Scholarlink

Purpose <p>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.</p> Methods <p>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&#xa0;mg orally daily for a minimum of 7 days. In addition to safety and tolerability, pharmacokinetics of navitoclax and vistusertib were evaluated.</p> Results <p>14 patients received combination treatment which was well-tolerated at dose level 1 (navitoclax 150&#xa0;mg orally daily plus vistusertib 35&#xa0;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&#xa0;mg orally daily plus vistusertib 35&#xa0;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.</p> Conclusions <p>A tolerable dose of navitoclax at 150&#xa0;mg orally daily plus vistusertib at 35&#xa0;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.</p> Trial registration <p>NCT03366103 (First posted December 8, 2017).</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

A phase 1 study of the combination of BH3-mimetic, navitoclax, and mTORC1/2 inhibitor, vistusertib, in patients with advanced solid tumors

  • 期刊论文

  • 发表日期：

    2025年2月25日

查看全文
  • Susan C. Scott,
  • Anna Farago,
  • W. Victoria Lai,
  • Marianna Zahurak,
  • Michelle A. Rudek,
  • Judy Murray,
  • Michael A. Carducci,
  • Tamar Uziel,
  • Naoko Takebe,
  • Steven D. Gore,
  • Charles M. Rudin,
  • Christine L. Hann

摘要

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Trial registration

NCT03366103 (First posted December 8, 2017).