Khawaja Muhammad R, Nick Alpa M, Madhusudanannair Vinu, Fu Siqing, Hong David, McQuinn Lacey M, Ng Chaan S, Piha-Paul Sarina A, Janku Filip, Subbiah Vivek, Tsimberidou Apostolia, Karp Daniel, Meric-Bernstam Funda, Lu Karen H, Naing Aung
Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.
Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, TX, USA.
Cancer Chemother Pharmacol. 2016 May;77(5):973-7. doi: 10.1007/s00280-016-3009-7. Epub 2016 Mar 24.
Mammalian target of rapamycin (mTOR) inhibitors like temsirolimus may result in undesirable AKT upregulation. Metformin inhibits mTOR through different mechanisms and may enhance temsirolimus's antitumor activity. We conducted an open-label phase I dose escalation trial of this drug combination in patients with advanced/refractory cancers.
Temsirolimus, 25 mg weekly, was combined with an escalating daily dose of metformin (level 1: 500; level 2: 1000; level 3: 1500; level 4: 2000 mg) by utilizing a standard 3 + 3 trial design. Treatment was administered in 28-day cycles following initial 2-week metformin titration during the first cycle.
Twenty-one patients (median age, 56 years) with sarcoma (n = 8), colorectal (n = 3), endometrial (n = 4), uterine carcinosarcoma (n = 2), ovarian (n = 2), and other (n = 2) cancers were enrolled. Patients had received median of four prior systemic treatments. Two dose-limiting toxicities were observed (grade 3 mucositis, grade 3 renal failure); both patients continued treatment after dose modification. Fifty-six percent patients had stable disease as best response; clinical benefit rate was 22 %. Patients continued treatment for median of 11 weeks.
Combination temsirolimus/metformin was well tolerated with modestly promising effectiveness among this heavily pretreated patient cohort. We recommend a dose of temsirolimus 25 mg weekly and metformin 2000 mg daily for phase II study.
西罗莫司等哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂可能导致不良的AKT上调。二甲双胍通过不同机制抑制mTOR，可能增强西罗莫司的抗肿瘤活性。我们对这种药物组合在晚期/难治性癌症患者中进行了一项开放标签的I期剂量递增试验。
采用标准的3+3试验设计，将西罗莫司（每周25mg）与递增的二甲双胍每日剂量（1级：500；2级：1000；3级：1500；4级：2000mg）联合使用。在第一个周期的最初2周二甲双胍滴定后，以28天周期进行治疗。
入组了21例患者（中位年龄56岁），患有肉瘤（n=8）、结直肠癌（n=3）、子宫内膜癌（n=4）、子宫癌肉瘤（n=2）、卵巢癌（n=2）和其他癌症（n=2）。患者之前接受的全身治疗中位数为4次。观察到2例剂量限制性毒性（3级粘膜炎、3级肾衰竭）；2例患者在剂量调整后继续治疗。56%的患者最佳反应为疾病稳定；临床获益率为22%。患者继续治疗的中位时间为11周。
在这个经过大量预处理的患者队列中，西罗莫司/二甲双胍联合用药耐受性良好，有效性有一定前景。我们推荐在II期研究中使用每周25mg西罗莫司和每日2000mg二甲双胍的剂量。
