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Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory CLL or SLL (TRANSCEND-CLL-004)

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ClinicalTrials.gov Identifier: NCT03331198
Recruitment Status : Recruiting
First Posted : November 6, 2017
Last Update Posted : March 5, 2018
Sponsor:
Information provided by (Responsible Party):
Juno Therapeutics, Inc.

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 randomized part to assess JCAR017 monotherapy treatment versus standard of care. A separate Phase 1 cohort will assess the combination of JCAR017 and concurrent ibrutinib. In all subjects, the safety, efficacy, and pharmacokinetics (PK) of JCAR017 will be evaluated.

Condition or disease Intervention/treatment Phase
Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, Small Lymphocytic Biological: JCAR017 (lisocabtagene maraleucel) Biological: JCAR017 (lisocabtagene maraleucel) + ibrutinib Drug: Standard of care Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 205 participants
Allocation: 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 randomized to receive JCAR017 or standard of care. Patients who receive standard of care may cross over to receive JCAR017 in the event of disease progression.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Phase 1 Safety and Phase 2 Randomized Study of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (017004)
Actual Study Start Date : December 26, 2017
Estimated Primary Completion Date : October 1, 2019
Estimated Study Completion Date : March 1, 2021


Arm Intervention/treatment
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 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.

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, and ibrutinib treatment will continue. 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.

Experimental: Phase 2 JCAR017
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 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.

Active Comparator: Phase 2 control
Subjects will receive standard of care treatment
Drug: Standard of care
Participants will receive standard-of-care therapy. These participants may cross over to receive treatment with JCAR017 at the time of progression.




Primary Outcome Measures :
  1. Phase 1 monotherapy arm: recommended dose [ Time Frame: 28 days ]
    Recommended dose based on assessment of data from each dose level

  2. Phase 1 combination therapy arm: adverse events [ Time Frame: 30 days ]
    Proportion of subjects experiencing adverse events

  3. Phase 1 combination therapy arm: laboratory abnormalities [ Time Frame: 30 days ]
    Proportion of subjects experiencing laboratory abnormalities

  4. Phase 2: antitumor activity [ Time Frame: through post-randomization Month 24 ]
    Complete response rate based on Independent Review Committee assessment using iwCLL 2008 guidelines


Secondary Outcome Measures :
  1. Phase 2: adverse events [ Time Frame: 30 days ]
    Proportion of subjects experiencing adverse events

  2. Phase 2: laboratory abnormalities [ Time Frame: 30 days ]
    Proportion of subjects experiencing laboratory abnormalities

  3. Phase 2: overall response rate [ Time Frame: Through post-randomization Month 24 ]
    Overall response rate based on Independent Review Committee assessment using iwCLL 2008 guidelines

  4. Phase 2: minimal residual disease (MRD)-negative response rate [ Time Frame: Through post-randomization Month 24 ]
    MRD will be measured via IgHV deep sequencing and flow cytometry of peripheral blood and bone marrow

  5. Phase 2: overall survival [ Time Frame: Through post-randomization Month 24 ]
    Overall survival

  6. Phase 2: Progression-free survival [ Time Frame: Through post-randomization Month 24 ]
    Progression-free survival

  7. Phase 2: PK [ Time Frame: Through post-randomization Month 24 ]
    AUC of JCAR017 in blood and bone marrow

  8. Phase 2: PK [ Time Frame: Through post-randomization Month 24 ]
    Cmax of JCAR017 in blood and bone marrow

  9. Phase 2: PK [ Time Frame: Through post-randomization Month 24 ]
    Tmax of JCAR017 in blood and bone marrow

  10. Phase 2: health-related quality of life and health economics and outcomes research [ Time Frame: Through post-randomization Month 24 ]
    EuroQol instrument EQ-5D-5L Numbers of intensive care unit (ICU) inpatient days and non-ICU inpatient days

  11. Phase 2: health-related quality of life and health economics and outcomes research [ Time Frame: Through post-randomization Month 24 ]
    EORTC QLQ-C30 Numbers of intensive care unit (ICU) inpatient days and non-ICU inpatient days

  12. Phase 2: health-related quality of life and health economics and outcomes research [ Time Frame: Through post-randomization Month 24 ]
    CLL-specific module QLQ-CLL Numbers of intensive care unit (ICU) inpatient days and non-ICU inpatient days



Information from the National Library of Medicine

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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:

  • Diagnosis of:

    1. CLL with an indication for treatment based on iwCLL guidelines and clinical measurable disease, or
    2. SLL (lymphadenopathy and/or splenomegaly and < 5×10^9 CD19+ CD5+ clonal B lymphocytes/L [< 5000/µL] in the peripheral blood at diagnosis with measurable disease that is biopsy-proven SLL)
  • Subjects (other than those in the ibrutinib + JCAR017 combination therapy arm) must have received and failed Bruton tyrosine kinase inhibitor (BTKi) treatment or have been deemed ineligible for BTKi therapy.
  • Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must have received previous treatment as follows:

    1. Subjects with CLL or SLL and high-risk features must have failed at least 2 lines of prior therapy, including a BTKi.
    2. Subjects with CLL or SLL and standard-risk features must have failed at least 3 lines of prior therapy, including a BTKi.
    3. Subjects with CLL or SLL who are BTKi intolerant and have received < 6 months of BTKi therapy or are ineligible for BTKi must have failed at least 1 (high-risk) or 2 (standard-risk) other lines of non-BTKi therapy.
  • Subjects in the ibrutinib + JCAR017 combination therapy cohort must be either:

    1. receiving ibrutinib and progressing at the time of study enrollment
    2. receiving ibrutinib for at least 6 months with a response less than CR and have high-risk features as defined in inclusion criterion 5a
    3. have BTK or PLCgamma2 mutations per local laboratory assessment, with or without progression on ibrutinib
  • Eastern Cooperative Oncology Group performance status of ≤ 1
  • Assessed by the Investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy
  • Adequate organ function, defined as:

    1. Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance > 30 mL/min
    2. Alanine aminotransferase ≤ 5 × ULN and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert's syndrome or leukemic infiltration of the liver)
    3. Adequate pulmonary function, defined as ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 dyspnea and saturated oxygen (SaO2) ≥ 92% on room air
    4. Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40% as assessed by echocardiogram or multiple uptake gated acquisition scan performed within 30 days prior to determination of eligibility
  • Subject either currently has central vascular access or is a candidate to receive central vascular access or peripheral vascular access for leukapheresis procedure.
  • If prior CD19-targeted therapy has been administered, subject must have CD19-positive disease confirmed by immunohistochemistry or flow cytometry since completing the prior CD19-targeted therapy.

Exclusion Criteria:

  • Subjects with known active 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 any 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, paresis, aphasia, stroke with current neurologic sequelae, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, 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 within 2 days prior to leukapheresis
    13. Lenalidomide within 1 day prior to leukapheresis
    14. Experimental agents, including off-label use of approved drugs, 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

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): NCT03331198


Contacts
Contact: Juno Medical Information 866-599-JUNO (5866) medicalinformation@junotherapeutics.com

Locations
United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Cara Nolan    626-218-3241    canolan@coh.org   
Principal Investigator: Tanya Siddiqi, MD         
United States, Illinois
University of Chicago Medical Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Sadi Dixon, RN    773-702-2070    sdixon2@medicine.bsd.uchicago.edu   
Contact: Preeti Karmali    773-702-9440    pkarmali@medicine.bsd.uchicago.edu   
Principal Investigator: Peter Riedell, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Jacob D Soumerai, MD    617-724-4000    jsoumerai@mgh.harvard.edu   
Principal Investigator: Jacob D Soumerai, MD         
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Emma Logan, RN    617-667-5984    eklogan@bidmc.harvard.edu   
Principal Investigator: Jon Arnason, MD         
United States, Pennsylvania
UPMC Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Linda Fukas         
Contact    412-623-6037    fukaslj@upmc.edu   
Principal Investigator: Kathleen Dorritie, MD         
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: William G Wierda, MD, PhD    713-792-7026    wwierda@mdanderson.org   
Principal Investigator: William G Wierda, MD, PhD         
Sponsors and Collaborators
Juno Therapeutics, Inc.
Investigators
Study Director: Heidi Gillenwater, MD Juno Therapeutics, Inc.

Responsible Party: Juno Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03331198     History of Changes
Other Study ID Numbers: 017004
First Posted: November 6, 2017    Key Record Dates
Last Update Posted: March 5, 2018
Last Verified: February 2018
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, Inc.:
JCAR017
chimeric antigen receptor
CLL
SLL
chronic lymphocytic leukemia
small lymphocytic lymphoma
CAR
CAR T cells
autologous T cell therapy
immunotherapy

Additional relevant MeSH terms:
Lymphoma
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell