combination of an anti-pd1 antibody with tisagenlecleucel reinfusion in children, adolescents and young adults with acute lymphoblastic leukemia after loss of persistence

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

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


Eligibility criteria:
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 \ 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.