Nivolumab plus ONC201 plus in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients: a Brown University Oncology Research Group phase Ib/II study (BrUOG379).

Background: Immune checkpoint inhibitors alone, or in combination with chemotherapy failed to provide meaningful clinical activity for patients with microsatellite stable (MSS) colorectal cancer (CRC). ONC201 is a small molecule that inactivates AKT and ERK signaling and actives the TRAIL pathway. Preclinical studies indicated potential benefits of combining ONC201 with checkpoint inhibitors. This is a phase Ib/II trial of ONC201 plus nivolumab for patient with MSS CRC who progressed on standard treatment.

Methods: Enrolled patients received ONC201 plus nivolumab in a dose de-escalation fashion to determine the maximum tolerated dose (MTD). Additional patients were enrolled in the dose-expansion cohort. ONC201 at a dose of 625 mg was given orally at day -7 of cycle 1, followed by weekly dosing. Nivolumab was given every 2 weeks at 240 mg IV starting on day 1 of every cycle (cycle =28 days). The primary end point was dose-limiting toxicity (DLT) during the observation window (run-in dose day -7, cycle 1 to assessment pre-dosing cycle 2). The plan was to enroll 28 additional patients at the MTD so that a total of 34 patients would be treated at the MTD. Pharmacokinetics (PKs) and tumor biopsies were collected at several time points per study protocol.

Results: A total of 13 patients (8 patients in the dose escalation *6 evaluable*) were enrolled between December 4, 2019 and March 2021. All patients had received ≥2 previous lines of chemotherapy and had confirmed microsatellite stability or mismatch repair-proficient tumors. No DLTs were observed with 625 mg ONC201 in the first three patients. Three additional patients were enrolled at the same dose to confirm safety. Two patients progressed during the DLT period and had to be replaced. During the dose-expansion part, five patients were enrolled and none required dose reduction or modification. No objective tumor response was observed in the 13 treated patients. Disease progression was confirmed at the time of the first imaging evaluation at 8 weeks following cycle 2. Post discussion at the Data and Safety Monitoring Board (DSMB) on May 25, 2021, the principal investigator (PI) and Committee voted to close the study to new patient enrollment prior to reaching accrual of 34 patients, secondary to lack of efficacy.

Conclusions: In this study of patients with advanced MSS CRC, combination ONC201/nivolumab was well-tolerated; objective responses to ONC201/nivolumab were not observed.