A Study Evaluating the Safety and Effectiveness of JCAR017 to Treat Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Overview

About this study

The purpose of this study is to determine the effectiveness and safety of JCAR017 in adult subjects with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (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 effectiveness and safety of JCAR017 monotherapy treatment at the recommended dose. 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.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria: 

  • Age ≥ 18 years at the time of consent.
  • Signed written informed consent.
  • JCAR017 monotherapy and ibrutinib + JCAR017 combination cohorts must have diagnosis of:
    • CLL with an indication for treatment based on the Investigator’s opinion and measurable disease (any of the following: bone marrow involvement by ≥ 30% lymphocytes, peripheral blood lymphocytosis > 5 × 10^9 /L, and/or measurable lymph nodes ≥ 1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly); or
    • 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 defined as at least one lesion ≥ 1.5 cm in the greatest transverse diameter) that is biopsy-proven SLL Venetoclax + JCAR017 combination cohorts 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.
  • Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must have received and failed BTKi treatment or have been deemed ineligible for BTKi therapy due to requirement for full dose anticoagulation or history of arrhythmia. Failure to BTKi is defined as having stable disease or progressive disease (PD) as best response, or progression after previous response, or discontinuation due to intolerance. Intolerance is defined as failure to tolerate treatment due to unmanageable toxicity.
  • Subjects in the JCAR017 monotherapy cohorts must have received previous treatment as follows:
    • Subjects with CLL or SLL and high-risk features, defined as having complex cytogenetic abnormalities (3 or more chromosomal abnormalities), 17p deletion, TP53 mutation, or unmutated immunoglobulin heavy chain variable region (IGHV), must have failed at least 2 lines of prior therapy;
    • Subjects with CLL or SLL and standard-risk features must have failed at least 3 lines of prior therapy.
  • Subjects in the ibrutinib + JCAR017 combination cohorts must either:
    • be receiving ibrutinib, or other BTKi, and progressing at the time of study enrollment; or
    • be receiving ibrutinib, or other BTKi, for at least 6 months with a response less than CR and have high-risk features, as defined in inclusion criterion 5a; or
    • have BTK or phospholipase C gamma 2 (PLCγ2) mutations per local laboratory assessment, with or without progression on ibrutinib; or
    • have previously received ibrutinib, or other BTKi, and have no contraindications to initiate or reinitiate ibrutinib (i.e., ibrutinib was not discontinued due to intolerability and subject has no medical contraindications such as arrhythmia or need for anticoagulation) Subjects in the ibrutinib + JCAR017 combination therapy cohorts enrolled under at least amendment 5, must also meet the below criteria:
    • have progressed on a BTKi and f. have received prior therapy with venetoclax which is considered if they meet one of the following criteria:
      • the subject continued on venetoclax due to disease progression or intolerability and if the subject’s disease met indications for further therapy per iwCLL 2018 criteria; or
      • the subject failed to achieve an objective response within 3 months of initiating therapy. Subjects in the venetoclax + JCAR017 combination cohorts must:
    • Have failed at least 1 prior line of therapy, including having failed BTKi therapy or have been deemed ineligible to receive BTKi, as defined in Inclusion Criterion #4;
    • Be venetoclax naïve (required for dose expansion cohort); or
      • If prior venetoclax, (only for dose escalation cohort) (1) have no contraindications to reinitiation of venetoclax based on prior intolerance and (2) have had at least 6 months elapsed since the last dose of venetoclax, if either of the following criteria are met:
      • the best response was stable disease; or
      • the subject experienced disease progression on venetoclax within 6 months of venetoclax discontinuation.
  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
  • Assessed by the Investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy.
  • Adequate organ function, defined as:
    • Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance (Cockcroft and Gault) > 30 mL/min;
    • Alanine aminotransferase (ALT) ≤ 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);
    • Adequate pulmonary function, defined as ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 dyspnea and saturated oxygen (SaO2) ≥ 92% on room air;
    • Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA) scan performed within 30 days prior to determination of eligibility Subjects in the venetoclax + JCAR017 combination dose escalation and expansion cohorts must have:
      • Hemoglobin ≥ 9 g/dL, absolute neutrophil count (ANC) ≥ 500/mm^3 , and platelets ≥ 75,000/mm^3 , unless cytopenias judged by the Investigator to be due to CLL infiltration of the bone marrow.
  • 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.
  • Females of childbearing potential must either commit to true abstinence from heterosexual contact or agree to use one highly effective method of contraception from screening until at least 1 year after receiving lymphodepleting chemotherapy.
  • Females of childbearing potential must have a negative serum beta human chorionic gonadotropin (ß-hCG) pregnancy test result at screening and within 48 hours prior to the first dose of lymphodepleting therapy.
  • Males who have partners of childbearing potential must practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for at least 1 year after receiving lymphodepleting chemotherapy even if he has undergone a successful vasectomy.

Exclusion Criteria:

  • Subjects with known active central nervous system (CNS) involvement by malignancy. Subjects 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, or active hepatitis C (Subjects with a negative polymerase chain reaction (PCR) assay for viral load for hepatitis B or C are permitted; subjects positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody with negative viral load are eligible and should be considered for prophylactic antiviral therapy), or history of or active human immunodeficiency virus (HIV) infection.
  • Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
  • 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:
    • Alemtuzumab within 6 months prior to leukapheresis;
    • Allogeneic hematopoietic stem cell transplant within 100 days prior to leukapheresis;
    • Cladribine within 3 months prior to leukapheresis;
    • Donor lymphocyte infusions (DLI) within 2 months prior to leukapheresis;
    • Radiation including large bone marrow fields such as sternum or pelvis within 6 weeks prior to leukapheresis;
    • Fludarabine within 4 weeks prior to leukapheresis;
    • 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;
    • Cyclophosphamide, ifosfamide, bendamustine, chlorambucil, or melphalan within 2 weeks prior to leukapheresis;
    • Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis;
    • Anti-CD20 monoclonal antibodies within 7 days prior to leukapheresis;
    • Venetoclax within 4 days prior to leukapheresis;
    • Idelalisib or duvelisib within 2 days 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 unless progression is documented on the experimental therapy and at least 3 halflives 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.
  • 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.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Saad Kenderian, M.B., Ch.B.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Jacksonville, Fla.

Mayo Clinic principal investigator

Mohamed Kharfan Dabaja, M.D., M.B.A.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

Not yet available

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CLS-20467631

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