Abstract OT2-19-07: A phase I/Ib trial of the CDK4/6 antagonist ribociclib (RIB) and the HDAC inhibitor belinostat (BEL) in patients with metastatic triple negative breast cancer and recurrent ovarian cancer with response prediction by genomics (CHARGE)
Authors: Sama Shashank , Kelley Kristen , Vaklavas Christos , Bild Andrea , Boucher Kenneth , Lamb John , Lehman Julia , Moos Philip , Werner Theresa , Cohen Adam 
Published: March 2022

Abstract
Background: Cytotoxic chemotherapy is the mainstay of treatment in metastatic triple negative breast cancer (TNBC), a phenotype predictive of poor survival. Similarly, ovarian cancer is the leading cause of death from gynecologic malignancies and shares genomic similarities with TNBC. New treatment paradigms are needed for people with these malignancies. CDK4/6 (CDKi) and histone deacetylase (HDACi) inhibitors are promising treatment approaches in breast cancer though neither has been successfully translated as monotherapy in TNBC. HDACi have single-agent activity against TNBC in vivo, possibly through decreasing epithelial mesenchymal transition, migration, and metastases. CDKi cause cell cycle arrest and tumor regression in TNBC models. HDACi increase inhibitors of cell cycle progression including RB1, CDKN1A, CDKN1C, CDKN2B, and CDKN2D in TNBC in vitro. We hypothesized that HDACi would increase the sensitivity of breast cancer to CDKi. RIB + BEL demonstrated growth inhibition in TNBC cell lines with synergy seen at multiple doses. RIB and BEL are expected to be safe in combination. BEL has no effect on CYP3A4, the main metabolizing enzyme for RIB. Although RIB can inhibit CYP3A4, which partially metabolizes BEL, BEL is primarily metabolized by UGT1A1. Although both drugs can cause myelosuppression, thrombocytopenia occurs more often with BEL and leukopenia with RIB. The primary objective is to assess the maximum tolerated dose of RIB and BEL in combination. Secondary objectives include safety and efficacy. Exploratory objectives include development of a predictive biomarker, exploration of subclonal structure and phenotypic pathway activation through serial biopsies, and efficacy within RB1 mutation status subgroups. We hypothesized that RIB plus BEL will be well-tolerated and demonstrate activity in people with metastatic TNBC or recurrent ovarian cancer. Methods: 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 10 person expansion cohort at the Recommended Phase 2 Dose (RP2D). Dose escalation will be open to patients with TNBC or ovarian cancer and only TNBC will be enrolled at dose expansion. The first cohort uses RIB 200 mg daily and BEL 600 mg/m2 daily on days 1-5 of a 28 day cycle. Tumor is assessed at baseline and every 8 weeks. Biopsies occur at screening and cycle 2 day 15 to establish a predictive biomarker panel that will be validated with future study. Patients ≥ 18 years of age who have measurable and metastatic or unresectable disease are included. Patients previously treated with a CDKi or HDACi are excluded. Additional exclusion criteria include use of valproic acid during the study or within 5 days of the first dose of BEL, prolonged QTc, grade ≥2 unresolved diarrhea, or new or progressive brain metastases. Statistical analysis of safety data will be descriptive. Efficacy will be reported in the study population as well as in RB1 mutation status subgroups. PFS will be estimated using Kaplan-Meier methods. Cox regression will be used to determine if there is a relationship between biomarker predictor and PFS. The estimated duration for accrual is 18 months with patient participation of around 36 months. Enrollment began January 2021 with 2 patients currently enrolled. Clinical Trial registry Number: NCT04315233
Citation Format: Shashank Sama, Kristen Kelley, Christos Vaklavas, Andrea Bild, Kenneth Boucher, John Lamb, Julia Lehman, Philip Moos, Theresa Werner, Adam Cohen. A phase I/Ib trial of the CDK4/6 antagonist ribociclib (RIB) and the HDAC inhibitor belinostat (BEL) in patients with metastatic triple negative breast cancer and recurrent ovarian cancer with response prediction by genomics (CHARGE) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-07.