A Phase I Trial of the Oral, Multikinase Inhibitor Sorafenib in Combination with Carboplatin and Paclitaxel

Abstract

Purpose: This study evaluated the safety, maximum tolerated dose, pharmacokinetics, and antitumor activity of sorafenib, a multikinase inhibitor, combined with paclitaxel and carboplatin in patients with solid tumors. Patients and Methods: Thirty-nine patients with advanced cancer (24 with melanoma) received oral sorafenib 100, 200, or 400 mg twice daily on days 2 to 19 of a 21-day cycle. All patients received carboplatin corresponding to AUC6 and 225 mg/m 2 paclitaxel on day 1. Pharmacokinetic analyses were done for sorafenib on days 2 and 19 of cycle 1and for paclitaxel on day 1of cycles 1and 2. Pretreatment tumor samples from 17 melanoma patients were analyzed for BRAF mutations. Results: Sorafenib was well tolerated at the doses evaluated. The most frequent severe adverse events were hematologic toxicities (grade 3 or 4 in 33 patients, 85%). Twenty-seven (69%) patients had sorafenib-related adverse events, the most frequent of which were dermatologic events (26 patients, 67%). Exposure to paclitaxel was not altered by intervening treatment with sorafenib. Treatment with sorafenib, paclitaxel, and carboplatin resulted in one complete response and nine partial responses, all among patients with melanoma. There was no correlation between BRAF mutational status and treatment responses in patients with melanoma. Conclusions:The recommended phase II doses are oral 400 mg twice daily sorafenib, carboplatin at an AUC6 dose, and 225 mg/m 2 paclitaxel. The tumor responses observed with this combined regimen in patients with melanoma warrant further investigation.

Developments in targeted therapy in melanoma

“…36,37,39e41,47 Severe adverse events (SAE) were reported in 51% of patients, with the most common being hematologic toxicities. 47 The most commonly observed drug-related AEs under sorafenib monotherapy were skin reactions (rash and palmarplantar erythrodysesthesia syndrome), gastrointestinal and constitutional disorders (corresponding grade 1e2 intensity). 36,37 Combination treatments with sorafenib led to hematotoxicity, fatigue, sensory neuropathy and skin reactions.…”

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

“…C max was achieved within 2-12 h [54][55][56][57][58][59][60][61][62][63][64]. The mean relative bioavailability of tablets compared to oral solutions was identified to be within the range of 38 and 49 % [51].…”

Angiogenesis in cutaneous disease: Part II

“…A phase I trial combined sorafenib with carboplatin and paclitaxel in advanced melanoma patients and was able to induce one complete response and nine partial responses. 34 In a phase II trial, oral sorafenib (400 mg twice a day) and IV dacarbazine (1000 mg/m 2 on day 1 of a 21-day cycle) showed a 50% improvement in progression-free survival as compared to placebo plus dacarbazine. 35 However, overall survival was not improved.…”