Phase I trial of edatrexate plus carboplatin in advanced solid tumors: Amelioration of dose-limiting mucositis by ice chip cryotherapy

Purpose: Edatrexate (10-Edam) is a methotrexate analog with improved intracellular transport, polyglutamation, and antitumor activity compared to the parent compound. Edatrexate shows schedule-dependent synergism with platinum compounds in preclinical studies. We performed a phase I trial to determine toxicities and establish the maximum tolerated dose (MTD) of edatrexate in combination with carboplatin. Based on the short initial plasma half-life of edatrexate, prophylactic ice chip cryotherapy was used to reduce the severity of mucositis. Patients and methods: Forty-six chemotherapy-naive patients with advanced solid tumors were treated. Edatrexate was given weekly for 5 doses (50% on day 8), and then every other week, followed by carboplatin at a fixed dose of 350 mg/m² on day 1 and then every 4 weeks for 8 cycles. Edatrexate dose was increased at increments of 10 mg/m²/dose level beginning at 60 mg/m²/week (range 60-120 mg/m²). Results: All patients were assessable for toxicity and response analysis. The median number of cycles administered per patients was 4. This combination chemotherapy regimen was well tolerated. Using ice chip cryotherapy, no grade IV mucositis was observed. Grade III mucositis occurred in only 7/46 pts and was not dose-related. Protocol-defined dose-limiting toxicity occurred at a edatrexate dose level of 120 mg/m², yielding an MTD of 110 mg/m² Responding tumor types included non-small cell and small lung cancer, head and neck cancer, and bladder cancer. Conclusions: 1) This phase I study demonstrated the safety and tolerability of this edatrexate and carboplatin combination. 2) Dose-limiting mucositis did not occur allowing escalation of edatrexate dose above levels previously achieved with this edatrexate dose schedule. This was most likely a result of prophylactic ice chip cryotherapy. 3) An edatrexate dose of 110 mg/m² with ice chip cryotherapy is recommended for Phase II trials of this combination.