Scott Susan C, Farago Anna, Lai W Victoria, Zahurak Marianna, Rudek Michelle A, Murray Judy, Carducci Michael A, Uziel Tamar, Takebe Naoko, Gore Steven D, Rudin Charles M, Hann Christine L
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
Cancer Chemother Pharmacol. 2025 Feb 25;95(1):37. doi: 10.1007/s00280-025-04760-1.
To determine the, safety, tolerability and recommended phase 2 dosing of the combination of navitoclax, a dual Bcl-2/xL inhibitor, and vistusertib, a TORC1/2 inhibitor.
Patients with advanced solid tumors received navitoclax plus vistusertib following a 3 + 3 dose escalation design. To mitigate thrombocytopenia, a known toxicity of navitoclax, all patients received lead-in dosing of navitoclax alone at 150 mg orally daily for a minimum of 7 days. In addition to safety and tolerability, pharmacokinetics of navitoclax and vistusertib were evaluated.
14 patients received combination treatment which was well-tolerated at dose level 1 (navitoclax 150 mg orally daily plus vistusertib 35 mg orally twice daily). The main dose-limiting toxicity, grade 3 serum aminotransferase elevation, occurred in two of five patients at dose level 2 (navitoclax 250 mg orally daily plus vistusertib 35 mg orally twice daily). Navitoclax and vistusertib exposures appeared consistent with levels reported in prior studies of each agent. No responses were observed among the 8 response evaluable patients.
A tolerable dose of navitoclax at 150 mg orally daily plus vistusertib at 35 mg orally twice daily was identified in patients with advanced solid tumors and established as the recommended phase 2 dose (RP2D). Further efficacy assessment of this combination, in a planned phase 2 expansion in patients with relapsed small cell lung cancer, was terminated due to discontinuation of vistusertib.
NCT03366103 (First posted December 8, 2017).
确定双重Bcl-2/xL抑制剂维托克洛司（navitoclax）与TORC1/2抑制剂维司他利布（vistusertib）联合使用的安全性、耐受性及推荐的2期给药方案。
晚期实体瘤患者按照3+3剂量递增设计接受维托克洛司加维司他利布治疗。为减轻维托克洛司已知的毒性血小板减少症，所有患者先接受维托克洛司导入剂量，口服150mg，每日一次，至少服用7天。除安全性和耐受性外，还评估了维托克洛司和维司他利布的药代动力学。
14例患者接受了联合治疗，在剂量水平1（维托克洛司口服每日150mg加维司他利布口服每日两次，每次35mg）时耐受性良好。主要剂量限制性毒性为3级血清转氨酶升高，在剂量水平2（维托克洛司口服每日250mg加维司他利布口服每日两次，每次35mg）的5例患者中有2例出现。维托克洛司和维司他利布的暴露量似乎与每种药物先前研究中报告的水平一致。在8例可评估反应的患者中未观察到反应。
在晚期实体瘤患者中确定了每日口服150mg维托克洛司加每日口服两次、每次35mg维司他利布的可耐受剂量，并将其确定为推荐的2期剂量（RP2D）。由于维司他利布停药，在计划中的复发性小细胞肺癌患者2期扩展试验中，对该联合方案的进一步疗效评估终止。
NCT03366103（首次发布于2017年12月8日）
