NIVOLUMAB for B-cell acute lymphoblastic leukaemia (B-ALL)|Relapsed or refractory B-ALL

Inclusion criteria

• {"criterion_text":"- •\tPatients 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)"}
• {"criterion_text":"- •\tpatient must have a second tisagenlecleucel (Kymriah®) product available"}
• {"criterion_text":"- •\tCohort 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"}
• {"criterion_text":"- •\tCohort 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 and/or CSF"}
• {"criterion_text":"- •\tLife expectancy > 12 weeks."}
• {"criterion_text":"- •\tKarnofsky (age > 16) Lansky (age < 16) > 70 at screening."}
• {"criterion_text":"- •\tNo organ dysfunction"}
• {"criterion_text":"- •\tWho have signed an informed consent Affiliation to social security or any health insurance (as a beneficiary or assignee)"}

Exclusion criteria

• {"criterion_text":"- •\tPatient has received intervening systemic therapy* for leukemia after first tisagenlecleucel infusion. (chemotherapy, anti leukemic immunotherapy, ITK, allogeneic HSCT) *systemic therapies exclude intrathecal therapy"}
• {"criterion_text":"- •\tActive CNS involvement by malignancy, defined as CNS-3 per NCCN guidelines at the time of reinfusion of CAR T cells. Note: Patients with history of CNS disease that has been effectively treated will be eligible."}
• {"criterion_text":"- •\tUncontrolled acute life threatening bacterial, viral or fungal infection at Screening."}
• {"criterion_text":"- •\tPatient has an active autoimmune disease requiring systemic treatment within the past 2 years."}
• {"criterion_text":"- •\tPrevious or concurrent malignancy with the following exceptions: o\tAdequately treated basal cell or squamous cell carcinoma o\tIn situ carcinoma of the cervix or breast, treated curatively and without evidence ofreccurrence of at least 3 years prior to the trial o\tA primary malingnacy completelyresected and in CR for ≥ 5 years"}
• {"criterion_text":"- •\tPregnant or lactating women (female trial 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."}
• {"criterion_text":"- •\tPatient has known history of, or any evidence of active, non-infectious pneumonitis."}
• {"criterion_text":"- •\tPatient has a history of non-infectious pneumonitis that required steroid or has current pneumonitis."}
• {"criterion_text":"- •\tHad receive prior therapy with an anti-PD1, Anti- PDL1 or anti-PDL2 agent"}
• {"criterion_text":"- •\tPatient has hypersensivity to pembrolizumab/ nivolumab or one of its excipients"}
• {"criterion_text":"- •\tPatient has received a live vaccine injection within 45 days of planned start of trial therapy."}
• {"criterion_text":"- •\tPrior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease."}
• {"criterion_text":"- •\tPatients 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."}
• {"criterion_text":"- •\tPatients with Burkitt’s lymphoma/leukemia"}
• {"criterion_text":"- Patient with hypersensivity to Fludarabine and/or cyclophosphamide and/or tisagenlecleucel and/or nivolumab or one of their excipients."}
• {"criterion_text":"- •\tPrior treatment with any gene therapy product except first tisagenlecleucel (Kymriah®) injection."}
• {"criterion_text":"- •\tPrior 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®)."}
• {"criterion_text":"- •\tPrior anti-cancer monoclonal antibody within 4 weeks before starting the trial."}
• {"criterion_text":"- •\tPrior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to reinfusion of CAR T cells or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent."}
• {"criterion_text":"- •\tActive or latent hepatitis B or active hepatitis C (test within 8 weeks of Screening), or any uncontrolled infection at Screening."}
• {"criterion_text":"- •\tHuman immunodeficiency virus (HIV) positive test within 8 weeks of Screening."}
• {"criterion_text":"- •\tPresence of grade 2 to 4 acute or extensive chronic GVHD."}

Primary endpoints

• {"endpoint_text":"- Safety: absence of Limiting-toxicities between infusion and D28","definition_or_measurement_approach":"Assessment of limiting toxicities occurring between infusion and Day 28 post-infusion (D28)."}
• {"endpoint_text":"- Efficacy: evaluation at M3 after tisagenlecleucel reinfusion and defined by MRD negative CR AND B cell aplasia","definition_or_measurement_approach":"Efficacy evaluated at Month 3 after tisagenlecleucel reinfusion; defined as complete remission with undetectable minimal residual disease (MRD negative CR) AND B-cell aplasia (B-cell aplasia defined in protocol/cohorts by blood B lymphocytes < 10/mm3 and/or < 3% of total lymphocytes)."}

Secondary endpoints

• {"endpoint_text":"- •\tIncidence of B cell aplasia at 6 months","definition_or_measurement_approach":"Incidence measured at 6 months post-reinfusion using B-cell aplasia definition (blood B lymphocytes < 10/mm3 and/or < 3% of total lymphocytes)."}
• {"endpoint_text":"- •\tIncrease of B cell aplasia duration compared to the previous one observed after the first infusion of tisagenlecleucel (up to 24 months)","definition_or_measurement_approach":"Duration of B-cell aplasia compared to prior duration after first infusion; follow-up up to 24 months."}
• {"endpoint_text":"- •\tDisease best response","definition_or_measurement_approach":"Assessment of best overall disease response per protocol response criteria (timepoints include M1, M3, M6, M12 as applicable)."}
• {"endpoint_text":"- •\tComplete remission (at M1 M3 M6 M12 after reinfusion)","definition_or_measurement_approach":"Complete remission assessed at Months 1, 3, 6 and 12 after reinfusion using standard marrow/blood criteria and MRD measurements."}
• {"endpoint_text":"- •\tMinimal residual disease (at M1 M3 M6 M12 after reinfusion)","definition_or_measurement_approach":"MRD assessed at Months 1, 3, 6 and 12 post-reinfusion using protocol-specified MRD assays."}
• {"endpoint_text":"- •\t1-year OS","definition_or_measurement_approach":"Overall survival measured at 1 year after reinfusion."}
• {"endpoint_text":"- •\t1-year EFS","definition_or_measurement_approach":"Event-free survival measured at 1 year after reinfusion."}
• {"endpoint_text":"- •\tIncidence of Grade 3 adverse up to 2 years events such as -\tnivolumab-related adverse events: myocarditis, pneumonitis, encephalitis -\ttisagenlecleucel reinfusion-related events, in particular CRS or ICANs or aGVH, prolonged cytopenias","definition_or_measurement_approach":"Incidence of specified Grade ≥3 adverse events up to 2 years post-reinfusion per CTCAE grading and protocol definitions (includes nivolumab-related and tisagenlecleucel-related events)."}
• {"endpoint_text":"- •\tIncidence of Grade 3, 4 or 5 nivolumab-related adverse events up to 2 years: gut, liver, endocrine, stomatitis, rash or hematologic toxicity","definition_or_measurement_approach":"Incidence of Grade 3-5 nivolumab-related toxicities up to 2 years graded by CTCAE."}
• {"endpoint_text":"- •\tIncidence of GVHD up to one year","definition_or_measurement_approach":"Incidence of graft-versus-host disease up to one year post-reinfusion assessed per protocol criteria."}
• {"endpoint_text":"- Long term efficacy: 2-year OS and EFS","definition_or_measurement_approach":"Overall survival and event-free survival assessed at 2 years after reinfusion."}
• {"endpoint_text":"- To explore the PD1 PDL1 axis and its correlation with success or failure","definition_or_measurement_approach":"Exploratory biomarker analyses of PD-1/PD-L1 axis and correlation with clinical outcomes per protocol-specified assays."}

France

Earliest CTIS Part Ii Submission Date

23-07-2024

Latest Decision Or Authorization Date

19-08-2024

Processing Time Days

27

Number Of Sites

13

Number Of Participants

26

Primary sponsor

Full Name

Assistance Publique Hopitaux De Paris

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France

Third parties

• {"country":"","full_name":"French Health ministry","duties_or_roles":"","organisation_type":""}