Axitinib (AG-013736; AG) in combination with paclitaxel (P)/carboplatin (C) in patients (pts) with advanced solid tumors

A157 Background: AG isan oral, potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, 3. An initial phase I study of single-agent AG in solid tumors identified 5 mg BID as the recommended phase II starting dose. A purpose of this phase I study was to assess the safety, tolerability and pharmacokinetics (PK) of AG, P and C (individually and in combination) in pts with advanced solid tumors. Methods: Pts received AG BID orally in combination with P (200 mg/m2; 3-hour infusion) and C (AUC 6 mg*min/mL; 30-minute infusion) every 3 weeks. On chemotherapy days, pts received lead-in AG doses of 1 mg, 3 mg and 5 mg BID in cohorts 1, 2, and 3 respectively. AG was increased to 5 mg BID post the lead-in period for all cohorts. Results: 13 pts are evaluable with demographics M:F = 8:5; Caucasian 85%, median age 60 (range 37-75); PS 0-1 100%. Primary tumor sites: ovarian (3), NSCLC (2), melanoma (4), head and neck (2), RCC (1), unknown primary (1). Treatment-related adverse events (AEs) included hypertension (54%), fatigue (54%), hand-foot syndrome (38%), proteinuria (38%), diarrhea (31%), epistaxis (31%), and rash (31%). AEs were generally CTC grade 1-2 and manageable. One DLT of febrile neutropenic fever was observed. Antitumor activity included 1 CR, 6 PR, and 4 SD out of 13 evaluable patients. PK results were obtained from 12 pts to date. P and C PK parameters and plasma profiles were similar in the presence of AG in all three cohorts and were pooled across all 3 cohorts. Mean (±SD) plasma AUCinf for P alone without AG was 21983 ± 7346 vs 18984 ± 5969 ng.h/mL with AG. The mean AUCinf for C alone (measured as total platinum in plasma ultrafiltrate) without AG was 40467 ± 12089 vs 45690 ± 11653 ng.h/mL with AG. All other PK parameters for P and C were similar with and without AG. In addition, AG plasma PK parameters and plasma profiles at all 3 doses appeared unchanged with and without P/C. Conclusion: The combination of AG at a starting dose of 5 mg BID with P/C is feasible and appears to have promising antitumor activity. Mean PK parameters of AG (up to the full 5 mg BID starting dose) and P/C are unaltered when administered in combination.