Clinical Trials /

Trial to Determine the Efficacy and Safety of JCAR017 in Adult Subjects With Aggressive B-Cell Non-Hodgkin Lymphoma

NCT03484702

Description:

Phase 2 single-arm, multi-cohort study to determine the efficacy and safety of JCAR017 (autologous T cells expressing anti-CD19 chimeric antigen receptor) in adult subjects with aggressive B-NHL (diffuse large B-cell lymphoma (DLBCL) NOS [de novo or transformed follicular lymphoma (tFL)], double/triple-hit lymphoma [DHL/THL], follicular lymphoma Grade 3B [FL3B], primary central nervous system lymphoma [PCNSL] and Richter's transformation).

Related Conditions:
  • B-Cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Double-Hit Lymphoma
  • Grade 3b Follicular Lymphoma
  • Primary Central Nervous System Lymphoma
  • Richter Syndrome
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial to Determine the Efficacy and Safety of JCAR017 in Adult Subjects With Aggressive B-Cell Non-Hodgkin Lymphoma
  • Official Title: A Phase 2, Single-arm, Multi-center Trial to Determine the Efficacy and Safety of JCAR017 in Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma or With Other Aggressive B-Cell Malignancies

Clinical Trial IDs

  • ORG STUDY ID: JCAR017-BCM-001
  • SECONDARY ID: U1111-1209-4055
  • SECONDARY ID: 2017-000106-38
  • NCT ID: NCT03484702

Conditions

  • Lymphoma, Non-Hodgkin

Interventions

DrugSynonymsArms
JCAR017Administration of JCAR017

Purpose

Phase 2 single-arm, multi-cohort study to determine the efficacy and safety of JCAR017 (autologous T cells expressing anti-CD19 chimeric antigen receptor) in adult subjects with aggressive B-NHL (diffuse large B-cell lymphoma (DLBCL) NOS [de novo or transformed follicular lymphoma (tFL)], double/triple-hit lymphoma [DHL/THL], follicular lymphoma Grade 3B [FL3B], primary central nervous system lymphoma [PCNSL] and Richter's transformation).

Detailed Description

      This is a single-arm, multi-cohort, multi-center, Phase 2 study to determine the efficacy and
      safety of JCAR017 in adult subjects with aggressive B-cell NHL. The study will enroll
      subjects in Europe and Japan with DLBCL NOS (de novo or tFL), high-grade B-cell lymphoma with
      MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL), FL3B, PCNSL and
      Richter's transformation. Subjects with secondary central nervous system (CNS) involvement
      are allowed.

      Once enrolled subjects will undergo leukapheresis to enable JCAR017 cell product generation.
      Upon successful JCAR017 cell product generation, subjects will receive LD followed by
      infusion of JCAR017. JCAR017 will be administered at a dose of 1 x 10^8 JCAR017-positive
      transfected viable T cells by intravenous infusion.

      Subjects will be followed for approximately 2 years after their JCAR017 infusion for safety,
      disease status, survival and health-related quality of life. Delayed adverse events following
      exposure to gene modified T cells will be assessed and long-term persistence of these
      modified T cells will continue to be monitored under a separate long-term follow-up protocol
      for up to 15 years after JCAR017 infusion as per competent authority guidelines.
    

Trial Arms

NameTypeDescriptionInterventions
Administration of JCAR017ExperimentalJCAR017 will be infused at a dose of 1 x 10^8 JCAR017-positive transfected viable T cells (5×10^7 CD8+ CAR+ T cells and 5×10^7 CD4+ CAR+ T cells), on Day 1 (2 to 7 days after completion of lymphodepleting chemotherapy [LD]).
  • JCAR017

Eligibility Criteria

        Inclusion Criteria:

        Subjects must satisfy the following criteria to be enrolled in the study:

          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. Investigator considers the subject is appropriate for adoptive T cell therapy.

          5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

          6. Subjects with one of the following:

               -  Cohort 1: Subjects with DLBCL NOS (de novo or tFL), high-grade B-cell lymphoma
                  with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) and
                  FL3B per WHO 2016 classification, after ≥ 2 lines of therapy, including an
                  anthracycline and rituximab (or other CD20-targeted agent).

               -  Cohort 2: Transplant not eligible subjects with DLBCL NOS (de novo or tFL), high
                  grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL
                  histology (DHL/THL) and FL3B per WHO 2016 classification, who failed first line
                  therapy including an anthracycline and rituximab (or other CD20-targeted agent).

                    -  Transplant not eligible subjects will include those who are deemed
                       ineligible for high-dose chemotherapy and HSCT due to age, performance
                       status or comorbidity. At the very least, subjects have to meet one of the
                       following criteria: age ≥ 70 years, ECOG performance status ≥ 2, impaired
                       pulmonary function DLCO ≤ 60%), impaired cardiac function (LVEF < 50%),
                       impaired renal function (CrCl < 60 mL/min/1.73m2) or impaired hepatic
                       function (AST/ALT > 2x ULN, bilirubin > 2 mg/dL or cirrhosis Child-Pugh B or
                       C).

               -  Cohort 3 (Japan only): Subjects meeting eligibility criteria for either Cohort 1
                  or 2.

               -  Cohort 4: Subjects with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6
                  rearrangements with DLBCL histology (DHL/THL) who failed first line therapy.
                  Subjects may be screened at time of initial diagnosis and leukapheresis may be
                  performed prior to initiation of first line therapy.

               -  Cohort 5: Subjects with PCNSL after ≥ 1 line of therapy, including high-dose
                  methotrexate.

               -  Cohort 6: Subjects with Richter's transformation after ≥ 1 line of therapy for
                  Richter's transformation.

             Note: Subjects with secondary DLBCL CNS involvement are eligible (not applicable for
             Cohort 5).

          7. Histological confirmation of diagnosis at last relapse. Enough tumor material must be
             available for central confirmation of diagnosis, otherwise a new tumor biopsy is
             mandated. NOTE: if subsequent therapies are given after last relapse with SD/PD as
             best response, the tissue from that last relapse will be considered adequate to
             participate in the trial.

          8. For subjects with NHL and Richter's transformed CLL: Subject must have positron
             emission tomography (PET)-positive disease as per Lugano Classification.

          9. For subjects with PCNSL: Subjects must have disease that is objectively measurable by
             International Workshop to Standardize Baseline Evaluation and Response Criteria in
             Primary Central Nervous System (CNS) Lymphoma, cerebrospinal fluid (CSF) cytology (in
             case of leptomeningeal only disease), or vitreal aspiration cytology and/or retinal
             photographs (in case of ocular lymphoma if clinically indicated).

         10. Adequate organ function, defined as:

               -  Adequate bone marrow function to receive LD chemotherapy as assessed by the
                  Investigator.

               -  Serum creatinine < 1.5 x age-adjusted upper limit of normal (ULN) or creatinine
                  clearance > 30 mL/min (estimated glomerular filtration rate [eGFR] by
                  Cockroft-Gault).

               -  Alanine aminotransferase (ALT) ≤ 5 x ULN and total bilirubin < 2.0 mg/dL (or <
                  3.0 mg/dL for subjects with Gilbert's syndrome or lymphomatous infiltration of
                  the liver).

               -  Adequate pulmonary function, defined as ≤ Grade 1 dyspnea according to Common
                  Toxicity Criteria for Adverse Events (CTCAE) and SaO2 ≥ 92% on room air.

               -  Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥
                  40% as assessed by echocardiogram or multigated acquisition (MUGA) scan performed
                  within 4 weeks prior to leukapheresis.

         11. Adequate vascular access for leukapheresis procedure.

         12. Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for
             usage in other individuals until at least 12 months after the JCAR017 infusion and
             until CAR T cells are no longer present by quantitative polymerase chain reaction
             (qPCR) on two consecutive tests, whichever occurs last.

         13. Female subjects of childbearing potential (FCBP) must:

               -  Have two negative pregnancy tests as verified by the Investigator (one negative
                  serum beta human chorionic gonadotropin [ß-hCG] pregnancy test result at
                  screening and one negative serum pregnancy test within 48 hours prior to the
                  first dose of LD chemotherapy). Subjects must agree to have another pregnancy
                  test performed 90 days post JCAR017 infusion. This applies even if the subject
                  practices true abstinence* from heterosexual contact.

               -  Either commit to true abstinence* from heterosexual contact (which must be
                  reviewed on a monthly basis and source documented) or agree to use, and be able
                  to comply with, effective contraception without interruption. Contraception
                  methods must include 1 highly effective and 1 additional effective (barrier)
                  method of contraception from screening until at least 12 months following JCAR017
                  infusion and until CAR T cells are no longer present by qPCR on two consecutive
                  tests, whichever occurs last.

               -  Agree to abstain from breastfeeding during study participation and for at least
                  90 days after JCAR017 infusion and until CAR T cells are no longer present by
                  qPCR on two consecutive tests, whichever occurs last.

         14. Male subjects must:

               -  Practice true abstinence* (which must be reviewed on a monthly basis and source
                  documented) or agree to use a condom during sexual contact with a pregnant female
                  or a female of childbearing potential while participating in the study and until
                  at least 12 months following JCAR017 infusion even if he has undergone a
                  successful vasectomy and until CAR T cells are no longer present by qPCR on two
                  consecutive tests, whichever occurs last.

                    -  True abstinence is acceptable when this is in line with the preferred and
                       usual lifestyle of the subject. In contrast, periodic abstinence (eg,
                       calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal
                       are not acceptable methods of contraception.

        Exclusion Criteria:

        The presence of any of the following will exclude a subject from enrollment:

          1. Subject has any significant medical condition, laboratory abnormality, or psychiatric
             illness that would prevent the subject from participating in the study.

          2. Subject has any condition including the presence of laboratory abnormalities, which
             would place the subject at unacceptable risk if participating in the study.

          3. Subject has any condition that confounds the ability to interpret data from the study.

          4. Subjects with T cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary
             cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV
             positive DLBCL of the elderly and Burkitt lymphoma.

          5. History of another primary malignancy that has not been in remission for at least 2
             years prior to enrollment. The following are exempt from the 2-year limit if
             curatively treated:

               -  Non-melanoma skin cancer

               -  Localized prostate cancer

               -  Cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP
                  smear

          6. Treatment with any prior gene therapy product.

          7. Subjects who have received previous CD19-targeted therapy.

          8. Previous history of or active hepatitis B, hepatitis C, or human immunodeficiency
             virus (HIV) infection.

          9. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection
             (including tuberculosis) despite appropriate antibiotics or other treatment at the
             time of leukapheresis or JCAR017 infusion.

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

         11. Active autoimmune disease requiring immunosuppressive therapy.

         12. History of any one of the following cardiovascular conditions within the past 6
             months:

               -  Heart failure class III or IV as defined by the New York Heart Association (NYHA)

               -  Cardiac angioplasty or stenting

               -  Myocardial infarction

               -  Unstable angina

               -  Other clinically significant cardiac disease

         13. History or presence of clinically relevant CNS pathology such as epilepsy, seizure,
             paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease,
             cerebellar disease, organic brain syndrome, or psychosis.

         14. Pregnant or nursing women

         15. Treatment with alemtuzumab within 6 months of leukapheresis, or treatment with
             fludarabine or cladribine within 3 months of leukapheresis

         16. Use of the following:

               -  Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or
                  equivalent) within 7 days prior to leukapheresis or 72 hours prior to JCAR017
                  infusion. Physiologic replacement, topical, and inhaled steroids are permitted.

               -  Low-dose chemotherapy (eg, vincristine, rituximab, cyclophosphamide ≤ 300 mg/m2)
                  given after leukapheresis to maintain disease control must be stopped ≥ 7 days
                  prior to LD chemotherapy.

               -  Cytotoxic chemotherapeutic agents that are not considered lymphotoxic (see below)
                  within 1 week prior to leukapheresis. Oral anticancer agents, including
                  lenalidomide and ibrutinib, are allowed if at least 3 half-lives have elapsed
                  prior to leukapheresis.

               -  Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide, ifosfamide,
                  bendamustine) within 2 weeks prior to leukapheresis.

               -  Experimental agents within 4 weeks prior to leukapheresis unless no response or
                  progressive disease (PD) is documented on the experimental therapy and at least 3
                  half-lives have elapsed prior to leukapheresis.

               -  Immunosuppressive therapies within 4 weeks prior to leukapheresis and JCAR017
                  infusion (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics,
                  mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as
                  antitumor necrosis factor [TNF], anti-IL-6, or anti-IL-6R).

               -  Donor lymphocyte infusions (DLI) within 6 weeks prior to JCAR017 infusion.

               -  Radiation within 6 weeks prior to leukapheresis. Subjects must have progressive
                  disease in irradiated lesions or have additional non-irradiated, PET-positive
                  lesions to be eligible. Radiation to a single lesion, if additional
                  non-irradiated, measurable PET positive lesions are present, is allowed up to 2
                  weeks prior to leukapheresis.

               -  Allogeneic HSCT within 90 days prior to leukapheresis.

         17. Prior hematopoietic stem cell transplant (only applicable to Cohort 2).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR) of JCAR017 in subjects with Non-Hodgkin Lymphoma (NHL; including secondary central nervous system (CNS) involvement)
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Proportion of subjects achieving a complete response (CR) or partial response (PR) based on the Lugano classification (Cheson, 2014)

Secondary Outcome Measures

Measure:Adverse Events (AEs)
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Type, frequency, and severity of AEs, including serious adverse events (SAEs) and laboratory abnormalities
Measure:Overall Response Rate (ORR)on the underlying chronic lymphocytic leukemia (CLL) in subjects with Richter´s transformation
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Proportion of subjects achieving a CR, CR with incomplete bone marrow recovery (CRi), nodular PR (nPR), PR or PR with lymphocytosis (PRL) based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines
Measure:Complete response rate (CRR)
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Proportion of subjects achieving a CR (or CR and CRu for subjects with PCNSL) following JCAR017 infusion
Measure:Event-free survival (EFS)
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Time from JCAR017 infusion to death from any cause, progressive disease (PD), or starting a new anticancer therapy, whichever occurs first
Measure:Progression-free survival (PFS)
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Time from JCAR017 infusion to the first documentation of PD, or death due to any cause, whichever occurs first
Measure:Overall survival (OS)
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Time from JCAR017 infusion to time of death due to any cause
Measure:Duration of response (DOR)
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Time from first response to progressive disease or death from any cause, whichever occurs first
Measure:Pharmacokinetic - Cmax
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Maximum concentration
Measure:Pharmacokinetic - Tmax
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Time to peak concentration
Measure:Pharmacokinetic - AUC
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Area under the curve
Measure:Patient-Reported Outcomes - EORTC QLQ-C30
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:European Organisation for Research and Treatment of Cancer - Quality of Life C30 questionnaire: The EORTC QLQ-C30 questionnaire will be used as a measure of health-related quality of life.
Measure:Patient-Reported Outcomes - EQ-5D-5L
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:European Quality of Life-5 Dimensions health state classifier to 5 Levels questionnaire: EQ-5D is a standardized measure of health status developed by the EuroQol Group to provide a simple, generic measure of health for clinical and economic appraisal.
Measure:Patient-Reported Outcomes - FACT-Lym
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Functional Assessment of Cancer Therapy-Lymphoma "Additional concerns" subscale: Only the LYM subscale will be administered in this study. This scale addresses symptoms and functional limitations (15 item) that are important to lymphoma patients.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celgene

Trial Keywords

  • Non-Hodgkin lymphoma
  • Aggressive B-cell non-Hodgkin lymphoma
  • Diffuse large B-cell lymphoma
  • Relapse / refractory lymphoma
  • Transplant not eligible
  • Double-hit lymphoma
  • Triple-hit lymphoma
  • Primary/secondary central nervous system lymphoma
  • Richter's transformation/syndrome
  • Transformed follicular lymphoma
  • Follicular lymphoma Grade 3B
  • JCAR017
  • CAR T cell therapy
  • CD19 targeted therapy.
  • Efficacy and safety
  • Europe / Japan
  • TPTD

Last Updated

<p/>