The Courage study: A first-in-human phase 1 study of the CBP/p300 inhibitor FT-7051 in men with metastatic castration-resistant prostate cancer.

TPS5085 Background: Prostate cancer is the second leading cause of cancer-related death among men in the U.S., largely due to metastatic disease that progresses despite hormonal therapy (tx). The role for androgen receptor (AR) signaling in prostate cancer and hormone tx resistance is well-established. CBP/p300 are essential co-activators of AR-mediated transcription. FT-7051 is an oral, potent, and selective inhibitor of CBP/p300 with activity in preclinical models of prostate cancer including models resistant to currently used AR inhibitors like enzalutamide. The Courage Study (NCT04575766) is a first-in-human, multicenter, phase 1, open-label study examining the safety, pharmacokinetics (PK), preliminary anti-tumor activity, and pharmacodynamics (PD) of FT-7051 for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have progressed despite prior tx and have been treated with at least one approved androgen receptor pathway inhibitor. The study will enroll up to 45 men with mCRPC at ̃8-15 US sites. Methods: The study employs a Bayesian optimal interval (BOIN) design with an accelerated titration. Patients (pts) will initially be enrolled in a dose level cohort size of 1 until a Grade 2 or higher toxicity occurs that is considered related to FT-7051 or the highest dose level is reached. Upon completion of the accelerated titration phase, subsequent cohorts will enroll 3-5 pts. Treatment: FT-7051 capsules will be administered on a 28 d cycle (21 d on / 7 d off) with Dose Levels -1 to 7 assigned per protocol using the BOIN design. Key inclusion criteria: Diagnosis of mCRPC with either adenocarcinoma or mixed histology AND rising PSA; previously failed at least one approved androgen receptor pathway inhibitor; ≥ 18 yrs of age; prior taxane chemotherapy permitted. Key exclusion criteria: Previous solid organ transplant, prior anticancer tx including prior tx with small molecules within 4 wks of first dose of study treatment, prior radiation tx within 4 wks prior to initiation of study treatment, prior androgen antagonist tx within 2 wks, prior radium-223 tx within 6 wks. Endpoints: Primary endpoints are to define the recommended phase 2 monotherapy dose of FT-7051 through assessments of DLTs, SAEs, clinically relevant AEs, and clinically relevant safety laboratory values. Key secondary endpoints include: PSA at 12 wks, time to PSA progression, time to radiographic progression, overall response rate, and plasma PK parameters. PD assessments of CBP/p300 inhibition in surrogate tissue, biomarker assessments in CTCs (AR, AR-v7), and peripheral blood are included. Duration: Pts will remain on study treatment until they are deemed to be no longer clinically benefiting (NLCB) by the treating Investigator or until unacceptable toxicity. Pt may be followed for survival for up to 24 months from last dose of study treatment. The first pt was dosed January 2021. Clinical trial information: NCT04575766.