Hexamethylmelamine (HMM) and oral etoposide (VP-16) have shown to be active against platinum-resistant epithelial ovarian cancer. On this basis a three-drug regimen including carboplatin (CBDCA) plus HMM and oral VP-16 was tested in previously untreated ovarian cancer patients with tumor size > 2 cm. Since October 1991, 29 chemotherapy-naive ovarian cancer patients with tumor larger than 2 cm (20 stage III and 9 stage IV) have been treated for a total of 153 courses. CBDCA was administered i.v. on Day 1. The dose was individualized using the Calvert formula (the target dose was AUC = 5). VP-16 was administered orally at the dose of 50 mg/m2 Days 1-14, HMM at the dose of 150 mg/m2 po Days 14-28. Therapy was repeated every 28 days for a total of 6 courses. In order to avoid severe leukopenia and delays in the treatment administration, G-CSF 5 micrograms/kg/day sc Days 8-14 (or until postnadir recovery of neutrophil count > 10,000/mm3) and Days 22-28 was administered. All patients were evaluable for toxicity. No treatment-related deaths occurred. Myelotoxicity was the main side effect. It was grade 3-4 in a total of 13/29(45%) patients. One patient discontinued treatment after the first course due to HMM-related gastrointestinal toxicity. The actual delivered dose intensity was 89% of the planned dose. At the time of this analysis (April 1994) 26 patients are evaluable for response. Fifteen patients achieved a clinical complete remission and 9 a partial response for a 92% overall response rate. Fourteen patients accepted second-look laparotomy. We observed 11 pathological complete regressions (42%; 95% CI, 21-63). At a median follow-up of 16 months 3 deaths have occurred. Only 2 patients with NED at second-look laparotomy have relapsed. We stopped the accrual since the 95% confidence interval of the pCR-rate observed exceeded 20%. This new first-line regimen seems to be highly effective in patients with poor-prognosis advanced ovarian cancer, although the data are not yet sufficiently mature for a final analysis of time to progression and overall survival.