PHASE-I STUDY OF CARBOPLATIN, CISPLATIN, AND CYCLOPHOSPHAMIDE WITHOUTAND WITH LENOGRASTIM FOR THE TREATMENT OF OVARIAN-CANCER

Cisplatin and carboplatin are both active in ovarian cancer with diffe rent toxicity profiles; thus, dose intensification may be possible by combining them. The aim of the present study was to determine the maxi mum tolerated dose of carboplatin combined with fixed doses of cisplat in and cyclophosphamide without and with support of lenograstim. Cispl atin (60 mg/m(2)), cyclophosphamide (600 mg/m(2)) and carboplatin (sta rting dose 200 mg/m(2)) were given on day 1 every 3 weeks for 4 cycles . Escalated dose levels for carboplatin were planned by increments of 50 mg/m(2) per level. Lenograstim (L) (150 mu g/m(2)/day subcutaneousl y) was given in case of grade 4 leukopenia (levels without support) or from day 5 up to leukocyte >10,000/mm(3) after nadir (levels with sup port). Four levels were studied (200, 250, 250 + lenograstim, 300 + le nograstim) with 7, 7, 8, and 7 patients enrolled, respectively. Unacce ptable toxicity was induced in 1 patient at the level I (grade 4 throm bocytopenia), in 4 patients at the level 2 (2 prolonged grade 2 leukop enia, 1 grade 4 leukopenia with concomitant grade 4 thrombocytopenia a nd 1 grade 4 thrombocytopenia), in 1 patient at the level 2 + L (grade 4 thrombocytopenia) and in 3 patients at the level 3 + L (3 grade 4 t hrombocytopenia). Thus, 200 mg/m(2) and 250 mg/m(2) were defined as ca rboplatin MTDs without and with lenograstim support, respectively. Med ian total platinum (cisplatin + 1/4 carboplatin) delivered dose-intens ities were 33, 32, 38 and 44 mg/m(2)/week at the four levels, respecti vely. Hematological toxicity was overall mild. In no case was febrile neutropenia recorded. Grade 4 thrombocytopenia was always transient an d never symptomatic. Grade 3 vomiting was the only severe non-hematolo gical toxicity reported in 5 patients. Out of 16 patients with measura ble disease, 11 objective responses were obtained (5 complete and 6 pa rtial) for an overall response rate of 69% (95% exact CL 41-89%). Reco mmended dose of carboplatin is 200 mg/m(2) without and 250 mg/m(2) wit h support of lenograstim when combined with cisplatin 60 mg/m(2) and c yclophosphamide 600 mg/m(2). Dose limiting toxicity is persistent leuk openia without and grade 4 thrombocytopenia with support of lenograsti m.