Phase I trial of a novel first-in-class drug ONC201 as a post-transplant maintenance for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) Free

Background: Relapses of AML and MDS remain the principal cause of mortality after allogeneic hematopoietic cell transplantation (HCT). ONC201 is a novel first-in-class small molecule imipridone that acts as a selective antagonist of the G protein-coupled receptor DRD2, and as an allosteric agonist of mitochondrial protease caseinolytic protease P. In preclinical studies, it has demonstrated activity against leukemia cells including those with TP53 mutation and complex karyotype. ONC201 is toxic to leukemia stem cells but not to normal bone marrow cells. We report the results of the first trial to use ONC201 as post-transplant maintenance.

Methods: We conducted a phase 1 trial (3+3 design) (ClinicalTrials.gov ID: NCT03932643). The primary objective was to determine the rate of dose-limiting toxicities (DLT) during the first cycle and grade ≥3 toxicities. Key inclusion criteria included adult recipients of HCT for high-risk AML or MDS; Karnofsky Performance Status (KPS) of ≥70; absolute neutrophil count (ANC) greater than 1000/μL, and platelet count ≥50,000/µL. Key exclusion criteria included a history of acute graft-versus-host disease (GVHD) grade III/IV; uncontrolled serious infection or significant cardiopulmonary comorbidities; significant hepatic dysfunction (aspartate transaminase, alanine transaminase or bilirubin >2 times the upper limit of normal); and creatinine clearance <30 mL/min. Patients received oral weekly ONC201 for up to 13 cycles, with each cycle being 4-week long. ONC201 was started at a dose of 250 mg with dose escalation by 125 mg up to a maximum dose of 625 mg weekly. Patients were monitored for Adverse Events, AEs (using Common Terminology Criteria for Adverse Events v. 5.0), rates of disease relapse, and mortality.

Results: Between 12/2019 to 8/2023,we enrolled a total of 20 patients (12 with AML and 8 with MDS) with a median age of 68 year (range 39-75 years). 40% were >70 years, and 60% were men. 58% of patients with AML had adverse risk per European Leukemia Network 2017 criteria (58%); 75% of those with MDS had very poor-risk per International Prognostic Scoring Sytem-Revised. 39% had TP53 mutations; 30% had complex karyotype. Other common high-risk mutations included U2AF1 (18%), ASXL1 (17%), BCOR (17%), STAG2 (17%). 25% of AML had measurable residual disease before HCT. KPS was 80 (range 70-90). 60% had HCT comorbidity index of ≥3. 70% received reduced intensity and 30% received myeloablative conditioning. GVHD prophylaxis included tacrolimus and methotrexate with or without antithymocyte globulin. All patients received peripheral blood grafts, mostly from matched unrelated (55%) or related donors (35%). 10 patients (1 unevaluable) received doses of 250-500 mg, whereas the remaining 10 patients received 625 mg doses. Patients received a median of 8.5 cycles (range 1-13) of ONC201. No DLTs were noted. One patient died (after 8 cycles of treatment) from late-onset acute liver GVHD, likely triggered by tacrolimus taper, and not attributed to the study drug. Grade 1-4 acute GVHD was noted in 30%, with grade 3-4 acute GVHD noted in 5%. No graft failure was noted. Any grade AEs, and grade ≥3 AEs occurred in 95% (70% related) and 45% (15% related), respectively. Serious AEs were reported in 40% (15% related). Grade 3-4 cytopenias were infrequent: anemia (15%), neutropenia (10%), and thrombocytopenia (15%). At 2 years, relapse-free and overall survival (OS) were 65% (95% confidence interval, CI 47-90%) and 70% (95% CI 53-93%), respectively.

Conclusion: ONC201 was well tolerated with no observed DLT and a manageable safety profile. The AE profile was not different from AEs expected in a post-transplant population. Rates of cytopenias were low. The 2-year OS of 70% in this high-risk population is encouraging. Given its favorable safety profile, oral weekly dosing, and preclinical synergy with other drugs such as azacitidine, ONC201 is well suited for further development including as a combinatorial therapy to prevent post-transplant relapses of AML and MDS.