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A Study to Evaluate the Safety and Efficacy of JCAR017 in Pediatric Subjects With Relapsed/Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (B-ALL) and B-cell Non-Hodgkin Lymphoma (B-NHL)

NCT03743246

Description:

This is a Phase 1b/2, open-label, single arm, multicohort study to evaluate the safety and efficacy of JCAR017 in pediatric subjects aged ≤ 25 years with CD19+ r/r B-ALL and B-NHL. Phase 1b will evaluate two dose levels to identify a recommended Phase 2 dose (RP2D). Phase 2 will evaluate the efficacy of JCAR017 RP2D in the following three disease cohorts: Cohort 1 (r/r B-ALL), Cohort 2 (MRD+ B-ALL) and Cohort 3 (r/r B-NHL, [DLBCL, BL, or PMBCL]). A Simon's Optimal two-stage study design will be applied to Cohort 1 and 2 in Phase 2.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
  • B-Cell Non-Hodgkin Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate the Safety and Efficacy of JCAR017 in Pediatric Subjects With Relapsed/Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (B-ALL) and B-cell Non-Hodgkin Lymphoma (B-NHL)
  • Official Title: A Phase 1 B/2, Open-label, Single Arm, Multi-cohort, Multicenter Trial to Evaluate the Safety and Efficacy of JCAR017 in Pediatric Subjects With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia (B-ALL) and B-cell Non-hodgkin's Lymphoma (B-NHL)

Clinical Trial IDs

  • ORG STUDY ID: JCAR017-BCM-004
  • SECONDARY ID: U1111-1220-3324
  • SECONDARY ID: 2018-001246-34
  • NCT ID: NCT03743246

Conditions

  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, Non-Hodgkin

Interventions

DrugSynonymsArms
JCAR017Administration of JCAR017
LymphodepletingAdministration of JCAR017
FludarabineAdministration of JCAR017
CyclophosphamideAdministration of JCAR017

Purpose

This is a Phase 1b/2, open-label, single arm, multicohort study to evaluate the safety and efficacy of JCAR017 in pediatric subjects aged ≤ 25 years with CD19+ r/r B-ALL and B-NHL. Phase 1b will evaluate two dose levels to identify a recommended Phase 2 dose (RP2D). Phase 2 will evaluate the efficacy of JCAR017 RP2D in the following three disease cohorts: Cohort 1 (r/r B-ALL), Cohort 2 (MRD+ B-ALL) and Cohort 3 (r/r B-NHL, [DLBCL, BL, or PMBCL]). A Simon's Optimal two-stage study design will be applied to Cohort 1 and 2 in Phase 2.

Detailed Description

      This is a Phase 1b/2, open-label, single arm, multicohort study incorporating Simon's Optimal
      two-stage design to evaluate the safety and efficacy of JCAR017 in pediatric subjects aged ≤
      25 years with CD19+ r/r B-ALL and B-NHL.

      In the Phase 1b, twenty r/r B-ALL pediatric (< 18 years of age) subjects will be treated. The
      first 10 pediatric subjects will be treated at a target dose of 0.5x10^6 JCAR017 CAR+ T
      cells/kg, with a maximum dose of 0.5x10^8 JCAR017 CAR+ T cells (non-weight adjusted). If this
      dose is confirmed to be safe and tolerable, an additional 10 pediatric subjects will be
      treated at a target dose of 1x10^6 JCAR017 CAR+ T cells/kg, with a maximum dose of 1.0x10^8
      JCAR017 CAR+ T cells (non-weight adjusted). The highest dose tested with no more than 2
      subjects experiencing a dose-limiting toxicity (DLT) will be declared the RP2D that will be
      applied in Phase 2. A Safety Review Committee (SRC) will recommend the Phase 2 dose (defined
      as RP2D) based on an integrated assessment of the safety, PK and preliminary efficacy
      information.

      In Phase 2, a minimum of 71 additional subjects (< 18 years of age) will be enrolled into one
      of the 3 cohorts listed below. The sample size for Cohorts 1 and 2 is calculated according to
      Simon's Optimal two-stage design.

        -  Cohort 1 (r/r B-ALL): 38 evaluable pediatric subjects. The 10 pediatric subjects treated
           at the RP2D in Phase 1b will be included in, and form part of, the sample size of Phase
           2, totaling 48 evaluable pediatric subjects in Cohort 1 (13 subjects in Stage 1 and 35
           in Stage 2)

        -  Cohort 2 (MRD+ B-ALL): 23 evaluable pediatric subjects (9 subjects in Stage 1 and 14
           subjects in Stage 2)

        -  Cohort 3 (r/r B-NHL [DLBCL, BL, or PMBCL]): 10 evaluable pediatric subjects. Due to the
           very low incidence rate and therefore expected low subject accrual, there is no formal
           sample size for this arm.

      Up to 20 additional subjects between 18 and 25 years of age will be enrolled in Phase 2.

      Following treatment with JCAR017 subjects will then enter the post-treatment period for
      disease progression/relapse, safety, CAR T cell persistence, and survival up to 24 months
      after administration of JCAR017.

      Efficacy will be assessed both locally and by an Independent Review Committee. Response
      assessments will be based on bone marrow and blood morphologic criteria, physical examination
      findings, along with laboratory assessments of cerebral spinal fluid (CSF) and bone marrow
      MRD (B-ALL only) assessments. B-NHL subjects will also have radiographic disease assessment
      by CT/MRI scans and tumor biopsies, if accessible.

      Post-study follow-up for survival, relapse, long-term toxicity, and lentiviral vector safety
      will continue under a separate long-term follow-up protocol for up to 15 years after the
      JCAR017 infusion as per health authority regulatory guidelines.

      An Independent Data Monitoring Committee will monitor the study conduct.
    

Trial Arms

NameTypeDescriptionInterventions
Administration of JCAR017ExperimentalSubjects will receive Lymphodepleting chemotherapy with intravenous (IV) fludarabine (30 mg/m2/day for 3 days) plus cyclophosphamide IV (300 mg/m2/day for 3 days) (flu/cy) concurrently, followed by JCAR017 cells infusion. Phase 1 will have 2 JCAR017 cells dose levels, the highest dose tested with no more than 2 subjects experiencing a DLT will be applied to the subjects enrolled in Phase 2.
  • JCAR017
  • Lymphodepleting
  • Fludarabine
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

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

          1. Phase 1b: Subject < 18 years of age and weighs ≥ 12 kg (for subjects receiving a dose
             of 0.5x10^6 JCAR017 CAR+ T cells/kg) or ≥ 6 kg (for subjects receiving a dose of
             1x10^6 JCAR017 CAR+ T cells/kg) at the time of signing the informed consent form
             (ICF)/informed assent form (IAF). Phase 2: Subject ≤ 25 years of age and weighs ≥ 12
             kg (if RP2D is 0.5 x 10^6 JCAR017 CAR+ T cells/kg) or ≥ 6 kg (if RP2D is 1 x 10^6
             JCAR017 CAR+ T cells/kg) at the time of signing the ICF/IAF.

          2. Subject (when applicable, parental/legal representative) must understand and
             voluntarily provide permission to the ICF/IAF prior to conducting any study-related
             assessments/procedures.

          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. Evidence of CD19 expression via flow cytometry (peripheral blood or bone marrow) or
             immunohistochemistry (bone marrow biopsy)

          6. Subject has a Karnofsky score of ≥ 50 (subjects ≥ 16 years of age) or a Lansky score ≥
             50 (subjects < 16 years of age).

          7. Phase 1b: Subjects with r/r B-ALL, defined as morphological evidence of disease in BM
             (5% or greater lymphoblast by morphology) and either of the following:

               -  First or greater marrow relapse, or

               -  Any marrow relapse after allogeneic HSCT, or

               -  Primary refractory defined as not achieving a CR or a CRi after 2 or more
                  separate induction regimens (or chemo-refractory as not achieving CR/CRi after 1
                  cycle of standard chemotherapy for relapsed leukemia), or

               -  Ineligible for allogeneic HSCT

             Phase 2: Subjects with one of the following:

               -  Cohort 1: r/r B-ALL, defined as morphological evidence of disease in BM (5% or
                  greater lymphoblast by morphology) and either:

                    -  First or greater marrow relapse, or

                    -  Any marrow relapse after allogeneic HSCT, or

                    -  Primary refractory defined as not achieving a CR or a CRi after 2 or more
                       separate induction regimens (or chemo-refractory as not achieving CR/CRi
                       after 1 cycle of standard chemotherapy for relapsed leukemia), or

                    -  Ineligible for allogeneic HSCT.

               -  Cohort 2: MRD+ B-ALL, defined as:

                    -  < 5% lymphoblasts by morphology

                    -  MRD detected by a validated assay at a frequency of 1 x10-4 or greater in BM
                       cells after two lines of therapy.

               -  Cohort 3: r/r B-NHL, defined as measurable disease after 1 or more lines of
                  chemotherapy and/or having failed HSCT or being ineligible for HSCT.

          8. Subjects with Philadelphia chromosome positive ALL are eligible if they are intolerant
             to or have failed one or more lines of tyrosine-kinase inhibitor (TKI) therapy or if
             TKI therapy is contraindicated.

          9. Adequate organ function, defined as:

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

               -  Subject with adequate renal function, which is defined as:

             Creatinine clearance calculated using the Schwartz formula, or radioisotope glomerular
             filtration rate (GFR) > 70 mL/min/1.73 m2.

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

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

         10. Adequate vascular access for leukapheresis procedure.

         11. Participants must agree to use effective 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
             places the subject at unacceptable risk if he/she were to participate in the study.

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

          4. Subject with a history of another primary malignancy that has not been in remission
             for at least 2 years prior to enrollment.

          5. Subjects who have received previous CD19-targeted therapy must have CD19-positive
             disease confirmed since completing the prior CD19-targeted therapy.

          6. Prior CAR T cell or other genetically-modified T cell therapy.

          7. Subject with a previous history of or active hepatitis B, hepatitis C, or human
             immunodeficiency virus (HIV) infection.

          8. 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.

          9. Subject has presence of acute or chronic graft-versus-host disease (GVHD).

         10. Subject with active autoimmune disease requiring immunosuppressive therapy.

         11. Subject has cardiac disorders (CTCAE version 4.03 Grade 3 or 4) within the past 6
             months.

         12. Subject with a concomitant genetic syndrome, with the exception of Down's syndrome.

         13. Subject with active CNS disease and significant neurological deterioration. Subjects
             with CNS-2 or CNS-3 involvement are eligible provided they are asymptomatic and do not
             have significant neurological deterioration and, in the opinion of the study
             investigator.

         14. Subject with a history or presence of clinically relevant CNS pathology.

         15. Subject is pregnant or nursing.

         16. Subject has used 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
                  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 PD in
                  irradiated lesions or have additional non-irradiated lesions to be eligible.
                  Radiation to a single lesion, if additional non-irradiated, measurable lesions
                  are present, is allowed up to 2 weeks prior to leukapheresis.

               -  Allogeneic HSCT within 90 days prior to leukapheresis.
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase 2 Dose (RP2D) of JCAR017
Time Frame:Up to 28 days after JCAR017 infusion
Safety Issue:
Description:The dose recommended for use in phase 2 studies on the basis of dose limiting toxicities observed in phase 1 studies.

Secondary Outcome Measures

Measure:Adverse Events (AEs)
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Type, frequency and severity of adverse events (AEs), serious adverse events (SAE), and laboratory abnormalities (overall and in clinical, histological and molecular subgroups)
Measure:Overall response rate (ORR) in the non-selected dose from Phase 1b
Time Frame:On day 28 and day 56
Safety Issue:
Description:Total number of subjects achieving a confirmed Complete response (CR) or CR with incomplete blood count recovery (CRi) on Day 28, confirmed on Day 56 as determined by IRC assessment
Measure:Duration of response (DOR)
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Time from first response until progressive disease (PD), disease relapse, or death from any cause, whichever occurs first
Measure:Relapse-free survival (RFS)
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Time from first response to documentation of PD, disease relapse, or death due to any cause, whichever occurs first
Measure:Event-free survival (EFS)
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Time from JCAR017 infusion to PD, disease relapse, start of a new anticancer therapy, or death from 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:MRD response rate
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Percentage of r/r B-ALL subjects achieving a CR or CRi and a negative MRD bone marrow
Measure:Rate of hematopoietic stem cell transplant (HSCT) after response to JCAR017 infusion
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Percentage of subjects who achieve a response after JCAR017 infusion and then proceed to HSCT
Measure:Pharmacokinetics - Cmax
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Maximum concentration
Measure:Pharmacokinetics - Tmax
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Time to peak concentration
Measure:Pharmacokinetics - AUC
Time Frame:Up to 2 years after JCAR017 infusion
Safety Issue:
Description:Area under the curve

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celgene

Trial Keywords

  • Pediatric
  • JCAR017
  • CAR-T
  • CART
  • CD19
  • ALL
  • NHL
  • DLBCL
  • BL
  • PMBCL
  • Cell Therapy
  • LisoCell
  • Young Adults
  • Lymphoproliferative disorders
  • Immune system diseases
  • Leukemia
  • Lymphoma
  • lymphatic diseases

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