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Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

  • Clinicaltrials.gov identifier

    NCT03331198

  • Recruitment Status

    Recruiting

  • First Posted

    November 6, 2017

  • Last update posted

    May 7, 2021

Study Description

Brief summary:

This is a Phase 1/2, open-label, multicenter study to determine the efficacy and safety of JCAR017 in adult subjects with relapsed or refractory CLL or SLL. The study will include a Phase 1 part to determine the recommended dose of JCAR017 monotherapy in subjects with relapsed or refractory CLL or SLL, followed by a Phase 2 part to further assess the efficacy and safety of JCAR017 monotherapy treatment at the recommended dose. A separate Phase 1 cohort will assess the combination of JCAR017 and concurrent ibrutinib. Another separate Phase 1 cohort will assess the combination of JCAR017 and concurrent venetoclax. In all subjects, the safety, efficacy, and pharmacokinetics (PK) of JCAR017 will be evaluated.

  • Condition or Disease:Leukemia, Lymphocytic, Chronic, B-Cell
    Lymphoma, Small Lymphocytic
  • Intervention/Treatment: Biological: JCAR017 (lisocabtagene maraleucel)
    Biological: JCAR017 (lisocabtagene maraleucel) + ibrutinib
    Biological: JCAR017 (lisocabtagene maraleucel) + venetoclax
  • Phase: Phase 1/Phase 2

Detailed Description

N/A

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 200 participants
  • Allocation: Non-Randomized
  • Intervention Model: Parallel Assignment
  • Intervention Model Description: Phase 1: subjects will be assigned to receive JCAR017, or JCAR017 + ibrutinib Phase 2: subjects will be assigned to receive JCAR017 at the recommended dose
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: An Open-Label, Phase 1/2 Study of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (017004)
  • Actual Study Start Date: December 2017
  • Estimated Primary Completion Date: September 2022
  • Estimated Study Completion Date: December 2027

Arms and interventions

Arm Intervention/treatment
Experimental: Phase 1 JCAR017 + venetoclax
Subjects will receive venetoclax as bridging anticancer therapy until lymphodepletion chemotherapy/ JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm. After JCAR017 infusion subjects will receive venetoclax until Day 90.
Biological: JCAR017 (lisocabtagene maraleucel)
Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants will receive venetoclax as bridging anticancer therapy on a weekly ramp up dosing schedule until stopping one day prior to lymphodepletion. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection, and the day after infusion venetoclax will be re-initiated.

Biological: JCAR017 (lisocabtagene maraleucel) + venetoclax
Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants will receive venetoclax as bridging anticancer therapy on a weekly ramp up dosing schedule until stopping one day prior to lymphodepletion. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection, and the day after infusion venetoclax will be re-initiated.
Experimental: Phase 1 JCAR017 monotherapy
Subjects will be assigned to receive JCAR017 (lisocabtagene maraleucel)
Biological: JCAR017 (lisocabtagene maraleucel)
Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants will receive venetoclax as bridging anticancer therapy on a weekly ramp up dosing schedule until stopping one day prior to lymphodepletion. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection, and the day after infusion venetoclax will be re-initiated.
Experimental: Phase 2 JCAR017 monotherapy
Subjects will receive JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm
Biological: JCAR017 (lisocabtagene maraleucel)
Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants will receive venetoclax as bridging anticancer therapy on a weekly ramp up dosing schedule until stopping one day prior to lymphodepletion. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection, and the day after infusion venetoclax will be re-initiated.
Experimental: Phase 1 JCAR017 + ibrutinib
Subjects receiving ibrutinib at baseline will be assigned to receive JCAR017 (lisocabtagene maraleucel) at the recommended dose + ibrutinib
Biological: JCAR017 (lisocabtagene maraleucel) + ibrutinib
Participants eligible for this cohort should be receiving ibrutinib at the time of screening. For participants who previously discontinued ibrutinib, ibrutinib will be started as soon as possible after eligibility is confirmed. Ibrutinib treatment will continue for up to 90 days after JCAR017 infusion (or longer for participants who are receiving benefit from ibrutinib). Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants may receive bridging chemotherapy for disease control. Upon successful generation of JCAR017 product, participants will receive treatment with JCAR017 therapy. Each cycle will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection.

Outcome Measures

  • Primary Outcome Measures: 1. Phase 1 JCAR017 and ibrutinib combination dose escalation therapy arm: adverse events [ Time Frame: Through post treatment Day 90 ]
    Proportion of subjects experiencing adverse events
  • 2. Phase 1 JCAR017 and ibrutinib combination dose escalation therapy arm: laboratory abnormalities [ Time Frame: Through post treatment Day 90 ]
    Proportion of subjects experiencing laboratory abnormalities
  • 3. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm [ Time Frame: Through post treatment up to Month 48 ]
    Proportion of subjects who have CR after treatment with JCAR017 + ibrutinib using iwCLL 2018 guidelines
  • 4. Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm [ Time Frame: Through post treatment Day 90 ]
    Recommended dose of venetoclax in combination with JCAR017 based on assessment of data from each dose level of venetoclax
  • 5. Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: adverse events [ Time Frame: Through post treatment Day 90 ]
    Proportion of subjects experiencing adverse events
  • 6. Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: laboratory abnormalities [ Time Frame: Through post treatment Day 90 ]
    Proportion of subjects experiencing laboratory abnormalities
  • 7. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm [ Time Frame: Through post treatment up to Month 48 ]
    Proportion of subjects who have CR after treatment with JCAR017 + venetoclax using iwCLL 2018 guidelines
  • Secondary Outcome Measures: 1. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: ORR [ Time Frame: Up to 48 months post treatment ]
    Defined as the rate of CR (including CRi)
  • 2. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: adverse events [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects experiencing adverse events
  • 3. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: laboratory abnormalities [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects experiencing laboratory abnormalities
  • 4. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: MRD negative response rate in peripheral blood [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects who achieve MRD CR
  • 5. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: MRD-negative CR rate in peripheral blood [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects who achieve MRD CR
  • 6. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Duration of response (DOR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from first response (CR, CRi, nPR, or PR) to the earlier date of PD or death due to any cause
  • 7. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Duration of complete response (DoCR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from first CR or CRi to the earlier date of PD or death due to any cause
  • 8. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Time to response (TTR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the interval from JCAR017 infusion to the first documentation of CR, CRi, nPR, or PR
  • 9. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: PFS [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from JCAR017 infusion to the earlier date of PD or death due to any cause
  • 10. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: OS [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from JCAR017 infusion to the date of death due to any cause
  • 11. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Time to complete response (TTCR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the interval from JCAR017 infusion to the first documentation of CR
  • 12. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: ORR [ Time Frame: Through post treatment Day 90 ]
    Defined as the rate of CR (including CRi)
  • 13. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: adverse events [ Time Frame: Up to 48 months post treatment ]
    Proportion of subject experiencing adverse events
  • 14. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: lab abnormalities [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects experiencing laboratory abnormalities
  • 15. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: MRD-negative response rate in peripheral blood [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects who achieve MRD CR
  • 16. Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: MRD-negative CR rate in peripheral blood [ Time Frame: Through post treatment Day 90 ]
    Proportion of subjects who achieve MRD CR
  • 17. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Duration of response (DOR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from first response (CR, CRi, nPR, or PR) to the earlier date of PD or death due to any cause
  • 18. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Duration of complete response (DoCR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from first CR or CRi to the earlier date of PD or death due to any cause
  • 19. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Time to response (TTR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the interval from JCAR017 infusion to the first documentation of CR, CRi, nPR, or PR
  • 20. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Time to complete response (TTCR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the interval from JCAR017 infusion to the first documentation of CR
  • 21. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: PFS [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from JCAR017 infusion to the earlier date of PD or death due to any cause
  • 22. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: OS [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from JCAR017 infusion to the date of death due to any cause

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:

- Diagnosis of:

1. CLL with an indication for treatment based on the Investigator's opinion and
measurable disease, or

2. SLL (lymphadenopathy and/or splenomegaly and < 5×10^9 CD19+ CD5+ clonal B lymphocytes/L [ 30 mL/min

2. Alanine aminotransferase ≤ 5 × ULN and total bilirubin < 2.0 mg/dL (or =9 g/dL,
absolute neutrophil count >=500mm3 and platelets>= 75,000/mm3, unless cytopenias are
judged by investigator to be due to CLL infiltration of the bone marrow

- must have diagnosis of CLL or SLL with an indication for treatment based on the
investigator's opinion and measurable disease (any of the following measurable lymph
nodes ≥1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly)
and demonstration of CLL cells in the peripheral blood by flow cytometry

Exclusion Criteria:

- Subjects with known active central nervous system (CNS) involvement by malignancy.
Those with prior CNS disease that has been effectively treated will be eligible if
treatment was completed at least 3 months prior to enrollment with no evidence of
symptomatic disease and stable abnormalities on repeat imaging.

- History of another primary malignancy that has not been in remission for at least 2
years. (The following are exempt from the 2-year limit: nonmelanoma skin cancer,
completely resected stage 1 solid tumor with low risk for recurrence, curatively
treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous
intraepithelial lesion on Pap smear, and in situ breast cancer that has been
completely resected.)

- Subjects with Richter's transformation

- Prior treatment with any gene therapy product

- Active hepatitis B, active hepatitis C, or active human immunodeficiency virus (HIV)
infection

- Systemic fungal, bacterial, viral, or other infection that is not controlled

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

- 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

- History or presence of clinically relevant CNS pathology such as epilepsy, generalized
seizure disorder, aphasia, stroke with current neurologic sequelae, severe brain
injuries, dementia, Parkinson's disease, cerebellar disease,cerebral edema, or
psychosis

- Pregnant or nursing (lactating) women

- Use of any of the following medications or treatments within the noted time prior to
leukapheresis:

1. Alemtuzumab within 6 months prior to leukapheresis

2. Allogeneic hematopoietic stem cell transplant within 100 days prior to
leukapheresis

3. Cladribine within 3 months prior to leukapheresis

4. Donor lymphocyte infusions (DLI) within 2 months prior to leukapheresis

5. Radiation including large bone marrow fields such as sternum or pelvis within 6
weeks prior to leukapheresis

6. Fludarabine within 4 weeks prior to leukapheresis

7. GVHD therapies such as calcineurin inhibitors, methotrexate or other
chemotherapeutics, mycophenolate mofetil, rapamycin, or immunosuppressive
antibodies (such as anti-tumor necrosis factor-α [TNFα], anti-interleukin-6
[IL-6], or anti-interleukin-6 receptor [IL 6R]) within 4 weeks prior to
leukapheresis

8. Cyclophosphamide, ifosfamide, bendamustine, chlorambucil, or melphalan within 2
weeks prior to leukapheresis

9. Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or
equivalent) within 7 days prior to leukapheresis

10. Anti-CD20 monoclonal antibodies within 7 days prior to leukapheresis

11. Venetoclax within 4 days prior to leukapheresis

12. Idelalisib or duvelisib within 2 days prior to leukapheresis

13. Lenalidomide within 1 day prior to leukapheresis

14. Experimental agents, including off-label use of approved drugs (with the
exception of acalabrutinib which may be continued up to the day before
leukapheresis), within 4 weeks prior to leukapheresis unless progression is
documented on the experimental therapy and at least 3 half-lives have elapsed
prior to leukapheresis

- Uncontrolled medical, psychological, familial, sociological, or geographical
conditions that do not permit compliance with the protocol, as judged by the
Investigator; or subject unwillingness or inability to follow the procedures required
in the protocol

- Progressive vascular tumor invasion, thrombosis, or embolism

- Deep vein thrombosis or embolism not managed on a stable regimen of anticoagulation

- Use of any of the following medications or treatments within the noted time prior to
leukapheresis lenalidomide or acalabrutinib within 1 day prior to leukapheresis
experimental agents, including off-label use of approved drugs, within 4 weeks prior
to leukapheresis.

- Venous thrombosis or embolism requiring treatment but not managed on a stable regimen
of anticoagulation

- For subjects in the venetoclax + JCAR017 combination cohorts only, concomitant
treatment with CYP3A moderate/strong inducers or moderate/strong inhibitors which
cannot be discontinued

Contacts and Locations

Contacts

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

Locations

United States, Alabama
University of Alabama at Birmingham
Birmingham

United States, Arizona
Banner MD Anderson Cancer Center
Gilbert

United States, California
City of Hope
Duarte

United States, California
UC San Diego Moores Cancer Center
La Jolla

United States, California
University of California, Los Angeles
Los Angeles

United States, California
University of California, San Francisco
San Francisco

United States, District of Columbia
Georgetown University Medical Center
Washington

United States, Florida
Mayo Clinic
Jacksonville

United States, Georgia
The Blood and Marrow Transplant Group of Georgia (BMTGA)
Atlanta

United States, Illinois
Northwestern University
Chicago

United States, Illinois
University of Chicago Medical Center
Chicago

United States, Massachusetts
Massachusetts General Hospital
Boston

United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston

United States, Michigan
University of Michigan Comprehensive Cancer Center
Ann Arbor

United States, Michigan
Barbara Ann Karmanos Cancer Institute
Detroit

United States, Minnesota
Mayo Clinic
Rochester

United States, Nebraska
University of Nebraska Medical Center
Omaha

United States, New Jersey
Hackensack University Medical Center
Hackensack

United States, New Jersey
Rutgers Cancer Institute of New Jersey
New Brunswick

United States, New York
Columbia University Medical Center
New York

United States, New York
Weill Cornell Medical College
New York

United States, North Carolina
Duke University Medical Center
Durham

United States, Ohio
University Hospitals Seidman Cancer Center (Case Western)
Cleveland

United States, Oklahoma
University of Oklahoma Health Sciences Center (Stephenson Cancer Center)
Oklahoma City

United States, Pennsylvania
University of Pennsylvania Perelman Center for Advanced Medicine
Philadelphia

United States, Pennsylvania
Thomas Jefferson University
Philadelphia

United States, Pennsylvania
UPMC Hillman Cancer Center
Pittsburgh

United States, Texas
Baylor University Medical Center
Dallas

United States, Texas
University of Texas Southwestern Medical Center
Dallas

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

United States, Utah
Huntsman Cancer Institute
Salt Lake City

United States, Virginia
Virginia Commonwealth University
Richmond

United States, Washington
Fred Hutchinson Cancer Research Center
Seattle

United States, Wisconsin
Medical College of Wisconsin
Milwaukee

Sponsors and Collaborators

Juno Therapeutics, a Subsidiary of Celgene

Investigators

Study Director: Heidi Gillenwater, MD Juno Therapeutics, Inc.

More Information

  • Responsible Party: Juno Therapeutics, a Subsidiary of Celgene
  • ClinicalTrials.gov Identifier: NCT03331198 History of Changes
  • Other Study ID Numbers: 017004, TRANSCEND-CLL-004
  • First Posted: November 6, 2017 Key Record Dates
  • Last Update Posted: May 7, 2021
  • Last Verified: April 2021
  • Individual Participant
    Data (IPD) Sharing
    Statement:

  • Plan to Share IPD: Undecided
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Juno Therapeutics, a Subsidiary of Celgene: TRANSCEND_CLL_004
  • Additional relevant MeSH terms: Lymphoma
    Leukemia
    Leukemia, Lymphoid
    Leukemia, Lymphocytic, Chronic, B-Cell