A multi-center, non-randomized, controlled, multi-arm, Phase 1 interventional, open label, biologic assignment-based umbrella study is planned to evaluate the feasibility, safety, and preliminary efficacy of repeated dose regimen of up to 2 doses of TSC-100 and TSC-101 (TSC-100 and TSC-101 is a genetically engineered, donor-derived T cell targeting HA-1 and HA-2 respectively) in patients with AML, MDS, or ALL following HCT from a haploidentical donor. The primary objective of this study is to investigate the safety of single and repeated dosing of TSC-100 and TSC-101 in HLA A*02:01 positive patients undergoing haploidentical allogeneic peripheral blood hematopoietic cell transplantation and determine the optimally tolerated dose range. The primary endpoints are: (1) incidence of dose-limiting toxicities (DLTs), and (2) incidence of adverse events (AEs) and serious AEs (SAEs) of TSC-100 and TSC-101 combined with the standard of care (SOC) compared with the SOC alone at 2 years of follow-up. The study will also investigate the efficacy of TSC-100 and TSC-101 combined with the SOC compared with that of the SOC alone to treat the study population and assess the immunogenicity of TSC-100 and TSC-101.~Depending on the HLA type and minor antigen positivity, patients will receive either TSC-100 or TSC-101 combined with the SOC or only SOC. TSC-100 or TSC-101 will be administered intravenously. Standard of care will include reduced intensity conditioning (RIC), hematopoietic cell infusion, and acute graft-versus-host disease (GvHD) prophylaxis. Patients will undergo one of the following RIC regimens, following standard institutional procedures: fludarabine+cyclophosphamide+total body irradiation, fludarabine+melphalan+/-total body irradiation, or thiotepa+busulfan+fludarabine. In addition, patients may receive other supportive care measures and infectioous prophylaxis as necessary, according to institutional guidelines or standards.~Successive cohorts of patients in the treatment arms will be started according to an interval 3+3 (i3+3) dose escalation design. Once the RP2D is identified, up to 15 additional patients may be enrolled in an expansion cohort at the RP2D. Dose escalations to the next cohort of TSC-100 and TSC-101 will be considered after the safety review committee (SRC) establishes reasonable safety for all patients enrolled into the current cohort. The safety and necessity of repeat dosing will also be determined by the SRC.~The safety data for all patients that received at least one dose of TSC-100 or TSC-101 in the treatment arms will be included in the safety assessment to proceed to the next dosing level and the dose escalation meeting will occur when the last patient in the cohort completes the 40-day DLT evaluation period. Depending on the number of DLTs observed, the range of patients that could be enrolled in the dose escalation stage of this i3+3 study is 27 to 108, including patients in the control arm.
This is a multi-center, non-randomized, concurrent controlled, multi-arm, Phase 1 interventional, open-label, biologic assignment-based umbrella study evaluating the feasibility, safety and preliminary efficacy of an escalating dose regimen of up to 2 doses of TSC-100 and TSC-101 in patients with AML, MDS, or ALL following HCT from a haploidentical donor.