Continuous intravenous infusion (CIVI) topotecan may be safely combined with tipifarnib

Abstract

2064 Background: Dose limiting (DL) myelosuppression occurred when topotecan 1.0 mg/m2/d × 5d was combined with tipifarnib (Proc ASCO, 2001, abst 321). We now report on a 3+3 cohort design to determine the safety and pharmacokinetics (PK) of this combination with topotecan given as CIVI in patients (pts) with refractory solid tumors. Methods: Pts were treated with escalating dose levels of topotecan (0.2–0.4 mg/m2/d) given as 21-day infusion in combination with tipifarnib 200 mg PO bid for 21 d every 28 d. Blood was drawn for topotecan PK and intracellular (PBMC) toposisomerase I on d 1 (baseline) and d 5 (tipifarnib omitted d1, cycle 1), and weekly × 8 for ras-farnesylation (membrane bound fraction). Plasma levels of the closed form of topotecan were determined by SPE and HPLC with fluorometric detection. Topoisomerase I in PBMCs was detected by Western blot. Results: 14 patients were accrued at 3 dose levels: topotecan 0.2 mg/m2/d (3 pts), 0.3 mg/m2/d (3), and 0.4 mg/m2/d (8), combined with tipifarnib. Median age was 50 years (33–62). 32 cycles (median 2) were given. Grade 1–3 fatigue, nausea, thrombocytopenia, neutropenia and anemia were common, and at dose level 3, two heavily-pretreated patients had DL myelosuppression. Six others had no significant toxicity over prolonged times. Of nine evaluable for response, a mucinous peritoneal cancer had a minor response for 5 m, an ovarian granulosa cell tumor had a mixed response in lung metastases for 15 m, and a PNET of bone had a minor response for 17 m; six had progression. Mean steady state (± SD) levels of topotecan for dose levels I, II and III were, respectively, 0.48 ± 08 (N = 3), 1.26 ± 0.32 (N = 3) and 1.47 ± 0.1 (N = 5) ng/ml, and were linear with respect to topotecan dose (r = 0.95). By the end of the 21 d infusion, 90% of baseline topoisomerase I signal was depleted in PBMCs. Conclusions: In contrast with bolus topotecan, CIVI topotecan may be combined at known effective doses with tipifarnib. Recommended phase II doses are 0.4 mg/m2/d × 21 days and 200 mg bid daily for those with limited prior therapy. Phase II studies in gynecologic and breast tumors are planned. Supported by UO1- 76642; CA 16087. [Table: see text]