Clinical Trials /

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

NCT03310619

Description:

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 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.

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
IbrutinibArm D: JCAR017 in combination with Ibrutinib
CC-220Arm C: JCAR017 in combination with CC-220

Purpose

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 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.

      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 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.
  • JCAR017
  • Durvalumab
Arm B: JCAR017 in combination with CC-122ExperimentalThis 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
  • JCAR017
  • CC-122
Arm C: JCAR017 in combination with CC-220ExperimentalThis arm will test JCAR017 in combination with the 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
  • JCAR017
  • CC-220
Arm D: JCAR017 in combination with IbrutinibExperimentalThis arm will test JCAR017 in combination with the 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 different doses
  • JCAR017
  • Ibrutinib

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 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 and computed tomography (CT)
                  measurable disease as per Lugano Classification

               2. Serum lactate dehydrogenase (LDH) ≥ 500 U/L and/or sum of product of
                  perpendicular diameters (SPD) of index lesions ≥ 50 cm² by CT scan (Phase 1 of
                  Arms C and D only)

          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:

               -  Basal cell carcinoma of the skin

               -  Squamous cell carcinoma of the skin

               -  Carcinoma in situ of the cervix

               -  Carcinoma in situ of the breast

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

               -  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 anti PD-1 or PD-L1 therapy (Arm A)

               -  Anti PD-1 or PD-L1 (Arm A)

               -  CC-122 (Arm B)

               -  CC-220 (Arm C)

               -  Prior treatment with ibrutinib is not exclusionary for subjects on any study arm

          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. 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

         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
      
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, for Phase I of Arm A and Arm B.
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, for Phase I of Arm A and Arm B
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
  • CC-220
  • Ibrutinib

Last Updated

February 25, 2020