Kyriakopoulos Christos E, Braden Amy M, Kolesar Jill M, Eickhoff Jens C, Bailey Howard H, Heideman Jennifer, Liu Glenn, Wisinski Kari B
University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA.
Invest New Drugs. 2017 Jun;35(3):290-297. doi: 10.1007/s10637-016-0418-8. Epub 2016 Dec 21.
Background A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. Tivantinib is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods This open-label phase I study used a 3 + 3 dose escalation design. Patients (pts) were treated with escalating doses of tivantinib (120-360 mg tablets orally twice daily) and temsirolimus (20 mg IV weekly) followed by dose expansion at the MTD. Separate cohorts were planned for extensive (normal) and poor tivantinib metabolizers based on CYP2C19 genotypes. Cycles were 28 days besides cycle 1 that was 35 days to allow for PK analysis. Results Twenty-nine pts. [median age 58 (range 28-77)] were enrolled (21 in dose escalation and 8 in dose expansion). All were extensive CYP2C19 metabolizers. The most common types of cancer were colorectal, ovarian and non-small cell lung. Sixteen out of 21 and 6 out of 8 pts. were evaluable for DLT evaluation per protocol in the dose escalation and dose expansion phases, respectively. Pts remained on study for a median of 71 days (range 18-296). The MTD and RP2D was tivantinib 240 mg twice daily and temsirolimus 20 mg weekly. DLTs included grade (gr) 4 neutropenia (2 pts.; 1 with gr 3 febrile neutropenia), gr 3 abdominal pain (1 pt) and gr 2 mucositis resulting in inadequate drug delivery. The most common treatment related AEs grade ≥ 2 included: anemia (gr 2 in 9 pts., gr 3 in 3 pts), fatigue (gr 2 in 10 pts), anorexia (gr 2 in 9 pts), hypoalbuminemia (gr 2 in 6 pts., gr 3 in 2 pts), hypophosphatemia (gr 2 in 2 pts., gr 3 in 5 pts) and nausea (gr 2 in 6 pts., gr 3 in 1 pt). One pt. with ovarian cancer had a confirmed partial response and remained on study for 10 months, a second patient with ovarian cancer had stable disease and remained on study for 6 months and a third pt. with squamous cell carcinoma of the tongue had stable disease and remained on study for 7 months. Pharmacokinetic analysis showed that there is no interaction in the plasma concentrations between tivantinib and temsirolimus. Conclusions The combination of tivantinib with temsirolimus appears to be well tolerated with evidence of clinical activity.
多种人类癌症表现出c-Met活性失调，这与肿瘤发生有关。c-Met的磷酸化导致PI3K/AKT/mTOR通路激活。在临床前研究中，联合阻断c-Met和mTOR通路已显示出疗效。替万替尼是一种c-Met抑制剂，替西罗莫司是一种选择性mTOR抑制剂。我们旨在确定该联合用药的最大耐受剂量（MTD）、推荐的II期剂量（RP2D）、剂量限制性毒性（DLT）、不良事件（AE）、临床活性和药代动力学（PK）参数。
这项开放标签的I期研究采用3+3剂量递增设计。患者接受递增剂量的替万替尼（120 - 360毫克片剂，口服，每日两次）和替西罗莫司（20毫克，静脉注射，每周一次）治疗，随后在MTD进行剂量扩展。根据CYP2C19基因型，计划为替万替尼代谢广泛（正常）和代谢不良的患者设立单独队列。除第1周期为35天以便进行PK分析外，其余周期均为28天。
29例患者[中位年龄58岁（范围28 - 77岁）]入组（21例在剂量递增阶段，8例在剂量扩展阶段）。所有患者均为CYP2C19代谢广泛者。最常见的癌症类型为结直肠癌、卵巢癌和非小细胞肺癌。在剂量递增阶段和剂量扩展阶段，分别有16/21例和6/8例患者可根据方案进行DLT评估。患者的中位研究时间为71天（范围18 - 296天）。MTD和RP2D为替万替尼每日两次240毫克和替西罗莫司每周20毫克。DLT包括4级中性粒细胞减少（2例；1例伴有3级发热性中性粒细胞减少）、3级腹痛（1例）和2级黏膜炎导致药物输送不足。最常见的≥2级治疗相关AE包括：贫血（9例2级，3例3级）、疲劳（10例2级）、厌食（9例2级）、低白蛋白血症（6例2级，2例3级）、低磷血症（2例2级，5例3级）和恶心（6例2级，1例3级）。1例卵巢癌患者出现确认的部分缓解，持续研究10个月；另1例卵巢癌患者病情稳定，持续研究6个月；第3例舌鳞状细胞癌患者病情稳定，持续研究7个月。药代动力学分析表明，替万替尼和替西罗莫司的血浆浓度之间无相互作用。
替万替尼与替西罗莫司联合用药似乎耐受性良好，并有临床活性证据。
