Metformin is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models, likely through inhibition of the mTOR pathway. The primary study objective was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in ovarian cancer patients. Secondary objectives were to describe safety and pharmacokinetics.
In this phase Ib single-centre trial the RP2D of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 escalation rule at 3 fixed dose levels: 500 mg tds, 850 mg tds and 1000 mg tds. Chemotherapy consisted of carboplatin AUC6 and paclitaxel 175 mg/m2 q3w. Metformin was started on day 3 of the first cycle and continued until three 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) during chemotherapy cycle 1 or 2. Safety was assessed according to CTCAE v4.0. Pharmacokinetic samples were collected during treatment cycles 1 and 2.
Fifteen patients undergoing 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. Preliminary safety data showed that most common low-grade toxicities were anemia and hypomagnesaemia. Grade 3 AE’s occurred in ten patients, most commonly leukopenia (n = 4), thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AE’s. Pharmacokinetic analysis showed a metformin induced increase in AUC of carboplatin (Δ24%, p = 0.028). All metformin trough levels were <4 mg/L.
The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000mg tds. This is higher than the metformin RP2D in combination with targeted agents. The clinical relevance of the metformin-induced increase in carboplatin AUC remains to be elucidated.
Clinical trial identification
Legal entity responsible for the study
University Medical Centre Groningen (UMCG).
Has not received any funding.
All authors have declared no conflicts of interest.