Study of CAR T-Cells Targeting the GD2 With IL-15+iCaspase9 for Relapsed/Refractory Neuroblastoma or Relapsed/Refractory Osteosarcoma

Summary

Participation Requirements

Description

We plan to conduct a single center, open-label, Phase I clinical trial to establish a safe dose (i.e., number of cells/kg) of autologous iC9.GD2.CAR.IL-15 T-cells in pediatric patients with relapsed or refractory neuroblastoma. The study will enroll a minimum of 10 subjects; all subjects will underg...

We plan to conduct a single center, open-label, Phase I clinical trial to establish a safe dose (i.e., number of cells/kg) of autologous iC9.GD2.CAR.IL-15 T-cells in pediatric patients with relapsed or refractory neuroblastoma. The study will enroll a minimum of 10 subjects; all subjects will undergo lymphodepleting chemotherapy prior to the cell infusion as outlined in section 4.2.2. The continual reassessment method (CRM) will be used to estimate the maximum-tolerated dose (MTD) of cells that can be administered in dose escalation cohorts comprised of 2-6 subjects. The final MTD will be the dose with estimated probability of DLT closest to the target toxicity rate of 20%. The three cell doses that will be evaluated are outlined in the table below starting at the lowest dose level 1: 0.5 x 106 CAR+ cells/kg iC9.GD2.CAR.IL-15 T cells. Cohort enrollment will be staggered and each subject must complete at least 2 weeks of cell treatment without incident of DLT before another subject can be enrolled at that dose level. A minimum of two subjects must complete the 4-week post-infusion DLT safety assessment period before cohort enrollment of subjects at the next higher dose level will be considered. If dose level 1 is determined to be above a tolerable dose, de-escalation would occur to dose level -1 where subjects would receive 0.25 x 106 CAR+ cells/kg. After dose escalation is completed, an expansion cohort will enroll up to 8 subjects at the maximum tolerated dose (MTD) to further assess the safety and efficacy of iC9.GD2.CAR.IL-15 T-cells. In the expansion phase, subjects will receive iC9.GD2.CAR.IL-15 T-cells at the maximum tolerated dose (MTD) with lymphodepletion given prior to a cell product administration. Cell Procurement Up to 3 mL/kg of peripheral blood will be obtained (in up to 3 collections) from patients for cell procurement. For subjects with inadequate lymphocyte count or who are unable to donate adequate amounts of peripheral blood, a leukopheresis may be performed to isolate sufficient T cells. The parameters for pheresis will be up to 2 blood volumes. Approximately 4-6 weeks later, subjects for whom cells have been successfully generated and who meet eligibility criteria for lymphodepletion will undergo lymphodepleting chemotherapy. Lymphodepleting Regimen All subjects will be given lymphodepleting chemotherapy with cyclophosphamide and fludarabine. This will consist of four days total and should be timed to be completed 2-14 days before planned infusion of CAR T-cells. Cyclophosphamide will be given IV 500 mg/m2/day on days 1-2 and fludarabine will be given IV 30 mg/m2/day on days 1-4. No mesna will be required, although it may be used at investigator discretion. Administration of iC9.GD2.CAR.IL-15 T cells Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will receive iC9.GD2.CAR.IL-15 T cells within 2-14 days after completing the lymphodepleting chemotherapy regimen. We will administer T-cells post lymphodepletion as dosed above. After dose escalation is completed, an expansion cohort will enroll up to 8 subjects to further assess the safety and efficacy of iC9.GD2.CAR.IL-15 T-cells. In the expansion phase, patients who meet criteria outlined in Section 4.2.5 will be allowed to receive a second cell infusion. Duration of Therapy Therapy in LCCC 1743-ATL involves infusion of iC9.GD2.CAR.IL-15 CAR T cells. Treatment will be administered unless: Subject decides to withdraw from study treatment, or General or specific changes in the subject's condition render the subject unacceptable for further treatment in the judgment of the investigator. Subject is ineligible for a second infusion Duration of Follow-up Subjects will be followed for up to 15 years for RCR evaluation or until death, whichever occurs first. In addition to this follow-up, subjects removed from study treatment for unacceptable adverse events will be followed until resolution or stabilization of the adverse event. Subjects who receive new therapy after receiving a cell infusion will still be required to complete abbreviated follow up procedures.

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