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)
Clinicaltrials.gov identifier recruitment status First Posted Last update posted
NCT03743246 Recruiting November 16, 2018 August 11, 2020

study description
Brief 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.

Condition or Disease: Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lymphoma, Non-Hodgkin
Intervention/treatment: Drug: JCAR017
Drug: Lymphodepleting
Drug: Fludarabine
Drug: Cyclophosphamide
Phase: Phase 1/Phase 2
Detailed 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.


study design
Study Type: Interventional
Estimated Enrollment : 121 participants
Intervention Model : Single Group Assignment
Masking: None (Open Label) ()
Primary Purpose: Treatment
Official Title: A Phase 1/2, 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 2018
Estimated Primary Completion Date: October 2022
Estimated Study Completion Date: October 2022

Arms and interventions
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 evaluate up to 5 JCAR017 cells dose levels and dose escalation/de-escalation will follow a modified toxicity probability interval (mTPI-2) algorithm. The declared RP2D in Phase 1 will be applied to the subjects enrolled in Phase 2
Drug: JCAR017
JCAR017

Drug: Lymphodepleting
Lymphodepleting

Drug: Fludarabine
Fludarabine

Drug: Cyclophosphamide
Cyclophosphamide
outcome measures
Primary Outcome Measures: 1. Recommended Phase 2 Dose (RP2D) of JCAR017 [ Time Frame: 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 CR or CRi with an MRD negative bone marrow (<0.01% tumor cells) 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. Pharmacokinetics - AUC [ Time Frame: Up to 2 years after JCAR017 infusion ]
Area under the curve
2. Best Overall Response (BOR) [ Time Frame: Up to 2 years after JCAR017 infusion ]
Number of r/r B-NHL subjects achieving BOR of CR/PR
3. 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)
4. Overall response rate (ORR) in the non-selected dose levels from Phase 1 [ Time Frame: On day 28 and day 56 ]
Percentage of r/r B-ALL subjects achieving a best overall response (BOR) of CR or CRi on Day 28, confirmed on Day 56 as determined by IRC assessment
5. 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
6. Relapse-free survival (RFS) [ Time Frame: Up to 2 years after JCAR017 infusion ]
Time from JCAR017 infusion to documentation of PD, disease relapse, or death due to any cause, whichever occurs first
7. 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
8. Overall survival (OS) [ Time Frame: Up to 2 years after JCAR017 infusion ]
Time from JCAR017 infusion to time of death due to any cause
9. MRD negative response rate [ Time Frame: Up to 2 years after JCAR017 infusion ]
Number of B-ALL subjects achieving CR or CRi and a negative MRD bone marrow.
10. 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
11. Pharmacokinetics - Cmax [ Time Frame: Up to 2 years after JCAR017 infusion ]
Maximum concentration
12. Pharmacokinetics - Tmax [ Time Frame: Up to 2 years after JCAR017 infusion ]
Time to peak concentration

Eligibility Criteria
Ages Eligible for Study: up to 25 / (18 to 64 years)
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 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. 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. 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 ( 70 mL/min/1.73 m2 are eligible.• Alanine aminotransferase (ALT) ≤ 5 x upper limit of normal (ULN) and total bilirubin < 2.0 mg/dL (or 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.

17. Tumor invasion of venous or arterial vessels (B-NHL subjects only).

18. 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.

19. Existence of CD19-negative clone(s) of leukemia cells


Contacts and Locations
Contacts

Contact:

Locations
United States, New York Memorial Sloan Kettering Cancer Center New York
United States, Washington Seattle Children's Hospital Seattle
Belgium UZ Gent Gent
France Institute for Pediatric Hematology - Oncology, Leon Berard Cancer Center Lyon
France Hopital d'Enfants de la Timone Marseille Cedex 01
France Hopital Robert Debre Paris
Italy Fondazione MBBM Monza
Italy Ospedale Bambin Gesu Roma
Netherlands Princess Maxima Center for Pediatric Oncology Utrecht
Spain Hospital San Joan de Deu Barcelona Esplugues de Llobregat
Spain Hospital Infantil Universitario Nino Jesus Madrid
Sponsors and Collaborators
Celgene
Investigator
Study Director : Ettore Biagi, MD, PhD Celgene
More Information
Responsible Party : Celgene
ClinicalTrials.gov Identifier : NCT03743246     
Other Study ID Numbers : JCAR017-BCM-004, U1111-1220-3324, 2018-001246-34
First Posted : November 16, 2018
Last Update Posted : August 11, 2020
Last Verified : August 2020
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Celgene: Cell Therapy
Pediatric
JCAR017
CAR-T
CART
CD19
ALL
NHL
DLBCL
BL
PMBCL
LisoCell
Lymphoproliferative disorders
Immune system diseases
Leukemia
Lymphoma
lymphatic diseases
Young Adults
Additional relevant MeSH terms :
Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Lymphoma, B-Cell