NCT05310591

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

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 26 (estimated)
• Sponsor: Assistance Publique - Hôpitaux de Paris · Academic / Other
• Sex: All
• Age: 1 Year – 25 Years
• Healthy volunteers: Not accepted

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

Conditions

• B Acute Lymphoblastic Leukemia
• Acute Lymphoblastic Leukemia, in Relapse

Interventions

Type	Name	Description
DRUG	Decreasing starting times for beginning nivolumab (Time to Event Continual Reassessment Method (TITE-CRM) )	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. 1. Four decreasing starting times for beginning nivolumab (day 14, day 11, day 5 and day -1) will be available for testing 2. 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.
DRUG	Nivolumab starting at day -1	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.

Timeline

• Start date: 2023-03-15
• Primary completion: 2027-03-01
• Completion: 2027-03-01
• First posted: 2022-04-05
• Last updated: 2024-05-29

Locations

13 sites across 1 country: France