SIMULTANEOUS DOSE-ESCALATION AND SCHEDULE INTENSIFICATION OF CARBOPLATIN-BASED CHEMOTHERAPY USING PERIPHERAL-BLOOD PROGENITOR CELLS AND FILGRASTIM - A PHASE-I TRIAL

Our purpose was to determine the maximum tolerated dose of, and the mi nimum interval between treatments with, multiple cycles of carboplatin (CBDCA) rescued with peripheral blood progenitors and filgrastim. Eli gible patients had advanced cancers without prior chemotherapy or radi otherapy. The study design involved a sequential cross-over in which p atients initially received two or three courses of cyclophosphamide (C PA) at a dose of 3.0 g/m(2), supported by filgrastim. Multiple leukaph ereses were then performed during the rebound phase of hematological r ecovery following each CPA-induced nadir to harvest peripheral blood p rogenitors, which were then reinfused as rescue following each of four courses of CBDCA. We attempted to administer the CBDCA at 14-day inte rvals. The CBDCA dose (mg/m(2)/course) was escalated as follows in suc cessive cohorts of patients: Level I, 500; Level II, 800; Level III, 1 200; Level IIIa, 1000. Following determination of the maximum tolerate d dose of CBDCA administered in this fashion, a subsequent cohort of p atients (Level TV) were treated with two courses of high-dose CPA and four courses of the combination of CBDCA (1000 mg/m(2)) plus CPA (1500 mg/m(2)). Thirty-one patients were enrolled in the trial. Five patien ts were removed from study prior to completion of protocol therapy, th ree due to toxicity and two who developed progressive cancer while on study. The maximum tolerated dose of CBDCA was 1000 mg/m(2), with dose -limiting ototoxicity occurring at 1200 mg/m(2). The median inter-trea tment interval for all cycles was 15 days (range, 12-30). The median i ntervals between CBDCA courses for each dose level were: Level I, 17 d ays; Level II, 17 days; Level III, 14 days; Level IIIa, 15 days; Level IV, 16 days. The median dose intensity of the CPA phase was 1493 mg/m (2)/week. The median (and range) CBDCA dose intensities (measured from the start of CBDCA) for each dose level were: I, 185 (151-222); II, 3 28 (305-380); III, 567 (512-646); IIIa, 465 (363-481); Level IV, 468 ( 333-500). Neutropenic fever complicated 35 of 113 CBDCA or CBDCA/CPA c ourses. Platelet transfusion was required in 51 of 113 courses. One pa tient had severe epistaxis. There were no treatment-related deaths. Am ong 27 patients with ovarian cancer who were evaluable for response, t here were 5 pathologically documented complete (Including 3 of 10 at L evel IV) and 16 partial responses. We concluded that peripheral blood progenitors facilitate the simultaneous dose escalation and schedule i ntensification of carboplatin chemotherapy. The effect is sustained ov er four courses of treatment. The maximum tolerated dose of earboplati n administered in this fashion, either as a single agent or in combina tion with CPA, is 1000 mg/m(2), with an intertreatment interval of app roximately 16 days.