Abstract P2-12-24: A phase I/Ib trial of the CDK4/6 antagonist ribociclib and the HDAC inhibitor belinostat in patients with metastatic triple negative breast cancer and recurrent ovarian cancer with response prediction by genomics (CHARGE)

Abstract Rationale: Metastatic triple negative breast cancer (TNBC) and recurrent ovarian cancer have poor prognoses with survival rates of approximately twenty-three months and thirty-two months, respectively. New treatment paradigms for these malignancies are needed. In Vivo studies have demonstrated promising results in single agent activity of histone deacetylase inhibitors (HDACi) against TNBC. In vitro studies have demonstrated cell cycle inhibition with the use of CDK4/6 inhibitors (CDKi) and synergistic inhibition with the combination of both HDACi and CDKi. We hypothesized that the CDKi ribociclib (RIB) plus the HDACi belinostat (BEL) would be well-tolerated and effective in people with metastatic TNBC or recurrent ovarian cancers. Research objectives: This open-label, multi-center, phase I study follows a modified 3+3 dose escalation design allowing independent escalation of the dose of each of the agents with a ten-person expansion cohort at the maximum tolerated dose (MTD) level. Dose escalation was open to patients with TNBC or ovarian cancer, and only TNBC will be enrolled in the dose expansion. The first cohort at dose level 0 was RIB 200 mg daily and BEL 600 mg/m2 daily on days 1-5 of a 28-day cycle. The RIB dose could be escalated to 400mg on days 8-28, and the BEL could be escalated to 1000mg/m2 daily on days 1-5 of the 28 day cycle. The primary objective of this trial was to assess the maximum tolerated dose of RIB in combination with BEL in patients with metastatic triple negative breast cancer or recurrent ovarian cancer. The secondary objectives were to assess the frequency, severity, and type of adverse events (AEs), and serious adverse events (SAEs). Here we report the final safety results from the 3+3 dose escalation cohort. Results: We enrolled three patients (two ovarian, one TNBC) at dose level 0: RIB 200 mg daily + BEL 600mg/m2 days 1-7 with no dose-limiting toxicities (DLTs). Three patients (one ovarian, two TNBC) were enrolled at dose level 1B: RIB 200 mg daily + BEL 1000 mg/m2 days 1-5 [increased dose of BEL compared to dose level 0]. Two patients experienced a DLT (one prolonged QTc, one allergic reaction). Six patients (three ovarian, three TNBC) were enrolled at dose level 1A: RIB 400 mg days 8-28 + BEL 600 mg/m2 days 1-5. One patient experienced a DLT (prolonged QTc). Therefore, the MTD has been established at dose level 1A: RIB 400 mg days 8-28 + BEL 600 mg/m2 days 1-5. The most common side effects experienced in at least 50% of patients were fatigue, dyspnea, constipation, headaches, and nausea with most AE being grades 1 or 2. Conclusions: The maximum tolerated dose for this regimen has been determined to be 400 mg RIB on days 8-28 with 600mg/m2 BEL dosing on days 1-5. EKG monitoring is needed due to risk of QTc prolongation. We saw no unexpected or IRB reportable serious adverse events, and no indications of significant liver toxicity. The trial has now proceeded to dose expansion and efficacy assessment. Citation Format: Talicia Savage, John G Lamb, Elyse D’Astous, Shashank Sama, Kristen Kelley, Christos Vaklavas, Namita Chittoria, Lauren Mauro, Kathleen Harnden, Takada Harris, Adam L Cohen, Theresa L Werner. A phase I/Ib trial of the CDK4/6 antagonist ribociclib and the HDAC inhibitor belinostat in patients with metastatic triple negative breast cancer and recurrent ovarian cancer with response prediction by genomics (CHARGE) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-12-24.