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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. <jats:italic>Methods<\/jats:italic> In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175\u00a0mg\/m<jats:sup>2<\/jats:sup> every 3\u00a0weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3\u2009+\u20093 escalation rule at three fixed dose levels: 500\u00a0mg three times daily (tds), 850\u00a0mg tds and 1000\u00a0mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3\u00a0weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or\u2009\u2264\u20091 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. <jats:italic>Results<\/jats:italic> Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (<jats:italic>n<\/jats:italic>\u2009=\u20095) or palliative (<jats:italic>n<\/jats:italic>\u2009=\u200910) 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\u00a0mg 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 (<jats:italic>n<\/jats:italic>\u2009=\u20094), thrombocytopenia (<jats:italic>n<\/jats:italic>\u2009=\u20093) and increased GGT (<jats:italic>n<\/jats:italic>\u2009=\u20093). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (\u039422%, <jats:italic>p<\/jats:italic>\u2009=\u20090.013) and decreased the Pt clearance (\u0394-28%, <jats:italic>p<\/jats:italic>\u2009=\u20090.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1\u20134\u00a0mg\/L). <jats:italic>Conclusion<\/jats:italic> The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000\u00a0mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.<\/jats:p>","DOI":"10.1007\/s10637-020-00920-7","type":"journal-article","created":{"date-parts":[[2020,3,7]],"date-time":"2020-03-07T18:02:46Z","timestamp":1583604166000},"page":"1454-1462","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Phase I study of metformin in combination with carboplatin\/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer"],"prefix":"10.1007","volume":"38","author":[{"given":"K. Esther","family":"Broekman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke A. 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Broekman, M.A.J. Hof, D.J. Touw, J.D. Lefrandt and A.K.L. Reyners have no conflicts of interest to declare.J.A. Gietema: research grants to the institution of Roche, AbbVie, Siemens.H.W. Nijman: Clinical studies: Aduro, Vicinivax, Merck, DCPrime, AIMM. Founder and stock owner of Vicinivax.M. Jalving<b>:<\/b> Advisory Boards: Merck, BMS, Novartis, Pierre Fabre, Tesaro, AstraZeneca. Speakers\u2019 fees: Sanofi. Clinical studies: BMS, AbbVie, Merck, Cristal Therapeutics. All fees paid to institution.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study protocol was approved by the Medical Ethics Committee of the University Medical Center Groningen (reference number 2013\/505) and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study was registered on , number NCT02312661.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Written informed consent was obtained from all individual participants included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}