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

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ClinicalTrials.gov Identifier: NCT03310619
Recruitment Status : Recruiting
First Posted : October 16, 2017
Last Update Posted : October 30, 2018
Sponsor:
Collaborator:
Juno Therapeutics, Inc.
Information provided by (Responsible Party):
Celgene

Brief Summary:

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).


Condition or disease Intervention/treatment Phase
Lymphoma, Non-Hodgkin Lymphoma, Large B-Cell, Diffuse Lymphoma, Follicular Biological: JCAR017 Drug: Durvalumab Drug: CC-122 Phase 1 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Intervention Model: Single Group 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 28, 2017
Estimated Primary Completion Date : March 4, 2022
Estimated Study Completion Date : March 4, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Arm A: JCAR017 in combination with Durvalumab
JCAR017 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.
Biological: JCAR017
Gene modified autologous T cells

Drug: Durvalumab
Anti-PD-L1
Other Name: MEDI4736

Experimental: Arm B: JCAR017 in combination with CC-122
Will 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
Biological: JCAR017
Gene modified autologous T cells

Drug: CC-122
Pleiotropic Pathway Modifier




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 ]
    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 ]
    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)



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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 (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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03310619


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

Locations
United States, California
City of Hope National Medical Center Recruiting
Duarte, California, United States, 91010
United States, Illinois
Northwestern University School of Medicine Recruiting
Chicago, Illinois, United States, 60611-5975
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198-7680
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
Celgene
Juno Therapeutics, Inc.
Investigators
Study Director: Jens Hasskarl, PD Dr. med Celgene

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT03310619     History of Changes
Other Study ID Numbers: JCAR017-BCM-002
U1111-1201-2046 ( Registry Identifier: WHO )
First Posted: October 16, 2017    Key Record Dates
Last Update Posted: October 30, 2018
Last Verified: October 2018

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

Additional relevant MeSH terms:
Lymphoma
Neoplasms
Lymphoma, Non-Hodgkin
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Follicular
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, B-Cell