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 i ntracellular transport, polyglutamation, and antitumor activity compar ed to the parent compound. Edatrexate shows schedule-dependent synergi sm with platinum compounds in preclinical studies. We performed a phas e 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 c ryotherapy was used to reduce the severity of mucositis, Patients and methods: Forty-six chemotherapy-naive patients with advanced solid tum ors 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/m(2) on day 1 and then every 4 weeks for 8 cycles. Edatrexa te dose was increased at increments of 10 mg/m(2)/dose level beginning at 60 mg/m(2)/week (range 60-120 mg/m(2)). Results: All patients were assessable for toxicity and response analysis. The median number of c ycles administered per patients was 4. This combination chemotherapy r egimen was well tolerated. Using ice chip cryotherapy, no grade TV muc ositis was observed. Grade III mucositis occurred in only 7/46 pts and was not dose-related. Protocol-defined dose-limiting toxicity occurre d at a edatrexate dose level of 120 mg/m(2), yielding an MTD of 110 mg /m(2). Responding tumor types included non-small cell and small lung c ancer, head and neck cancer, and bladder cancer. Conclusions: 1) This phase I study demonstrated the safety and tolerability of this edatrex ate and carboplatin combination. 2) Dose-limiting mucositis did not oc cur allowing escalation of edatrexate dose above levels previously ach ieved with this edatrexate dose schedule. This was most likely a resul t of prophylactic ice chip cryotherapy. 3) An edatrexate dose of 110 m g/m(2) with ice chip cryotherapy is recommended for Phase II trials of this combination.