Combination of an Anti-PD1 Antibody With Tisagenlecleucel Reinfusion in Children, Adolescents and Young Adults With Acute Lymphoblastic Leukemia After Loss of Persistence

Study Overview
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Brief Summary
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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

Official Title
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Combination of an Anti-PD1 Antibody With Tisagenlecleucel Reinfusion in Children, Adolescents and Young Adults With Acute Lymphoblastic Leukemia After Loss of Persistence

Conditions
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B Acute Lymphoblastic Leukemia, Acute Lymphoblastic Leukemia, in Relapse

Intervention / Treatment
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* Drug: Decreasing starting times for beginning nivolumab (Time to Event Continual Reassessment Method (TITE-CRM) )
* Drug: Nivolumab starting at day -1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) Exclusion Criteria: 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. Human immunodeficiency virus (HIV) positive test within 8 weeks of Screening. Presence of grade 2 to 4 acute or extensive chronic GVHD. Active CNS involvement by malignancy, defined as CNS-3 per NCCN guidelines. Note: Patients with history of CNS disease that has been effectively treated will be eligible. Uncontrolled acute life threatening bacterial, viral or fungal infection at Screening. Previous or concurrent malignancy with the following exceptions: Adequately treated basal cell or squamous cell carcinoma in situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study. A primary malignancy completely resected and in CR for ≥ 5 years Pregnant or lactating women (female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion) Patient with hypersensivity to Fludarabine and/or cyclophosphamide and/or tisagenlecleucel and/or nivolumab or one of their excipients.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with MRD negative disease status: Time to Event Continual Reassessment Method (TITE-CRM)<br> | Drug: Decreasing starting times for beginning nivolumab (Time to Event Continual Reassessment Method (TITE-CRM) )<br>* 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. Four decreasing starting times for beginning nivolumab (day 14, day 11, day 5 and day -1) will be available for testing 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.<br>|
| Experimental: For relapsed patients<br> | Drug: Nivolumab starting at day -1<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Proportion of patients with Complete remission |  | at 6 months | 
| Proportion of patients with Complete remission |  | at 12 months | 
| Proportion of patients with Minimal residual disease |  | at 1 month | 
| Proportion of patients with Minimal residual disease |  | at 3 months | 
| Proportion of patients with Minimal residual disease |  | at 6 months | 
| Proportion of patients with Minimal residual disease |  | at 12 months | 
| Overall survival |  | at one year | 
| Overall survival |  | at 2 years | 
| Event Free Survival (EFS) |  | at 1 year | 
| Event Free Survival (EFS) |  | at 2 years | 
| Incidence of Grade 3 adverse events |  | up to 2 years | 
| Incidence of Grade 3, 4 or 5 nivolumab-related adverse events |  | up to 2 years | 
| Incidence of GVHD |  | up to one year |