醋酸阿比特龙联合双靶点PI3K/mTOR抑制剂BEZ235治疗转移性去势抵抗性前列腺癌的I期研究
A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer.
作者信息
Wei Xiao X, Hsieh Andrew C, Kim Won, Friedlander Terence, Lin Amy M, Louttit Mirela, Ryan Charles J
机构信息
University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, California, USA
University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
出版信息
Oncologist. 2017 May;22(5):503-e43. doi: 10.1634/theoncologist.2016-0432. Epub 2017 Mar 17.
LESSONS LEARNED
The combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored.
BACKGROUND
Androgen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance.
METHODS
This phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy.
RESULTS
Six patients ( = 6) were treated at the starting dose level of abiraterone acetate 1,000 mg with prednisone 5 mg twice daily and BEZ235 200 mg twice daily in a 3 + 3 dose escalation design. The study was terminated early because three of the six patients (50%) experienced dose-limiting toxicities: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. All six patients had previously progressed on abiraterone/prednisone. The median treatment duration was 27 days (range: 3-130 days). No prostate-specific antigen (PSA) decline or objective response were observed.
CONCLUSION
The combination of standard-dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on-target and off-target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile. 2017;22:503-e43.
经验教训
对于转移性去势抵抗性前列腺癌（mCRPC）进展期男性患者，标准剂量醋酸阿比特龙与BEZ235（一种I类泛PI3K和mTORC1/2抑制剂）联合使用时耐受性较差。尽管BEZ235在前列腺癌中的临床开发已终止，但更具选择性地靶向PI3K-AKT-mTOR信号通路的药物可能具有更良好的治疗指数，应继续进行探索。
背景
雄激素受体（AR）和磷脂酰肌醇-3激酶（PI3K）信号通路是前列腺癌中两条常见的受干扰通路。临床前数据表明，当其中一条通路被抑制时，两条通路会相互补偿，联合抑制AR和PI3K信号通路可能是预防或克服去势抵抗的可行策略。
方法
本I期研究评估了醋酸阿比特龙和泼尼松联合BEZ235（一种双重PI3K和mTORC1/2抑制剂）在未接受过先前化疗的转移性去势抵抗性前列腺癌（mCRPC）进展期男性患者中的安全性和耐受性。
结果
6例患者按照3+3剂量递增设计，接受起始剂量水平的醋酸阿比特龙1000mg，每日两次泼尼松5mg和每日两次BEZ235 200mg治疗。该研究提前终止，因为6例患者中有3例（50%）出现了剂量限制性毒性：3级粘膜炎、3级低血压以及4级呼吸困难和肺炎。所有6例患者之前使用阿比特龙/泼尼松治疗时均已进展。中位治疗持续时间为27天（范围：3 - 130天）。未观察到前列腺特异性抗原（PSA）下降或客观缓解。
结论
标准剂量阿比特龙/泼尼松与每日两次200mg BEZ235联合使用时，mCRPC患者耐受性较差。双重PI3K和mTORC抑制的靶向和非靶向效应可能导致了不可接受的毒性反应。2017；22：503 - e43。
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