A phase I trial of the mTOR inhibitor temsirolimus in combination with capecitabine in patients with advanced malignancies

Background: Temsirolimus is an mTOR antagonist with proven anticancer efficacy. Preclinical data suggest greater anticancer effect when mTOR inhibitors are combined with cytotoxic chemotherapy. We performed a Phase I assessment of the combination of temsirolimus and capecitabine in patients with advanced solid tumors. Methods: Patients were enrolled in an alternating dose escalation of temsirolimus (at 15 or 25 mg IV weekly) and capecitabine (at 750, 1000, and 1250 mg/m² twice daily) in separate Q2-week and Q3-week cohorts. At the recommended Phase II doses (RP2Ds) of temsirolimus and capecitabine (Q2), seven patients were also treated with oxaliplatin (85 mg/m², day 1) to determine triplet combination safety and efficacy. Results: Forty-five patients were enrolled and 41 were evaluable for dose-limiting toxicities (DLTs). The most common adverse events (AEs) were mucositis, fatigue, and thrombocytopenia. The most common grade 3/4 AEs were hypophosphatemia and anemia. Five patients had DLTs, including hypophosphatemia, mucositis, and thrombocytopenia. The RP2Ds were temsirolimus 25 mg +capecitabine 1000 mg/m² (Q2); and temsirolimus 25 mg +capecitabine 750 mg/m² (Q3). Of the 38 patients evaluable for response, one had a partial response (PR) and 19 had stable disease (SD). The overall disease control rate was 52%. Five of the 20 patients with SD/PR maintained disease control for >6 months. Conclusions: The combination of temsirolimus and capecitabine is safe on both a Q2-week and a Q3-week schedule. The combination demonstrated promising evidence of disease control in this highly refractory population and could be considered for testing in disease-specific phase II trials.