A Phase 1/2 interventional study of Decreasing starting times for beginning nivolumab (Time to Event Continual Reassessment Method (TITE-CRM) ) and Nivolumab starting at day -1 in B Acute Lymphoblastic Leukemia and Acute Lymphoblastic Leukemia, in Relapse, sponsored by Assistance Publique - Hôpitaux de Paris. Recruiting at 13 sites in France. Open to participants aged 1 Year to 25 Years. Per ClinicalTrials.gov, last updated 2024-05-29.
Sponsored by Assistance Publique - Hôpitaux de Paris · Phase 1/2, Interventional, and Treatment
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:
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).
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
5,441 studies on the registry are indexed under Leukemia; 636 are open to participants now.
This study's planned enrollment of 26 is below the median of 38 across 4,247 interventional studies indexed under Leukemia.
Browse Leukemia studies →Assistance Publique - Hôpitaux de Paris is the lead sponsor of 3,505 studies on the registry; 1,006 are open to participants now.
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Exclusion Criteria:
Previous or concurrent malignancy with the following exceptions:
Drug: Decreasing starting times for beginning nivolumab (Time to Event Continual Reassessment Method (TITE-CRM) )
Drug: Nivolumab starting at day -1
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.
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.
Proportion of patients with limiting-toxicities
Limiting toxicities are defined by the occurrence of either - Related to CAR-T cells infusion: CRS or aGVH: limiting toxicity will be defined as toxicity ≥ 4 ICANs: limiting toxicity will be defined as toxicity ≥ 3 (excepted grade 3 seizure, ie focal, generalized seizure that resolves rapidly) - Related to nivolumab: immune related myocarditis, pneumonitis, encephalitis: limiting toxicity will be defined as toxicity ≥ 4
Time frame: at day 28
Efficacy assessed by Minimal residual disease (MRD) negative Complete remission (CR) and B cell aplasia.
MRD negative CR is defined by undetectable disease at a 10-4 sensitivity threshold B cell aplasia is defined by blood B lymphocytes \< 10 /mm3 and/or \< 3% of total lymphocytes
Time frame: at 3 months
Incidence of B cell aplasia
Time frame: at 6 months
Increase of B cell aplasia duration compared to the previous one observed
Time frame: up to 24 months
Proportion of patients with Disease best response
Time frame: up to three months
Proportion of patients with Complete remission
Time frame: at 1 month
Proportion of patients with Complete remission
Time frame: at 3 months
Proportion of patients with Complete remission
Time frame: at 6 months
Proportion of patients with Complete remission
Time frame: at 12 months
Proportion of patients with Minimal residual disease
Time frame: at 1 month
Proportion of patients with Minimal residual disease
Time frame: at 3 months
Proportion of patients with Minimal residual disease
Time frame: at 6 months
Proportion of patients with Minimal residual disease
Time frame: at 12 months
Overall survival
Time frame: at one year
Overall survival
Time frame: at 2 years
Event Free Survival (EFS)
Time frame: at 1 year
Event Free Survival (EFS)
Time frame: at 2 years
Incidence of Grade 3 adverse events
Time frame: up to 2 years
Incidence of Grade 3, 4 or 5 nivolumab-related adverse events
Time frame: up to 2 years
Incidence of GVHD
Time frame: up to one year
Plan to share: Undecided
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Assistance Publique - Hôpitaux de Paris