Trials in progress: Design of a registrational Phase 2 trial (ALLOHA) using an external control arm for TSC-101 for prevention of relapse post allogeneic HCT in patients with ALL, AML, or MDS

Abstract ALLOHA™ (NCT05473910) is a multi-center, Phase 1/2 study evaluating the safety and efficacy of TSC-101 to prevent relapse in HLA-A*02:01-positive adults with AML, MDS, or ALL eligible for reduced intensity conditioning-based allogeneic HCT (RIC-HCT) using an HLA-A*02-negative haploidentical (haplo) or mismatched unrelated donor (MMUD). TSC-101 is a TCR-engineered T-cell (TCR-T) therapy candidate targeting the minor antigen HA-2 presented on HLA-A*02:01 that is designed to eliminate patient hematopoietic cells post-HCT to prevent relapse while protecting donor graft cells. In the Phase 1 portion of the study, treatment-arm subjects receive one or two infusions of TSC-101 post-engraftment. HLA-A*02:01-negative patients and HLA-A*02:01-positive patients without an eligible HLA-A*02-negative donor are assigned to the control arm and receive standard of care RIC-HCT. Initial results from the ongoing Phase 1 study show encouraging safety and preliminary efficacy of TSC-101. Notably, no dose-limiting toxicities have been observed at any dose level, and TSC-101 treated subjects have demonstrated improved relapse rates, relapse-free survival (RFS), and overall survival (OS). Based on these encouraging initial results from the ongoing Phase 1 study, TSC-101 was granted Regenerative Medicine Advanced Therapy (RMAT) designation in 2024. The Phase 1 study will be amended to open a pivotal, multi-center, Phase 2 cohort designed to investigate the efficacy of two infusions of TSC-101 following RIC-HCT in HLA-A*02:01-positive patients with AML, MDS, or ALL compared to an external control arm derived from the CIBMTR registry. Up to approximately 150 treatment subjects will be enrolled from ~25 US HCT sites. At the time of the interim and final analyses, up to 3 well-matched controls will be selected for each treatment arm subject. Potential control arm subjects will first be identified from the CIBMTR database using similar inclusion/exclusion criteria (i.e., first allo-HCT from 2022 to present using haplo or MMUD with RIC-PTCy for AML, ALL, MDS). Eligible control-arm subjects will then be matched to treatment-arm subjects using a combination of exact and propensity score matching on key prognostic covariates such as disease type, conditioning regimen, and disease risk category to minimize potential bias. The primary endpoint is RFS, and the trial is powered to detect a hazard ratio of ≤0.6. Other endpoints will include OS, time to relapse, event-free survival, and exploratory biomarkers of efficacy. In conclusion, the ALLOHA study is designed to explore the novel paradigm of engineered TCR-T cells post allogeneic HCT to eliminate residual disease cells, prevent relapse, and maximize long-term remission and survival.