Clinical Trials /

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

NCT03310619

Description:

This is an open-label, multi-arm, 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. The first combination, defined as Arm A, will evaluate JCAR017 in combination with durvalumab. The second combination, defined as Arm B, will evaluate JCAR017 in combination with CC-122.Within each arm, cohorts and subcohorts will test different doses and/or schedules of the combination agent(s). The study will consist of 2 parts: dose finding (Phase 1) and dose expansion (Phase 2).

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Grade 3b Follicular Lymphoma
  • Mediastinal Large B-Cell Lymphoma
  • Non-Hodgkin Lymphoma
  • T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: JCAR017-BCM-002
  • SECONDARY ID: U1111-1201-2046
  • NCT ID: NCT03310619

Conditions

  • Lymphoma, Non-Hodgkin
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Follicular

Interventions

DrugSynonymsArms
JCAR017Arm A: JCAR017 in combination with Durvalumab
DurvalumabMEDI4736Arm A: JCAR017 in combination with Durvalumab
CC-122Arm B: JCAR017 in combination with CC-122

Purpose

This is an open-label, multi-arm, 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. The first combination, defined as Arm A, will evaluate JCAR017 in combination with durvalumab. The second combination, defined as Arm B, will evaluate JCAR017 in combination with CC-122.Within each arm, cohorts and subcohorts will test different doses and/or schedules of the combination agent(s). The study will consist of 2 parts: dose finding (Phase 1) and dose expansion (Phase 2).

Detailed Description

      This is a global, open-label, multi-arm, 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.

      During the Phase 1 part, different arms may be opened to test JCAR017 in combination with
      combination agent(s). 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 the
      Phase 2 part of the study, the expansion of any dose level and schedule that has been shown
      to be safe may occur.

      Arm A will test JCAR017 in combination with durvalumab in adult subjects with R/R aggressive
      B-cell NHL.

      Arm B, will evaluate JCAR017 in combination with CC-122 in adult subjects with R/R aggressive
      B-cell NHL.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: JCAR017 in combination with DurvalumabExperimentalJCAR017 will be administered at a single flat dose of 5 x 10^7 CAR+T cells or 1 x 10^8 CAR+T cells. The combination agent will be administered at different doses and/ or schedules.
  • JCAR017
  • Durvalumab
Arm B: JCAR017 in combination with CC-122ExperimentalWill test JCAR017 in combination with CC-122 in adult subjects with R/R aggressive B-cell NHL. JCAR017 will be administered at a dose of 1 x 10^8 CAR+T cells. The combination agent will be administered at different doses
  • JCAR017
  • CC-122

Eligibility Criteria

        Inclusion Criteria:

          1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).

          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 positron emission tomography (PET)-positive disease as per Lugano
             Classification

          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 as detailed in the protocol

         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:

          5. Basal cell carcinoma of the skin

          6. Squamous cell carcinoma of the skin

          7. Carcinoma in situ of the cervix

          8. Carcinoma in situ of the breast

          9. Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor,
             nodes, metastasis] clinical staging system) or prostate cancer that is curative.

         10. Other completely resected stage 1 solid tumor with low risk for recurrence

         11. Prior treatment with any prior gene therapy product

         12. Prior treatment with any adoptive T cell therapy; prior hematopoietic stem cell
             transplant (HSCT) is allowed

         13. Allogeneic HSCT within 90 days of leukapheresis

         14. Prior treatment with anti PD-1 or PD-L1 therapy (Arm A)

         15. Prior use of CC-122 (Arm B)

         16. Presence of acute or chronic graft-versus-host disease (GVHD)

         17. History of or active hepatitis B or hepatitis C or human immunodeficiency virus (HIV)
             infection

         18. Uncontrolled bacterial, viral or fungal infection at the time of leukapheresis,
             lymphodepleting chemotherapy or JCAR017 infusion

         19. 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

         20. 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

         21. Subjects with active CNS or cerebrospinal fluid (CSF) involvement by malignancy

         22. Pregnant or nursing (lactating) women.

         23. Subjects with active auto immune disorders/processes or active neurological or
             inflammatory disorders

         24. Treatment with alemtuzumab within 6 months of leukapheresis, or treatment with
             fludarabine or cladribine within 3 months of leukapheresis

         25. Use of the following:

         26. Therapeutic doses of corticosteroids within 7 days of leukapheresis or 72 hours prior
             to JCAR017 administration. Physiologic replacement, topical, inhaled, and intranasal
             steroids are permitted.

         27. Low dose chemotherapy given after leukapheresis to maintain disease control must be
             stopped ≥ 7 days prior to lymphodepleting chemotherapy.

         28. Cytotoxic chemotherapeutic agents that are not considered lymphotoxic within 1 week of
             leukapheresis. Oral chemotherapeutic agents are allowed if at least 3 half-lives have
             elapsed prior to leukapheresis.

         29. Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide, ifosfamide, bendamustine)
             within 2 weeks of leukapheresis.

         30. Experimental agents within 4 weeks of leukapheresis unless no response or disease
             progression is documented on the experimental therapy and at least 3 half-lives have
             elapsed prior to leukapheresis.

         31. GVHD therapies within 4 weeks of leukapheresis and JCAR017 administration.

         32. Donor lymphocyte infusions (DLI) within 6 weeks of JCAR017 administration

         33. Radiation within 6 weeks of leukapheresis.

         34. Live attenuated vaccines within 90 days prior to leukapheresis.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Percentage of participants experiencing DLTs

Secondary Outcome Measures

Measure:Adverse Events (AEs)
Time Frame:Up to approximately 24 months
Safety Issue:
Description: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.
Measure:Progression-free survival (PFS)
Time Frame:Up to approximately 24 months post-JCAR017 infusion
Safety Issue:
Description:Time from start of JCAR017, or start of combination agent, whichever occurs first, to progressive disease (PD) or death from any cause
Measure:Overall survival (OS)
Time Frame:Up to approximately 3.5 years
Safety Issue:
Description:Time from start of JCAR017, or start of combination agent, whichever occurs first, to death due to any cause
Measure:Overall response rate (ORR)
Time Frame:Up to approximately 24 months post-JCAR017 infusion
Safety Issue:
Description:Percentage of subjects achieving an objective response of partial response (PR) or better according to the Lugano Classification
Measure:Duration of response (DOR)
Time Frame:Up to approximately 24 months post-JCAR017 infusion
Safety Issue:
Description:Time from first response to disease progression or death from any cause
Measure:Event-free survival (EFS)
Time Frame:Up to approximately 24 months post-JCAR017 infusion
Safety Issue:
Description: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
Measure:Pharmacokinetic (PK)- Cmax
Time Frame:Up to approximately 24 months post-JCAR017 infusion
Safety Issue:
Description:Maximum observed concentration in plasma
Measure:Pharmacokinetic (PK)- Tmax
Time Frame:Up to approximately 24 months post-JCAR017 infusion
Safety Issue:
Description:Time to maximum concentration
Measure:Pharmacokinetic (PK)- AUC
Time Frame:Up to approximately 24 months post-JCAR017 infusion
Safety Issue:
Description:Area under the plasma concentration vs time curve
Measure:Health-related quality of life (HRQoL)
Time Frame:Up to approximately 24 months post-JCAR017 infusion
Safety Issue:
Description:Is described as parameters assessed by European Organization for Research and Treatment of Cancer
Measure:Quality of Life C30 questionnaire (EORTC-QLQ-C30)
Time Frame:Up to approximately 24 months post-JCAR017 infusion
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celgene

Trial Keywords

  • JCAR017
  • B-Cell Malignancies
  • NHL
  • non-Hodgkin lymphoma
  • CAR T cells
  • chimeric antigen receptor

Last Updated