Novel First-in-Class Drug ONC201 As a Post-Transplant Maintenance for AML and MDS: A Phase I Trial in Progress

Background: Relapses of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation represent an area of significant unmet clinical need and a research priority identified by the National Cancer Institute. For patients with high-risk AML and MDS, post-transplant relapses remain the principal cause of mortality. The role of chemotherapy agents outside of FLT3 inhibitors or TKIs, and post-transplant cellular therapy to prevent relapse of leukemia are not well established. However, chemotherapy agents are frequently utilized off-label in clinical practice, thus signifying an urgent need to develop effective therapeutic strategies. ONC201 is a novel first-in-class small molecule imipridone, that antagonizes G protein-coupled receptor, DRD2 resulting in AKT/ERK inactivation. ONC201 is also an allosteric agonist of mitochondrial caseinolytic protease P that activates an integrated stress responses. In preclinical studies, leukemia cells demonstrate sensitivity to ONC201 regardless of their genetic and mutation profiles. Leukemia cells with genetic and mutation changes such as TP53 mutation and complex karyotype that confer resistance to conventional therapy are sensitive to ONC201. ONC201 is also toxic to leukemia stem cells while sparing normal bone marrow cells [Sci Signal. 2016 Feb 16;9(415):ra17]. Several clinical trials in solid and hematologic malignancies have demonstrated that oral ONC201 has a low toxicity profile and is well tolerated. The profile of ONC201 is well suited for further development to prevent post-transplant relapses of AML and MDS. Here, we report the design of the first trial to use ONC201 as post-transplant maintenance (ClinicalTrials.gov ID: NCT03932643).

Study Design and Methods: The study will follow a 3+3 phase 1 trial design. The primary objective is to determine the rate of dose-limiting toxicities (DLT) during the first cycle and grade ≥3 toxicities during the first 3 cycles. Key inclusion criteria include adult recipients of allogeneic hematopoietic stem cell transplant within 6-20 weeks for a history of high-risk AML or MDS; <5% bone marrow blasts; Karnofsky Performance Status of ≥70; absolute neutrophil count (ANC) greater than 1000/μL, and platelet count ³50,000/µL. Key exclusion criteria include a history of acute graft-versus-host disease (GVHD) grade III/IV; initiation of any new systemic immunosuppressive agent for GVHD within 4 weeks of enrollment, current use of prednisone at a dose of ≥0.25 mg/kg/day; uncontrolled serious infection; active ischemic heart disease, heart failure or arrhythmia; severe chronic obstructive pulmonary disease; resting O2 saturation <90%; aspartate transaminase, alanine transaminase or bilirubin >2 times the upper limit of normal; and creatinine clearance <30 mL/min. Patients will receive oral weekly ONC201 at a starting dose of 250 mg and dose escalation by 125 mg up to a maximum dose of 625 mg weekly, in the absence of DLT. Patients will be monitored for toxicities (using Common Terminology Criteria for Adverse Events, CTCAE version 5.0), quality of life (QOL) (Functional Assessment of Cancer Therapy-Bone Marrow Transplant, FACT-BMT), changes in functional status (KPS, instrumental activities of daily living and short physical performance battery), rates of disease relapse and mortality (See Study Schema). We will enroll a total of 20 patients; the first 6-9 patients are expected to receive escalating doses of ONC 201, and the remaining patients will receive the maximum tolerated doses. Clinical studies in solid malignancies have indicated that ONC201 can expand and activate NK cells in peripheral blood, or recruit CD8+ T-cells to the tumor. Hence, the study will assess expansion and activation of NK and T cell populations in peripheral blood and utilize transcriptomic analyses of NK and T cells to explore the mechanisms behind the immunologic changes.

Bhatt:Jazz: Research Funding; National Marrow Donor Program: Research Funding; Pfizer: Research Funding; Servier Pharmaceuticals: Honoraria; Abbvie: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Genentech: Honoraria; Protagonist: Other: Member, Safety Monitoring Committee ; Chimerix: Other: Drug support for a trial. Al-Kadhimi:Moderna: Current equity holder in private company; Intellia: Current equity holder in private company; Pacific: Current equity holder in private company; Regeneron: Current equity holder in private company. Gundabolu:Blueprint Medicines: Honoraria; Novartis: Honoraria; BMS: Honoraria; BioMarin Pharmaceuticals: Honoraria; Jazz: Honoraria; Samus: Research Funding; Pfizer: Honoraria, Research Funding.