Overview

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 nonfunctionality.

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

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.