Phase II trial of tirapazamine combined with cisplatin in chemotherapy of advanced malignant melanoma

Purpose: A phase II study was undertaken to determine the efficacy oftirapazamine (TPZ) combined with cisplatin (cDDP) in patients with metastaticmelanoma.Patients and methods: Between June 1994 and November 1995, 48 patients withmetastatic melanoma were treated with TPZ (260 mg/m²,administered intravenously over two hours) followed in one-hour by cDDP (75mg/m² over one hour) every 21 days. Sixteen patients hadreceived prior chemotherapy, and 13 of these had failed to respond to priorcDDP. None of the patients had symptomatic brain metastasis.Results: Nine patients had partial responses, with an overall response rateof 19% (95% confidence interval (95% CI) of9%–33%). The median duration of response was six months.None of the responders had received prior chemotherapy. Responses were seenin 8 (33%, confidence interval of 16%–55%) of 24patients with primary cutaneous melanoma who had received no priorchemotherapy and in the only patient with previously untreated conjunctivalmelanoma. There were no responders among the seven patients with choroidalmelanoma and 16 patients with previously treated cutaneous melanoma. Twopatients with partial responses were rendered free of gross disease surgicallythree months after completing eight courses of TPZ-cDDP; they remain free oftumor recurrence. Responses were seen in lymph nodes (27%), lung(26%), skin (20%), adrenal gland (20%), soft tissues(17%) and liver (17%). Common toxicities included muscle cramps,fatigue, gastrointestinal effects and peripheral neuropathy. Fatigue, nausea,vomiting, anorexia, and muscle cramps were grade 3 or 4 in less than10% of the courses. Neutropenia and thrombocytopenia were rare.Conclusion: The TPZ-cDDP combination has definite activity againstchemotherapy-naïve patients with cutaneous melanoma and warrant furtherstudies in combination with other cytotoxic agents.