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 : March 17, 2020
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||Intervention/treatment||Phase|
|Precursor Cell Lymphoblastic Leukemia-Lymphoma Lymphoma, Non-Hodgkin||Drug: JCAR017 Drug: Lymphodepleting Drug: Fludarabine Drug: Cyclophosphamide||Phase 1 Phase 2|
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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||121 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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 17, 2018|
|Estimated Primary Completion Date :||October 27, 2022|
|Estimated Study Completion Date :||August 30, 2024|
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
- 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.
- 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.
- 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.
- 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.
- 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)
- 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
- 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
- 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
- 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
- Overall survival (OS) [ Time Frame: Up to 2 years after JCAR017 infusion ]Time from JCAR017 infusion to time of death due to any cause
- 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.
- 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
- Pharmacokinetics - Cmax [ Time Frame: Up to 2 years after JCAR017 infusion ]Maximum concentration
- Pharmacokinetics - Tmax [ Time Frame: Up to 2 years after JCAR017 infusion ]Time to peak concentration
- Pharmacokinetics - AUC [ Time Frame: Up to 2 years after JCAR017 infusion ]Area under the curve
- 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
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
|Contact: Associate Director Clinical Trial Disclosureemail@example.com|
|United States, New York|
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|New York, New York, United States, 10021|
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|Esplugues de Llobregat, Spain, 08950|
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|Madrid, Spain, 28009|
|Study Director:||Ettore Biagi, MD, PhD||Celgene|