Abstract LB_A13: Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer

Abstract

Abstract Background: The MCT inhibitor CYT-0851 potently inhibits MCT1, has activity against MCT4, and blocks lactate transport resulting in cell death in glycolytic cancer cells. In an in vitro CRISPR screen, thymidylate synthetase was a significant hit in 2 resistant cell models, sensitizing them to CYT-0851. Follow-up in vitro combination studies showed that CYT-0851 synergized with 5-FU to inhibit cancer cell growth. Monotherapy clinical activity of CYT-0851 has been reported previously in lymphoma and solid tumors. In the phase 1 dose escalation trial of CYT-0851 plus cape, 400 mg was identified as the recommended phase 2 dose. In three phase 2 trials, cape had a RECIST response rate of 5-8% in ovarian cancer. Methods: An expansion cohort of 10 patients (pts) with platinum resistant advanced ovarian cancer were treated with CYT-0851, 400 mg QD in combination with cape, 1000 mg/m2 PO BID x 14 days every 21 days and were evaluable. One additional pt treated at the 300 mg dose level was evaluable and added to the analysis. The primary objective was safety, and secondary objectives were pharmacokinetics and preliminary anti-tumor activity by RECIST. Results: As of Aug 21, 2023, 11 pts were treated and evaluable, 9 white, 1 African American black, and 1 American Indian or Alaskan native, with a median age of 64 (range 52-76). Median prior therapies were 6 (range 2-14). All but one had 3 or more prior therapies. Median CYT-0851 dose compliance with continuous daily dosing was 99% (range 91– 100%). There were no treatment discontinuations or CYT-0851 dose reductions for treatment related adverse events. 7 pts (64%) experienced a treatment-related adverse event, all were Grade 1-2. There were no grade 3+ treatment related adverse events. The most common related AEs were fatigue reported in 5 pts (46%), and decreased appetite, diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome and vomiting, each reported in 2 patients (18%). Exposure of CYT-0851 in combination with capecitabine exhibits dose proportional behavior and was similar between combination therapy and monotherapy. One pt had a confirmed PR with progression on day 294, and 2 additional pts achieved a PR that has not been confirmed yet, with treatment ongoing on day 113 and 41. 7 pts had SD, and one patient PD as best response. The disease control rate was 91%. 5 Pts discontinued for progressive disease with a median of 133 days of treatment (range 43-300), and 2 withdrew consent on days 131-134. 4 patients continue therapy on days 42,47,106, and 113. Median PFS was 170 days (95% CI 79-NA). Conclusions: The oral outpatient combination of CYT-0851 and cape has demonstrated an acceptable safety and tolerability profile without any unanticipated toxicities at clinically active doses. The disease control rate of 91% and unconfirmed response rate of 27% in refractory platinum resistant ovarian cancer is promising and warrants further exploration. Furthermore, this regimen should be evaluated in other tumor types commonly treated with 5-FU, including breast and colorectal cancer. Citation Format: Elizabeth Swisher, Gerald Steven Falchook, Pamela N. Munster, Nina Beri, Kathleen N. Moore, Timothy A. Yap, David R. Spigel, Susan Doleman, William D. Bradley, Thomas J. O'Shea, Markus F. Renschler, Ryan C. Lynch. Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A13.