Dose escalation of paclitaxel with high-dose cyclophosphamide, with analysis of progenitor-cell mobilization and hematologic support of advanced ovarian cancer patients receiving rapidly sequenced high-dose carboplatin/cyclophosphamide courses.

Abstract

PURPOSE We commenced a phase I study of escalating dose Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford, CT) in addition to cyclophosphamide, to assess its impact on both antitumor efficacy and mobilization of peripheral-blood progenitor cells (PBP). PATIENTS AND METHODS Induction therapy consisted of two cycles of cyclophosphamide 3.0 g/m2 plus escalating-dose Taxol (dose levels I to IV, 150, 200, 250, and 300 mg/m2, respectively) in cohorts of three, plus filgrastim granulocyte colony-stimulating factor [G-CSF]) and leukaphereses to harvest PBP, followed by four courses of rapidly cycled carboplatin and cyclophosphamide (1,000 and 1,500 mg/m2 per course, respectively), for which hematopoietic rescue was achieved with PBP. RESULTS Sixteen patients completed all planned cycles of Taxol/cyclophosphamide. Fifty-four cycles of carboplatin/cyclophosphamide were given and rescued with PBP. The median interval between treatments for Taxol/cyclophosphamide courses was 14 days (range, 13 to 21). Twelve patients completed all planned cycles of carboplatin/cyclophosphamide. The median inter-treatment interval for carboplatin/cyclophosphamide courses when rescue was achieved with Taxol/cyclophosphamide-primed PBP was 17 days (range, 14 to 25). The median number of days to recovery of an absolute neutrophil count (ANC) greater than 0.5 was 8 (range, 5 to 12), and of self-sustaining platelet count greater than 20 x 10(9)/L, 11 (range, 8 to 15). There was one episode of fatal sepsis. Of 13 patients assessable for response, there were five patients with pathologic complete responses (38.5%), six patients with microscopic residual disease (46%), and two patients with pathologic partial responses, for an overall response rate of 100%. CONCLUSION The addition of escalating-dose Taxol to high-dose cyclophosphamide does not compromise PBP mobilization. The use of PBP mobilized in this fashion provides reliable engraftment after sequential administration of high-dose carboplatin/cyclophosphamide. Toxicities produced with this approach are manageable. The response rates demonstrated are promising and warrant further evaluation.