A Phase 1/2, Open-Label, Randomized, Dose-Finding and Dose Expansion Study of Gedatolisib in Combination with Darolutamide in Metastatic Castration-Resistant Prostate Cancer (Mcrpc).

Elisabeth I. Heath,Adam Sharp,Delphine Borchiellini, Johann S. De Bono,Karim Fizazi,Gwenaelle Gravis,David Lorente,Hakim Mahammedi, Bego Na Mellado-Gonzalez,David Olmos,Simon Pacey,Josep M. Piulats, Sara Perez Ramirez,Igor Gorbatchevsky,Alice Bernard-Tessier

Journal of Clinical Oncology（2024）

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Abstract

TPS5109 Background: Progression to metastatic castration-resistant prostate cancer (mCRPC) occurs in most patients treated with androgen receptor signaling inhibitors (ARSi) for advanced disease. Preclinical studies demonstrate that AR and PI3K - AKT - mTOR (PAM) pathways interact through reciprocal negative feedback, whereby inhibition of one pathway activates the other. Thus, combining a PAM inhibitor with an ARSi may deliver improved anti-cancer activity in patients with mCRPC. A Phase 2 trial in 129 patients with mCRPC who progressed on abiraterone demonstrated improved median radiographic progression-free survival (rPFS) when samotolisib, a dual PI3K-mTOR inhibitor, was added to enzalutamide. These results form the basis for this clinical trial of gedatolisib, a potent PAM inhibitor, in combination with darolutamide in men with mCRPC who have previously progressed on ARSi. Methods: This open-label, multicenter, Phase 1/2 study will evaluate the safety and efficacy of gedatolisib in combination with darolutamide in men with mCRPC who have progressed on ARSi. In Phase 1, 36 patients will be randomized to one of two dose arms to evaluate dose limiting toxicities (DLTs) and determine the recommended Phase 2 dose (RP2D). Gedatolisib will be administered once weekly for 3-weeks-on/1-week-off: Arm 1 – 120 mg and Arm 2 – 180 mg, with darolutamide 600 mg orally administered twice daily. Arm 2 may be dose de-escalated depending on the number of DLTs observed. In Phase 2, 12 additional patients will be enrolled at the RP2D (n= 30). Key inclusion criteria include adult males (≥ 18 years) with mCRPC who have progressed on or after treatment with one next-generation ARSi. Key exclusion criteria include males with adenocarcinoma with a small cell component and with ≥10% neuroendocrine type cells; prior treatment with PI3K, AKT, or mTOR inhibitor; prior chemotherapy or radiopharmaceutical therapy for mCRPC; uncontrolled type 1/2 diabetes; or active brain or leptomeningeal metastases. Primary endpoints for Phase 1 are safety and tolerability (incidence of DLTs, adverse events, and determination of maximum tolerated dose) determination of the recommended Phase 2 dose (RP2D), PK, and Bayesian Optimal Interval utility score. Primary endpoints for Phase 2 are rPFS rate at 6 months based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 with modifications as specified in Prostate Cancer Working Group 3 criteria. Secondary endpoints include rPFS rates at 9 and 12 months, overall rPFS, prostate-specific antigen response of ≥50% decrease from baseline at 4, 8, 12, and 16 weeks, overall response rate, duration of response, clinical benefit rate, overall survival rate at 18 and 24 months, and safety. The trial is currently open for enrollment (NCT06190899). Clinical trial information: NCT06190899 .

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【要点】：本研究是一项开放标签、随机、剂量寻找和剂量扩展的1/2期临床试验，旨在评估gedatolisib与darolutamide联合用于治疗转移性去势抵抗性前列腺癌（mCRPC）的安全性和有效性，其创新点在于结合了PI3K/AKT/mTOR抑制剂与雄激素受体信号抑制剂来提高抗肿瘤活性。

【方法】：该研究采用开放标签、多中心的设计，首先在1期对36名患者进行剂量限制毒性（DLT）评估和推荐2期剂量（RP2D）的确定，然后在2期对12名额外患者进行评估。

【实验】：实验分为两个剂量组（Arm 1为120 mg，Arm 2为180 mg），gedatolisib每周一次，连续三周用药后休息一周，darolutamide每天两次，每次600 mg。该试验目前开放招募（NCT06190899），主要终点包括1期的安全性和耐受性（DLT的发生率、不良事件和确定最大耐受剂量）及2期的6个月时基于RECIST v1.1的放射学无进展生存率（rPFS）。