Carboplatin + Metformin + Paclitaxel

The combination of carboplatin, metformin, and paclitaxel is an investigational treatment regimen primarily studied for advanced epithelial ovarian cancer. This combination brings together two established chemotherapy agents (carboplatin and paclitaxel) with metformin, an oral anti-diabetic medication that has shown potential anti-cancer properties in preclinical studies. ## Mechanism and Development This combination therapy works through multiple mechanisms. Carboplatin and paclitaxel are chemotherapy drugs that destroy quickly dividing cells, such as cancer cells[3]. Carboplatin functions as an alkylating agent, while paclitaxel disrupts cell division. Metformin, traditionally used for diabetes, has demonstrated anti-cancer properties by inhibiting intracellular pathways, particularly through AMPK activation and mTOR inhibition[6]. Clinical trials have established that the recommended Phase II dose (RP2D) of metformin in combination with carboplatin and paclitaxel is 1000 mg three times daily (3000 mg/day)[1]. This dosage is higher than in other early phase trials where metformin was combined with different anti-cancer therapies, possibly due to the use of an intra-patient dose-escalation scheme that improved tolerability[1]. ## Clinical Studies and Efficacy A Phase II, open-label, non-randomized, prospective study evaluated this combination in first-line treatment of advanced-stage ovarian, fallopian tube, and primary peritoneal carcinoma. Thirty subjects received a median of 6 cycles of primary induction chemotherapy, with 23 patients exhibiting a complete response and 3 patients obtaining a partial response (overall response rate of 86.7%)[2]. The median progression-free survival was 21 months and overall median survival was 35 months[2]. Another ongoing Phase Ib/II study is investigating metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced ovarian cancer. The Phase II portion aims to determine the activity of adding metformin to carboplatin/paclitaxel neoadjuvant chemotherapy[4]. ## Safety Profile The combination of metformin with carboplatin and paclitaxel has been found to be tolerable with no dose-limiting toxicities in Phase I studies[1]. Common adverse events include: - Hematological toxicity: Grade 3-4 neutropenia (43.3%), thrombocytopenia (10%), and anemia (36.7%)[2] - Gastrointestinal effects: Diarrhea occurred in 53% of patients in one study (all grade 1-2)[1] and in 66.7% of patients (grade ≤2) in another study[2] - Hypomagnesemia: Observed in 80% of patients in one trial, though mostly mild (grade 1-2)[1] - Neurotoxicity: No grade 3-4 neuropathy was observed in one study, though 50% of patients developed grade ≤2 neurotoxicity[2] These side effects are generally consistent with what would be expected from carboplatin and paclitaxel chemotherapy, with the addition of metformin-related gastrointestinal effects. ## Administration In clinical trials, this combination was typically administered as follows: - Paclitaxel: Intravenous infusion over 3 hours - Carboplatin: Intravenous infusion over 30-60 minutes - Metformin: Oral administration, with dose escalation to improve tolerability The treatment is typically given in cycles, with each cycle lasting 21 days, and patients receiving up to 6 cycles of primary therapy followed by maintenance therapy in some protocols[2][3].

Other names

Metformin HydrochloridePaclitaxel/Carboplatin/Metformin