A PHASE-I TRIAL OF CYCLOSPHOSPHAMIDE AND CARBOPLATINUM COMBINED WITH INTERLEUKIN-3 IN WOMEN WITH ADVANCED-STAGE OVARIAN-CANCER

The hematopoietic growth factor, recombinant human interleukin-3 (rhu IL-3), stimulates production of both leukocytes and platelets, and thu s potentially has greater utility than growth factors that solely stim ulate leukocyte production when employed with dose-intensive chemother apeutic regimens. To determine the optimal schedule for administration of rhu IL-3 in combination with cyclophosphamide and carboplatin, an aggressive regimen for the treatment of advanced ovarian cancer, a pha se I trial was initiated by the New York Gynecologic Oncology Group. F ollowing surgical debulking, all patients received cyclophosphamide an d carboplatin for 6 cycles. rhu IL-3 was administered at 50, 250, or 5 00 mug subcutaneously for 5 days either immediately prior to or after administration of chemotherapy. Cohorts of six patients were treated a t each dose level (three pre- and three postchemotherapy). Eighteen pa tients received 91 cycles of treatment. The major toxicities attributa ble to rhu IL-3 included fevers, chills, malaise, nausea, and headache , but were not dose-limiting at the doses of rhu IL-3 employed. The ma jor finding of this study was that rhu IL-3 administered after chemoth erapy offered greater platelet protection than rhu IL-3 administered p rior to chemotherapy as assessed by median platelet nadir and duration of platelet counts <50,000/mm3. A second major finding was a dose-res ponse relationship for rhu IL-3: the two higher doses employed, 250 an d 500 mug, offered more effective platelet protection than the lower d ose employed, 50 mug. rhu IL-3 had no significant effects on leukocyte nadirs or duration of nadirs at any schedule or dose employed. rhu IL -3 may reduce the thrombocytopenia associated with aggressive treatmen t with cyclophosphamide and carboplatin, although this remains to be c onfirmed in a randomized, placebo-controlled trial. The effects of rhu IL-3 are dose- and schedule-dependent. (C) 1995 Academic Press, Inc.