Initial findings from an ongoing first-in-human phase 1 study of the CBP/p300 inhibitor FT-7051 in men with metastatic castration-resistant prostate cancer

Background: Prostate cancer is the 2^nd leading cause of cancer-related deaths among men in the US. CREB binding protein (CBP) and paralog p300 are co-activators of androgen receptor (AR) relevant to metastatic castration-resistant prostate cancer (mCRPC) progression and AR therapy resistance. FT-7051 is an oral, potent and selective inhibitor of CBP/p300 bromodomain with activity in preclinical prostate cancer models, including those resistant to enzalutamide. Methods: The Courage Study (NCT04575766) is a first-in-human, multicenter, phase 1, open-label study to examine the safety, PK/PD, and preliminary anti-tumor activity of FT-7051 in mCRPC patients (pts) who have progressed despite prior therapy, including at least one AR pathway inhibitor. The study uses a Bayesian optimal interval (BOIN) design with an accelerated titration phase. FT-7051 is dosed on a 28-d cycle (21-d on/7-d off). Following accelerated titration, dose escalation/de-escalation decisions are made by comparing the observed dose-limiting toxicity (DLT) rate at the current dose with pre-specified dose escalation/de-escalation boundaries. The primary objectives are to evaluate safety and tolerability of FT-7051 and determine the recommended phase 2 dose. Key secondary endpoints include PSA at 12 wks, time to PSA progression, time to radiographic progression, overall response rate, and PK parameters. Biomarker analyses include PD assessments of CBP/p300 inhibition in surrogate tissues and genetic analyses in circulating tumor cells (AR, AR-v7) and peripheral blood. Results: As of 18-June-2021, a total of 5 pts were enrolled with exposure data entered into the database, with 2 pts ongoing and 3 pts discontinued (disease progression, n=1; no longer clinically benefitting, n=1; subject withdrawal, n=1). Pts had a median age of 71 yrs (range: 66-82) with a median time since first mCRPC diagnosis of 2.3 yrs (0.4-4.7) and a median of 3 (1-5) prior lines of mCRPC therapy. Mutations reported by the investigator for 3 pts included MYC, p53, RB1, AR, and PTEN loss. Preliminary PK analyses indicated that FT-7051 exposure increased with dose in a greater than dose-proportional manner. Importantly, observed FT-7051 exposures were consistent with the predicted efficacious exposure threshold derived from PK/efficacy modeling in preclinical studies. TEAEs were reported in 4 (80%) pts. Most TEAEs were mild (Gr1) or moderate (Gr2), ≥Gr3 TEAEs included one event of possibly related Gr3 hyperglycemia and one event of unrelated Gr5 disease progression. Conclusions: Preliminary safety and PK data from the accelerated titration phase of this BOIN study support the continued investigation of FT-7051 in men with mCRPC. Initial PK data confirm that FT-7051 exposure is consistent with the predicted efficacious exposure threshold determined by PK/efficacy modeling. Additional analyses of PSA, PD assessments, and genetic analyses, including AR-v7 status, will be reported. Citation Format: Andrew J. Armstrong, Michael S. Gordon, Melissa A. Reimers, Arif Hussain, Vaibhav G. Patel, Elaine T. Lam, Alex Sedkov, Von Potter, Neal Shore. Initial findings from an ongoing first-in-human phase 1 study of the CBP/p300 inhibitor FT-7051 in men with metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P202.