Shin Sarah J, O'Sullivan Coyne Geraldine, Kummar Shivaani, Miller Sarah B, Johnson Barry C, Anderson Larry, Rubinstein Larry, Miller Brandon, Wilsker Deborah F, Ferry-Galow Katherine V, Piekarz Richard, Zlott Jennifer, Hogu Murielle, Juwara Lamin, Krushkal Julia, Konaté Mariam, Palmisano Alida, Zhao Yingdong, Collins Jerry, Parchment Ralph E, Doroshow James H, Chen Alice P
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
Biometric Research Program, National Cancer Institute, Bethesda, Maryland.
Clin Cancer Res. 2025 Jun 3;31(11):2124-2133. doi: 10.1158/1078-0432.CCR-24-3049.
We assessed the safety, maximum tolerated dose, and recommended phase 2 dose (RP2D), efficacy, pharmacokinetics, and pharmacodynamics of the nilotinib-paclitaxel combination in 44 patients with solid tumors.
Paclitaxel was administered intravenously (days 1, 8, and 15), and nilotinib was administered twice daily orally beginning on cycle 1 day 2 (C1D2; escalation) or C1D3 (expansion) in 28-day cycles using a 3 + 3 dose escalation design. Pharmacodynamic biomarkers of drug action were assessed in paired tumor biopsies and circulating tumor cells at the RP2D.
The RP2D was 300 mg nilotinib twice daily with 80 mg/m2 paclitaxel. Grade 4 (Gr4) neutropenia and Gr3 rash, photosensitivity, and transaminase elevation were dose-limiting. The most common Gr3-4 toxicities were hematologic and hypophosphatemia; one patient (2%) experienced Gr3 peripheral neuropathy. Three patients [two with adult ovarian granulosa cell tumors (AOGCT) and one with endometrial carcinoma] had confirmed partial responses (cPR); the patients with AOGCT remained on study for 5 and 6+ years, and mesenchymal-like circulating tumor cells were measured prior to progression or during treatment holiday (patients 12 and 10, respectively).
This study determined the maximum tolerated dose of this combination, demonstrated sustained cPRs in patients with AOGCT, and profiled molecular pharmacodynamic responses that will inform further mechanism-of-action studies. The rate of peripheral neuropathy suggests enhanced tolerability of this combination.
我们评估了尼洛替尼与紫杉醇联合用药在44例实体瘤患者中的安全性、最大耐受剂量、推荐的2期剂量（RP2D）、疗效、药代动力学和药效学。
紫杉醇静脉给药（第1、8和15天），尼洛替尼从第1周期第2天（C1D2；剂量爬坡）或C1D3（扩展）开始每日口服两次，每28天为一个周期，采用3 + 3剂量爬坡设计。在RP2D时，对配对的肿瘤活检组织和循环肿瘤细胞进行药物作用的药效学生物标志物评估。
RP2D为尼洛替尼每日两次，每次300 mg，紫杉醇80 mg/m²。4级（Gr4）中性粒细胞减少以及3级皮疹、光敏反应和转氨酶升高为剂量限制性毒性。最常见的3 - 4级毒性为血液学毒性和低磷血症；1例患者（2%）出现3级周围神经病变。3例患者[2例成人卵巢颗粒细胞瘤（AOGCT）和1例子宫内膜癌患者]获得确认的部分缓解（cPR）；AOGCT患者分别持续研究了5年和6年以上，在疾病进展前或治疗假期期间（分别为患者12和10）检测到间充质样循环肿瘤细胞。
本研究确定了该联合用药的最大耐受剂量，在AOGCT患者中证明了持续的cPR，并分析了分子药效学反应，这将为进一步的作用机制研究提供依据。周围神经病变的发生率表明该联合用药耐受性增强。
