Relapsed or refractory B-ALL (any relapse after HSCT, 2nd relapse or later, refractory ALL), aged 1-25 years old, previously treated by Tisagenlecleucel (Kymriah ®), Cohort 1 presenting early loss of B cell aplasia (< 6 months after infusion) And being in MRD negative complete remission or Cohort 2: presenting loss of B cell aplasia and having detectable marrow and/or blood CD19+ ALL cells.
Conditions
Interventions
Trade Name: Kymriah
Product Name: Tisagenleuclecel
Pharmaceutical Form: Dispersion for infusion
INN or Proposed INN: Tisagenlecleucel
Current Sponsor code: Tisagenlecleucel
Other descriptive name: KYM
Sponsors
Assistance Publique - Hôpitaux de Paris
Eligibility
Sex/Gender
All
Inclusion 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 12 weeks. •Karnofsky (age > 16) Lansky (age 50 at screening. •No organ dysfunction •Who have signed an informed consent •Affiliation to social security or any health insurance (as a beneficiary or assignee) Are the trial subjects under 18? yes Number of subjects for this age range: 20 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 6 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: • Patient has received intervening therapy for leukemia after first Tisagenlecleucel infusion. • Patient has an active auto-immune 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 30 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., = Grade 1 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: o Adequately treated basal cell or squamous cell carcinoma o In situ carcinoma of the cervix or breast, treated curatively and without evidence ofrecurrence for at least 3 years prior to the study. o 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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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;Secondary Objective: To assess the effect of these combined treatments on •Incidence of B cell aplasia at 6 months •Increase of B cell aplasia duration compared to the previous one observed after the first infusion of tisagenlecleucel. •Disease best response •Complete remission (at M1 M3 M6 M12 after reinfusion) •Minimal residual disease (at M1 M3 M6 M12 after reinfusion) •1-year and 2-year OS •1-year and 2-year EFS •Incidence of Grade 3 or 4 immune related adverse events (gut, liver, lung, endocrine) i.e. linked to Nivolumab treatment •Incidence of Grade 3 or 4 of other related adverse events related to Nivolumab use such as pneumonitis, stomatitis, rash, or hematologic toxicity. •Incidence of Grade 3 or 4 reinfusion of Tisagenlecleucel -related events, in particular -cytokine release syndrome -Immune Effector Cells Associated Neurologic Events (ICANs) -prolonged cytopenias •Incidence of acute and chronic GVHD To explore the PD1 PDL1 axis and its correlation with success or failure ; | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): To assess the effect of these combined treatments on • Incidence of B cell aplasia at 6 months • Increase of B cell aplasia duration compared to the previous one observed after the first infusion of tisagenlecleucel. • Disease best response • Complete remission (at M1 M3 M6 M12 after reinfusion) • Minimal residual disease (at M1 M3 M6 M12 after reinfusion) • 1-year and 2-year OS • 1-year and 2-year EFS • Incidence of Grade 3 or 4 immune related adverse events (gut, liver, lung, endocrine) i.e. linked to Nivolumab (Opdivo®) treatment • Incidence of Grade 3 or 4 of other related adverse events related to Nivolumab (Opdivo®) use such as pneumonitis, stomatitis, rash, or hematologic toxicity. • Incidence of Grade 3 or 4 reinfusion of Tisagenlecleucel (Kymriah®) -related events, in particular - cytokine release syndrome - Immune Effector Cells Associated Neurologic Events (ICANs) - prolonged cytopenias • Incidence of acute and chronic GVHD To explore the PD1 PDL1 axis and its correlation with success or failure;Timepoint(s) of evaluation of this end point: LSLV | — |
Countries
France
Contacts
Public Contactproject manager
Assistance Publique - Hôpitaux de Paris
Outcome results
None listed