A Phase I/II Clinical Trial of the First-in-Class GPCR Antagonist ONC201 in Relapsed/Refractory Acute Leukemias
Authors: Borthakur Gautam , Ishizawa Jo , DiNardo Courtney D , Kadia Tapan M. , Weise Katherine , Allen Joshua E , Oster Wolfgang , Cortes Jorge E. , Kantarjian Hagop M. , Andreeff Michael 
Published: October 2019

Abstract
ONC201 is a highly selective G protein-coupled receptor (GPCR) antagonist that is the first-in-class member of the imipridone class of anti-cancer compounds. Preclinical studies have shown that ONC201 is highly effective in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), regardless of resistance to standard-of-care therapies, TP53 mutations, or complex karyotypes. Furthermore, ONC201 equally induces cell death in both the bulk tumor and cancer stem cells (CSC) in a range of malignancies. The anti-CSC activity has been validated in preclinical hematological malignancy models in vitro and in vivo, as well as in primary relapsed/refractory AML patient samples using CD34+CD38- as leukemia stem cell marker (Ishizawa et al, Science Signaling, 2016).
On the basis of robust preclinical activity, a phase I/II clinical trial of single agent ONC201 is ongoing that enrolls adult patients with relapsed/refractory AML, ALL, or high-risk myelodysplastic syndrome. Phase I dose escalates from 125 to 625mg in 3 schedules; once a week, twice a week and once every 3 weeks, using an accelerated titration design. The primary endpoint of Phase I is to determine the recommended Phase II dose and the primary endpoint of phase II is to determine the overall response rate. Secondary endpoints include pharmacokinetics, pharmacodynamics, and other clinical outcomes.
Between December 2015 and July 2016, 6 relapsed/refractory AML patients (median of 4 prior therapies) have been enrolled in dose cohorts ranging from 125 to 625mg ONC201 administered every 3 weeks and one additional AML patient received weekly ONC201 at 125mg. All patients have successfully cleared the DLT window, dose escalation has proceeded uninterrupted, and no drug-related adverse events have been reported. Pharmacokinetic results indicate that all patients achieved a Cmax of >1.4 ug/mL (3.6 uM) that exceeds therapeutic thresholds in preclinical models. The second patient with relapsed/refractory AML and prior therapies that included decitabine, fludarabine and cytarabine and two investigational IDH2 inhibitors showed a reduction in circulating blasts from 78% to 3% after one dose of 250mg ONC201. Furthermore, a >2-log reduction in circulating CD34+CD38- cells was observed in parallel in a time-dependent manner after the first dose of ONC201 in this patient. The fifth AML patient remains on study with stable disease after 5 cycles of 500mg ONC201 despite prior treatments that included azacitidine, eltrombopag, bortezomib, ruxolitinib, and decitabine.
Patient enrollment in the weekly schedules and pharmacodynamics, are ongoing. In agreement with Phase I results in advanced solid tumors (NCT02250781), these early results suggest that ONC201 is a very well tolerated investigational therapy that achieves therapeutic plasma concentrations and shows encouraging preliminary signs of biological activity.
Note: The research being reported in this abstract is research in which The University of Texas MD Anderson Cancer Center has an institutional financial conflict of interest. Because MD Anderson is committed to the protection of human subjects and the effective management of its financial conflicts of interest in relation to its research activities, MD Anderson has implemented an Institutional Conflict of Interest Management and Monitoring Plan (Plan) to manage and monitor the conflict of interest with respect to MD Anderson' s conduct of this research.

Disclosures
DiNardo: Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Agios: Other: advisory board, Research Funding. Allen:Oncoceutics: Employment, Equity Ownership. Oster:Oncoceutics: Employment, Equity Ownership. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Kantarjian:Amgen: Research Funding; Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Andreeff:Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.