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A Phase Ib and Pharmacokinetic Trial of Patupilone Combined with Carboplatin in Patients with Advanced Cancer

Authors' Affiliations: ¹ Royal Marsden Hospital Gynecology Unit, London, United Kingdom; ² Princess Margaret Hospital, Toronto, Ontario, Canada; ³ Novartis Pharma AG Oncology BU, Basel, Switzerland; and ⁴ Novartis Pharmaceuticals Corporation, East Hanover, New Jersey

Requests for reprints: Martin Gore, The Royal Marsden NHS Foundation Trust, Fulham Rd, London SW3 6JJ, United Kingdom. E-mail: martin.gore{at}rmh.nhs.uk.

Purpose: Patupilone is a microtubule-targeting chemotherapeutic agent with clinical activity in a broad range of taxane-sensitive/resistant tumor types. The present phase Ib study examined the safety/tolerability and pharmacokinetics of patupilone in combination with carboplatin in patients with advanced solid tumors.

Experimental Design: Patients with advanced cancer received patupilone via a 5- to 10-min i.v. infusion at doses of 3.6 to 6.0 mg/m² q3w, immediately followed by carboplatin area under the curve (AUC) 5 or 6 mg/mL/min.

Results: Of the 37 patients enrolled, the majority previously received taxanes (81%) and/or platinum-containing drugs (97.3%). The maximum tolerated dose (MTD) of patupilone with carboplatin AUC 6 was 4.8 mg/m²; additional patients were enrolled to consolidate experience at this dose. Of the 22 patients who received the MTD, the most common nonhematologic adverse events were fatigue in six (27.3%) and diarrhea, nausea, vomiting, abdominal pain, and neuropathy in one each (4.5%; all grade 3); hematologic toxicities included two patients (9.1%) with grade 3 neutropenia. The pharmacokinetics of patupilone were similar to those in a previous study of patupilone monotherapy. Of the 26 patients with recurrent platinum-sensitive ovarian cancer, tumor response was assessable by response evaluation criteria in solid tumors in 17; 1 patient (6%) achieved a complete response, and 10 (59%) achieved a partial response.

Conclusions: The combination of patupilone 4.8 mg/m²/carboplatin AUC 6 was well tolerated and showed antitumor activity similar to established regimens in patients with recurrent platinum-sensitive ovarian cancer. The optimal dose for this regimen is currently being further refined in phase II trials.

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