life (HRQoL) scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each of the multi-item scales includes a different set of items - no item occurs in more than one scale.
  • 12. European Quality of Life-5 Dimensions health state classifier to 5 Levels (EQ-5D-5L) [ Time Frame: Up to approximately 24 months post-JCAR017 infusion, for Phase I of Arm A and Arm B ]
    The EQ-5D-5L consists of the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels (no problems, slight problems, moderate problems, severe problems, extreme problems)

Eligibility Criteria

  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No

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 histologically confirmed at last relapse aggressive B-cell NHL
according to "The 2016 revision of the WHO classification of lymphoid neoplasms"
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. History of or active hepatitis B or hepatitis C or 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.

Contacts and Locations

Contacts

Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

Locations

United States, California
City of Hope National Medical Center
Duarte

United States, Illinois
Northwestern University School of Medicine
Chicago

United States, Massachusetts
Massachusetts General Hospital
Boston

United States, Nebraska
University of Nebraska Medical Center
Omaha

United States, Pennsylvania
University of Pennsylvania
Philadelphia

United States, Texas
The University of Texas MD Anderson Cancer Center
Houston

Sponsors and Collaborators

Celgene

Investigators

Study Director: Ronald Dubowy, MD Celgene

More Information

  • Responsible Party: Celgene
  • ClinicalTrials.gov Identifier: NCT03310619 History of Changes
  • Other Study ID Numbers: JCAR017-BCM-002, U1111-1201-2046
  • First Posted: October 16, 2017 Key Record Dates
  • Last Update Posted: May 3, 2021
  • Last Verified: April 2021
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Celgene: JCAR017
    B-Cell Malignancies
    NHL
    non-Hodgkin lymphoma
    CAR T cells
    chimeric antigen receptor
    CC-220
    Ibrutinib
    relatlimab
    nivolumab
    CC-99282
  • Additional relevant MeSH terms: Lymphoma
    Neoplasms
    Lymphoma, Non-Hodgkin
    Lymphoma, Large B-Cell, Diffuse
    Lymphoma, Follicular