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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)

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ClinicalTrials.gov Identifier: NCT03743246
Recruitment Status : Recruiting
First Posted : November 16, 2018
Last Update Posted : November 16, 2018
Sponsor:
Information provided by (Responsible Party):
Celgene

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Precursor Cell Lymphoblastic Leukemia-Lymphoma Lymphoma, Non-Hodgkin Drug: JCAR017 Drug: Lymphodepleting Drug: Fludarabine Drug: Cyclophosphamide Phase 1 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 111 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2, Open-label, Single Arm, Multicohort, Multicenter Trial 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).
Actual Study Start Date : October 17, 2018
Estimated Primary Completion Date : November 15, 2021
Estimated Study Completion Date : December 1, 2023


Arm Intervention/treatment
Experimental: Administration of JCAR017
Subjects 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.
Drug: JCAR017
JCAR017

Drug: Lymphodepleting
Lymphodepleting

Drug: Fludarabine
Fludarabine

Drug: Cyclophosphamide
Cyclophosphamide




Primary Outcome Measures :
  1. Recommended Phase 2 Dose (RP2D) of JCAR017 [ Time Frame: Up to 28 days after JCAR017 infusion ]
    The dose recommended for use in phase 2 studies on the basis of dose limiting toxicities observed in phase 1 studies.

  2. Overall response rate (ORR)- Cohort 1 [ Time Frame: Up to day 56 ]
    Total number of subjects achieving a Complete response (CR) or CR with incomplete blood count recovery (CRi) on Day 28 and confirmed on Day 56 as determined by IRC assessment.

  3. Minimal residual disease (MRD) negative rate - Cohort 2 [ Time Frame: Up to day 56 ]
    Total number of subjects achieving a MRD negative response on Day 28 and confirmed on Day 56 as determined by IRC assessment

  4. Overall response rate (ORR)- Cohort 3 [ Time Frame: On day 28 ]
    Total number of subjects achieving a CR or PR on Day 28 as determined by IRC assessment


Secondary Outcome Measures :
  1. Adverse Events (AEs) [ Time Frame: Up to 2 years after JCAR017 infusion ]
    Type, frequency and severity of adverse events (AEs), serious adverse events (SAE), and laboratory abnormalities (overall and in clinical, histological and molecular subgroups)

  2. Overall response rate (ORR) in the non-selected dose from Phase 1b [ Time Frame: On day 28 and day 56 ]
    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

  3. Duration of response (DOR) [ Time Frame: Up to 2 years after JCAR017 infusion ]
    Time from first response until progressive disease (PD), disease relapse, or death from any cause, whichever occurs first

  4. Relapse-free survival (RFS) [ Time Frame: Up to 2 years after JCAR017 infusion ]
    Time from first response to documentation of PD, disease relapse, or death due to any cause, whichever occurs first

  5. Event-free survival (EFS) [ Time Frame: Up to 2 years after JCAR017 infusion ]
    Time from JCAR017 infusion to PD, disease relapse, start of a new anticancer therapy, or death from any cause, whichever occurs first

  6. Overall survival (OS) [ Time Frame: Up to 2 years after JCAR017 infusion ]
    Time from JCAR017 infusion to time of death due to any cause

  7. MRD response rate [ Time Frame: Up to 2 years after JCAR017 infusion ]
    Percentage of r/r B-ALL subjects achieving a CR or CRi and a negative MRD bone marrow

  8. Rate of hematopoietic stem cell transplant (HSCT) after response to JCAR017 infusion [ Time Frame: Up to 2 years after JCAR017 infusion ]
    Percentage of subjects who achieve a response after JCAR017 infusion and then proceed to HSCT

  9. Pharmacokinetics - Cmax [ Time Frame: Up to 2 years after JCAR017 infusion ]
    Maximum concentration

  10. Pharmacokinetics - Tmax [ Time Frame: Up to 2 years after JCAR017 infusion ]
    Time to peak concentration

  11. Pharmacokinetics - AUC [ Time Frame: Up to 2 years after JCAR017 infusion ]
    Area under the curve



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT03743246


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

Locations
Spain
Hospital Infantil Universitario Niño Jesús Recruiting
Madrid, Spain, 28009
Sponsors and Collaborators
Celgene
Investigators
Study Director: Nikolaus Trede, MD, PhD Celgene Corporation

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT03743246     History of Changes
Other Study ID Numbers: JCAR017-BCM-004
U1111-1220-3324 ( Registry Identifier: WHO )
2018-001246-34 ( EudraCT Number )
First Posted: November 16, 2018    Key Record Dates
Last Update Posted: November 16, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Celgene:
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

Additional relevant MeSH terms:
Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Lymphoma, B-Cell
Burkitt Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists