Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands.
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Invest New Drugs. 2020 Oct;38(5):1454-1462. doi: 10.1007/s10637-020-00920-7. Epub 2020 Mar 7.
Background Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or ≤ 1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n = 5) or palliative (n = 10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n = 4), thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (Δ22%, p = 0.013) and decreased the Pt clearance (Δ-28%, p = 0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.
在流行病学研究中，二甲双胍的使用与降低癌症风险有关，并且在卵巢癌模型中具有临床前抗癌活性。本研究的主要目的是确定二甲双胍联合卡铂/紫杉醇在卵巢癌患者中的推荐 II 期剂量（RP2D）。次要目标是描述安全性和药代动力学。
在这项单中心试验中，采用 3+3 递增规则，在三个固定剂量水平上确定了晚期上皮性卵巢癌患者中二甲双胍联合卡铂 AUC 6 和紫杉醇 175 mg/m2每 3 周（q3w）的 RP2D：每天 3 次，每次 500 mg（tds）、每天 3 次，每次 850 mg（tds）和每天 3 次，每次 1000 mg（tds）。二甲双胍在第 1 周期的第 3 天开始使用，并在最后一次化疗给药后 3 周内继续使用。RP2D 定义为 3 名可评估受试者中 0 名或 6 名可评估受试者中≤1 名发生与二甲双胍相关的剂量限制毒性（DLT）的剂量水平。根据 CTCAE v4.0 评估安全性。在第 1 和第 2 个治疗周期中采集用于药代动力学（PK）分析的血浆和血清样本。
共纳入 15 名上皮性卵巢癌患者，有新辅助（n=5）或姑息（n=10）治疗指征。未观察到 DLT。3 名患者在第 1 周期因非 DLT 原因停止治疗。6 名患者接受了二甲双胍 1000 mg tds 的 RP2D 治疗。最常见的低级别毒性是贫血、低镁血症和腹泻。3 级不良事件（AE）发生在 10 名患者中，最常见的是白细胞减少症（n=4）、血小板减少症（n=3）和 GGT 升高（n=3）。没有 4 级 AE。二甲双胍增加了铂（Pt）AUC（增加 22%，p=0.013）并降低了 Pt 清除率（减少 28%，p=0.013）。二甲双胍的血浆水平均在糖尿病患者的治疗范围内（0.1-4mg/L）。
晚期卵巢癌中二甲双胍联合卡铂和紫杉醇的 RP2D 为 1000 mg tds。这高于与靶向药物联合使用的报告 RP2D。确定了二甲双胍与卡铂之间的潜在 PK 相互作用。
