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)

  • STATUS
    Recruiting
  • End date
    Oct 27, 2022
  • participants needed
    121
  • sponsor
    Celgene
Updated on 1 February 2022
lymphoid leukemia
fludarabine
cyclophosphamide
tyrosine
lymphoma
philadelphia chromosome
hodgkin's disease
flow cytometry
ejection fraction
measurable disease
leukemia
gilbert's syndrome
b-cell acute lymphoblastic leukemia
oximetry
diffuse large b-cell lymphoma
b-cell lymphoma
lymphoblasts

Summary

This is a Phase 1/2, 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 1 will 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.

Description

This is a Phase 1/2, 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 1, up to 5 dose levels will be of JCAR017 will be evaluated. Enrollment will commence in pediatric subjects with r/r B-ALL at Dose Level 1 (DL1) of 0.05x10^6 CAR+ T cells/kg (maximum DL1 of 5x10^6 JCAR017 CAR+ T cells [non-weight adjusted]). If this dose is confirmed to be safe and tolerable, additional subjects will be enrolled at higher dose(s) up to 0.75 x10^6 CAR+ T cells/kg (maximum of 75x10^6 JCAR017 CAR+ T cells [non-weight adjusted]) with the aim to identify the RP2D. Dose escalation/de-escalation will follow a modified toxicity probability interval (mTPI-2) algorithm. 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 from at least 10 pediatric subjects treated at the RP2D.

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. The 10 or more pediatric subjects treated at the RP2D in Phase 1 will form part of the sample size (ie, Cohort 1 and Cohort 2). Therefore, the protocol intends to treat 81 primary endpoint evaluable pediatric subjects in Phase 2, if warranted by the evaluation of results at the completion of the first stage of the study in each cohort.

  • Cohort 1 (r/r B-ALL): 48 evaluable pediatric subjects (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 B-ALL subjects between 18 and 25 years of age may 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.

Details
Condition Precursor Cell Lymphoblastic Leukemia-Lymphoma, Lymphoma, Non-Hodgkin
Treatment cyclophosphamide, Fludarabine, JCAR017, Lymphodepleting
Clinical Study IdentifierNCT03743246
SponsorCelgene
Last Modified on1 February 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Subjects must satisfy the following criteria to be enrolled in the study
Phase 1: Subject < 18 years of age and weighs 6 kg at the time of signing the informed consent form (ICF)/informed assent form (IAF)
Phase 2: Subject 25 years of age and weighs 6 kg at the time of signing the
ICF/IAF
\. Subject (when applicable, parental/legal representative) must understand
and voluntarily provide permission to the ICF/IAF prior to conducting any
study-related assessments/procedures
\. Subject is willing and able to adhere to the study visit schedule and
other protocol requirements
\. Investigator considers the subject is appropriate for adoptive T cell
therapy
\. Evidence of CD19 expression via flow cytometry (peripheral blood or bone
marrow) or immunohistochemistry (bone marrow biopsy)
\. Subject has a Karnofsky score of 50 (subjects 16 years of age) or a Lansky
score 50 (subjects < 16 years of age)
\. Diagnosis of B-cell ALL or B-cell NHL as defined below
Phase 1: 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 Note: Subjects will be included regardless of MRD status
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 with
MRD detected by a validated assay at a frequency of 1 x10-4 or greater in BM cells. Subjects eligible for enrollment in Cohort 2 are those with MRD positive morphologic CR2 after re-induction when these subjects had previously experienced an early relapse (< 36 months) after first-line chemotherapy. Subjects who are in MRD+ morphologic CR3 and later, regardless of time to relapse in earlier lines, are also eligible. Subjects who are in morphologic relapse at screening (r/r B-ALL) and become MRD+ after bridging chemotherapy are also eligible for treatment in Cohort 2
Cohort 3: r/r B-NHL (DLBCL, BL or PMBCL), defined as measurable disease after 1 or more lines of chemotherapy and/or having failed HSCT or being ineligible for HSCT
Note: B-NHL subjects with secondary CNS lymphoma involvement are eligible
however subject selection must consider clinical risk factors for severe
neurological AEs and alternative treatment options. Subjects should only be
enrolled if the Investigator considers the potential benefit outweighs the
risk for the subject
\. 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
\. 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
Serum creatinine based on age/gender as described below. Subjects that do not
meet the criteria but who have a creatinine clearance or radioisotope
glomerular filtration rate (GFR) > 70 mL/min/1.73 m2 are eligible. Alanine
aminotransferase (ALT) 5 x upper limit of normal (ULN) and total bilirubin <
0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert's syndrome or
leukemic/lymphomatous infiltration of the liver)
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
Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
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
Subject has any condition that confounds the ability to interpret data from the study
Subject with a history of another primary malignancy that has not been in remission for at least 2 years prior to enrollment
Subjects who have received previous CD19-targeted therapy must have CD19-positive disease confirmed since completing the prior CD19-targeted therapy
Prior CAR T cell or other genetically-modified T cell therapy
Subject with a previous history of or active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection
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
Subject has presence of acute or chronic graft-versus-host disease (GVHD)
Subject with active autoimmune disease requiring immunosuppressive therapy
Subject has cardiac disorders (CTCAE version 4.03 Grade 3 or 4) within the past 6 months
Subject with a concomitant genetic syndrome, with the exception of Down's syndrome
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, the CNS disease burden can be controlled until JCAR017 infusion
Subject with a history or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, cerebral edema, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
Subject is pregnant or nursing
Subject has used the following
Therapeutic doses of corticosteroids (defined as > 0.4 mg/kg maximum 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 within 1 week prior to leukapheresis. Oral anticancer agents 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
Tumor invasion of venous or arterial vessels (B-NHL subjects only)
Deep Venous Thrombosis (DVT) or Pulmonary Embolism (PE) within 3 months prior to leukapheresis. Subjects with DVT or PE that occurred longer than 3 months prior to leukapheresis, who still require ongoing therapeutic levels of anti-coagulation therapy, are also excluded
Existence of CD19-negative clone(s) of leukemia cells
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