Combination of an Anti-PD1 Antibody With Tisagenlecleucel Reinfusion in Children, Adolescents and Young Adults With Acute Lymphoblastic Leukemia After Loss of Persistence
CAPTiRALL
1 other identifier
interventional
26
1 country
13
Brief Summary
Tisagenlecleucel (CTL019) is an anti-CD19 autologous Chimeric Antigen Receptor (CAR) T-cell therapy, which has shown dramatic early results in advanced ALLs. Early loss of B-cell aplasia (recovery of B-cells in marrow/ peripheral blood within 6 months after infusion), a marker of the loss or non-functionality of the CAR T-cells, is associated to a very high risk of relapse. A reinfusion of CTL019, even after Fludarabine-Cyclophosphamide reconditioning, frequently fails to induce further expansion as observed in UPENN studies and in the Robert Debré Hospital experience. Non-persistence of CAR T-cells may be due to immune- mediated rejection or environment-mediated suppression of their growth. Evidence for increased PD-1 expression in CAR T-cells between infusion and peak expansion has been demonstrated in clinical samples. Preclinical data and few clinical data support a role of PD- 1-PD-L1 blockade in improving the effectiveness of CAR T-cell therapy. The objectives of this phase I/II study is to determine the safety, efficacy and feasibility of Nivolumab (Opdivo®)- an anti-PD1 treatment- combined to tisagenlecleucel in a cohort of relapsed or refractory B-ALL patients, aged 1-25 years old, previously treated by tisagenlecleucel (Kymriah®), with a demonstrated early loss of B-cell aplasia (within 6 months), a surrogate marker of the loss of CAR T-cells or their non- functionality. More specifically, the main objectives are:
- In cohort 1 that includes patients with a MRD negative disease status combined to an early loss (within 6 months) of B-cell aplasia : To determine the optimal starting time of Nivolumab (Opdivo®) in terms of safety and efficacy among 4 candidate time points (day 14, day 11, day 5, and day - 1).
- In cohort 2 that includes relapsed patients with an early loss (within 6 months) of B-cell aplasia : To estimate the feasibility in terms of safety and efficacy of a very early start of nivolumab (day-1), prior to the reinfusion of tisagenlecleucel
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_1
Started Mar 2023
Longer than P75 for phase_1
13 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
March 9, 2022
CompletedFirst Posted
Study publicly available on registry
April 5, 2022
CompletedStudy Start
First participant enrolled
March 15, 2023
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 1, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
March 1, 2027
May 29, 2024
February 1, 2024
4 years
March 9, 2022
May 26, 2024
Conditions
Outcome Measures
Primary Outcomes (2)
Proportion of patients with limiting-toxicities
Limiting toxicities are defined by the occurrence of either \- Related to CAR-T cells infusion: CRS or aGVH: limiting toxicity will be defined as toxicity ≥ 4 ICANs: limiting toxicity will be defined as toxicity ≥ 3 (excepted grade 3 seizure, ie focal, generalized seizure that resolves rapidly) \- Related to nivolumab: immune related myocarditis, pneumonitis, encephalitis: limiting toxicity will be defined as toxicity ≥ 4
at day 28
Efficacy assessed by Minimal residual disease (MRD) negative Complete remission (CR) and B cell aplasia.
MRD negative CR is defined by undetectable disease at a 10-4 sensitivity threshold B cell aplasia is defined by blood B lymphocytes \< 10 /mm3 and/or \< 3% of total lymphocytes
at 3 months
Secondary Outcomes (18)
Incidence of B cell aplasia
at 6 months
Increase of B cell aplasia duration compared to the previous one observed
up to 24 months
Proportion of patients with Disease best response
up to three months
Proportion of patients with Complete remission
at 1 month
Proportion of patients with Complete remission
at 3 months
- +13 more secondary outcomes
Study Arms (2)
Patients with MRD negative disease status: Time to Event Continual Reassessment Method (TITE-CRM)
EXPERIMENTALFor relapsed patients
EXPERIMENTALInterventions
Patients included first receive a lympho-depleting chemotherapy by Fludarabine / Cyclophosphamide. tisagenlecleucel infusion should then be administered 2 to 14 days after completion of chemotherapy. Nivolumab (Opdivo®) will be given intravenously at 3mg/kg every 2 weeks. It will include patients with MRD negative disease status. 1. Four decreasing starting times for beginning nivolumab (day 14, day 11, day 5 and day -1) will be available for testing 2. Patients will be enrolled sequentially by cohorts of 3 with escalation between cohorts based only on the limiting toxicities between infusion and D28 Nivolumab will be given until 12 months after tisagenlecleucel infusion in case of response.
It will include relapsed patients. Patients included first receive a lympho-depleting chemotherapy by Fludarabine / Cyclophosphamide. tisagenlecleucel infusion should then be administered 2 to 14 days after completion of chemotherapy. Nivolumab (Opdivo®) will be given intravenously at 3mg/kg every 2 weeks. -nivolumab starting at day -1. Nivolumab will be given until 12 months after tisagenlecleucel infusion in case of response.
Eligibility Criteria
You may qualify if:
- Patients aged from 1 to 25 years (pediatric and young adults) with a history of CD19+ relapsed or refractory B-ALL (any relapse after HSCT, 2nd relapse or later, refractory ALL).
- Patient must have a second tisagenlecleucel (Kymriah ®) product available
- Cohort 1: previously treated by tisagenlecleucel (Kymriah ®), and who present an early loss of B-cell aplasia defined by blood B lymphocytes \< 10 /mm3 and/ or \< 3% of total lymphocytes (\< 6 months after infusion) while still being in CR with undetectable MRD
- Cohort 2: previously treated by tisagenlecleucel (Kymriah ®), who present a loss of B-cell aplasia defined by blood B lymphocytes \< 10 /mm3 and/ or \< 3% of total lymphocytes and a CD19+ ALL detectable disease in the marrow and/or Blood
- Life expectancy \> 12 weeks.
- Karnofsky (age \> 16) Lansky (age \< 16) \> 70 at screening.
- No organ dysfunction
- Who have signed an informed consent
- Affiliation to social security or any health insurance (as a beneficiary or assignee)
You may not qualify if:
- Patient has received intervening therapy for leukemia after first tisagenlecleucel infusion (chemotherapy, anti leukemic immunotherapy, ITK, allogeneic HSCT).
- Patient has an active autoimmune disease requiring systemic treatment within the past 2 years.
- Patient has known history of, or any evidence of active, non-infectious pneumonitis.
- Patient has a history of non-infectious pneumonitis that required steroid or has current pneumonitis.
- Had receive prior therapy with an anti-PD1, Anti- PDL1 or anti-PDL2 agent.
- Patient has hypersensivity to pembrolizumab/ nivolumab or one of its excipients
- Patient has received a live vaccine injection within 45 days of planned start of study therapy.
- Patients with concomitant genetic syndromes associated with bone marrow failure states: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down syndrome will not be excluded.
- Patients with Burkitt's lymphoma/leukemia
- Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
- Prior treatment with any gene therapy product except first tisagenlecleucel (Kymriah ®) injection.
- Prior treatment with any anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy, except for patients pre-treated with blinatumomab and/or tisagenlecleucel (Kymriah®)
- Prior anti-cancer monoclonal antibody within 4 weeks before starting the study.
- Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade1 or at baseline) from adverse events due to a previously administered agent.
- Active or latent hepatitis B or active hepatitis C (test within 8 weeks of Screening), or any uncontrolled infection at Screening.
- +10 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (13)
CHRU Bordeaux
Bordeaux, France
CHRU Lille
Lille, France
HCL - Lyon Sud
Lyon, France
HCL
Lyon, France
HCL
Lyon, France
Hôpital pour enfants - La Timone
Marseille, France
CHU Montpellier - Hopital Arnaud de Villeneuve
Montpellier, France
CHU Nancy
Nancy, France
CHU Nantes - Hopital Mère-enfants
Nantes, France
Robert Debre hospital
Paris, France
Saint Louis hospital
Paris, France
CHU Rouen
Rouen, France
CHRU Strasbourg
Strasbourg, France
MeSH Terms
Conditions
Condition Hierarchy (Ancestors)
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
March 9, 2022
First Posted
April 5, 2022
Study Start
March 15, 2023
Primary Completion (Estimated)
March 1, 2027
Study Completion (Estimated)
March 1, 2027
Last Updated
May 29, 2024
Record last verified: 2024-02