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.

The Brown University Oncology Group Experience With FOLFOX + Nab-paclitaxel [FOLFOX-A] for Metastatic and Locally Advanced Pancreatic, BrUOG-292 and BrUOG-318.

OBJECTIVES: To evaluate response rate, toxicity, and efficacy of the novel combination of nab-paclitaxel, oxaliplatin, 5-fluorouracil, and leucovorin [FOLFOX-A] in patients with advanced pancreatic ductal adenocarcinoma [PDAC]. METHODS: BrUOG-292 and BrUOG-318 were two concurrently run, prospective, single-arm phase II studies evaluating FOLFOX-A as first-line therapy in patients with metastatic and locally advanced/borderline resectable PDAC respectively. The FOLFOX-A regimen consisted of 5-fluorouracil, 1200 mg/m 2 /d as a continuous intravenous (IV) infusion over 46 hours, leucovorin 400 mg/m 2 IV, oxaliplatin 85 mg/m 2 IV, and nab-paclitaxel 150 mg/m 2 IV on day 1 every 14 days up to a maximum of 12 cycles. Patients with locally advanced or borderline resectable disease were permitted to stop treatment after 6 cycles and receive radiation therapy and/or surgical exploration if feasible. The primary end point was overall response rate [ORR]. Secondary end points were median progression-free survival [PFS], median overall survival [OS], and safety. RESULTS: Seventy-eight patients with previously untreated PDAC were enrolled between June 2014 and November 2019; 76 patients were evaluable. The median follow-up was 40 months and 32 months, respectively. overall response rate was 34%. Among the patients enrolled on BrUOG-292 [48 patients], the PFS was 5 months and OS was 11 months, respectively. For those enrolled on BrUOG 318 [28 patients], the PFS was 11 months and OS was 22 months. Treatment-related toxicities included grade 3 fatigue [40%], diarrhea [14%], and neuropathy [2%]. CONCLUSIONS: The combination of FOLFOX-A has promising activity in PDAC and may represent an alternative to FOLFIRINOX when reduction of gastrointestinal toxicity is required.

A Pilot Study of Short-course Nivolumab and Low-dose Ipilimumab for Adjuvant Treatment of Melanoma: Brown University Oncology Research Group Trial, BrUOG 324.

BACKGROUND: Combined cytotoxic T-lymphocyte-associated antigen 4 and programmed death 1 inhibitor blockade is a promising strategy in advanced melanoma and other solid tumors. This pilot study assessed the safety and toxicity of nivolumab plus low-dose ipilimumab in patients with high-risk completely resected melanoma. PATIENTS AND METHODS: Patients received ipilimumab, 1 mg/kg every 6 weeks, and nivolumab, 3 mg/kg every 2 weeks, for a total of 24 weeks (4 cycles). The primary objective was to assess the toxicity of the combined regimen. RESULTS: Twenty-one patients with resected melanoma were enrolled. One patient was stage IIC, 16 patients were stage III and 4 patients had resected stage 4 disease. Ten of 21 (48%) had grade 3 treatment-related toxicities but there was no grade 4 or grade 5 toxicities. The rate of grade 3 nonhematologic toxicities exceeded the toxicity limits defined by the study. Fifteen of 21 patients (71%) completed all 4 cycles of therapy. The median follow-up is 41 months. The 2-year recurrence-free survival is 85.7% and the 2-year overall survival is 90.5%. CONCLUSION: A 6-month course of nivolumab and low-dose ipilimumab may be a promising adjuvant treatment for patients with resected melanoma. Further studies of this regimen are indicated.