Purpose: This phase I study evaluated safety, tolerability, pharmacokinetics, and preliminary activity of the PI3K/mTORC1/2 dual inhibitor gedatolisib combined with carboplatin and paclitaxel. Patients and Methods: Patients with advanced solid tumors treated with ≤ 2 prior chemotherapies received intravenous gedatolisib on days 1, 8, 15, and 22 (95, 110, or 130 mg according to dose level); carboplatin (AUC5) on day 8 (day 1 following protocol amendment); and paclitaxel at 80 mg/m2 on days 8, 15, and 22 (1, 8, and 15 after amendment), every 28 days. Patients without progressive disease after cycle 6 received maintenance gedatolisib until progression. Results: Seventeen patients were enrolled [11 ovarian (10 clear cell ovarian cancer, CCOC), 4 endometrial, 2 lung cancers]. Median number of prior chemotherapies was 1 (range, 0–2). Median number of administered cycles was 6 (range, 2–16). Dose-limiting toxicities occurred in 4 patients: 2 (cycle 2 delay due to G2–G3 neutropenia) at 110 mg leading to a change in the treatment schedule, 2 at 130 mg (G2 mucositis causing failure to deliver ≥ 75% of gedatolisib at cycle 1). The recommended phase II dose is gedatolisib 110 mg on days 1, 8, 15, and 22 with carboplatin AUC5 on day 1 and paclitaxel 80 mg/m2 on days 1, 8, and 15. The most frequent ≥G3 treatment-related adverse events were neutropenia (35%), anemia (18%), and mucositis (12%). The overall response rate was 65% (80% in CCOC). Pharmacokinetic parameters of gedatolisib were consistent with single-agent results. Conclusions: Gedatolisib combined with carboplatin and paclitaxel is tolerable, and preliminary efficacy was observed especially in CCOC.

中文翻译：

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双 PI3K-mTORC1/2 抑制剂 Gedatolisib 联合紫杉醇和卡铂治疗晚期实体瘤患者的 I 期剂量递增研究

目的：本 I 期研究评估了 PI3K/mTORC1/2 双重抑制剂 gedatolisib 联合卡铂和紫杉醇的安全性、耐受性、药代动力学和初步活性。患者和方法：接受过 ≤ 2 次既往化疗的晚期实体瘤患者在第 1、8、15 和 22 天接受静脉注射 gedatolisib（根据剂量水平分别为 95、110 或 130 mg）；第 8 天（方案修订后第 1 天）的卡铂 (AUC5)；第 8、15 和 22 天（修正后的第 1、8 和 15 天）以 80 mg/m2 紫杉醇，每 28 天一次。第 6 周期后没有疾病进展的患者接受维持性 gedatolisib 直至疾病进展。结果：17 名患者入组 [11 例卵巢癌（10 例透明细胞卵巢癌，CCOC），4 例子宫内膜癌，2 例肺癌]。先前化疗的中位数为 1（范围，0-2）。给药周期的中位数为 6（范围，2-16）。4 例患者出现剂量限制性毒性：2 例（由于 G2-G3 中性粒细胞减少导致第 2 周期延迟）110 mg 导致治疗方案改变，2 例 130 mg（G2 期黏膜炎导致 75% 的 gedatolisib 给药失败）循环 1)。推荐的 II 期剂量是第 1、8、15 和 22 天使用 gedatolisib 110 mg，第 1 天使用卡铂 AUC5，第 1、8 和 15 天使用紫杉醇 80 mg/m2。最常见的≥G3 治疗相关不良事件中性粒细胞减少症（35%）、贫血（18%）和粘膜炎（12%）。总体响应率为 65%（CCOC 为 80%）。gedatolisib的药代动力学参数与单药结果一致。结论：Gedatolisib联合卡铂和紫杉醇是可耐受的，尤其是在CCOC中观察到初步疗效。