'Figure S1: ONC201 doses versus (A) Cmax and (B) AUC determined after the first dose of ONC201.; Figure S2: Covariant analyses of pharmacokinetic parameters; Figure S3: Caspase-cleaved versus total cytokeratin 18 at baseline and 21 days following the first dose of 625mg ONC201 in (A) an ovarian cancer patient (disease progression within 3 weeks) and (B) a prostate cancer patient (stable disease > 20 weeks). Figure S4: Serum TRAIL ELISA assay following the first dose of ONC201; Figure S5: Serum prolactin induction; Figure S6: Serum prolactin induction versus ONC201 exposure; Table S1. Patient demographics with ONC201 administered every three weeks in dose escalation phase and in the expansion phase with ONC201 RP2D.; Table S2: Adverse events occurring on study that were not attributed to ONC201; Table S3: Individual ONC201 pharmacokinetic parameters for patients in the dose escalation phase; Table S4: Select characteristics of patients in the dose escalation phase. Table S5. Clinical responses and pharmacodynamic in the dose escalation phase.'
ARTICLE ABSTRACTPurpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D).Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information.Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9–19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients.Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks. Clin Cancer Res; 23(15); 4163–9. ©2017 AACR.