Phase I study of sorafenib (S) with bevacizumab (B) and paclitaxel (P) in patients (pts) with refractory solid tumors.

Abstract

3043 Background: Prior data of dual VEGF-ligand/receptor blockade with B and S showed promising efficacy. P is active against many tumor types, and combined with B improves efficacy in breast and lung cancers. We conducted a phase I study to determine the safety and MTD of P with B and S. Methods: Eligible pts had good organ function, ECOG PS 0-1, and may have had prior therapy with P and either B or S. The study had a standard “3+3” design, using P 80 mg/m2 weekly × 3 q4wks cycle, B 5 mg/kg q2wks and escalating S from 200 mg BID, dosed 5 or 7 days/wk (5/7 or 7/7). The MTD cohort was expanded for further safety analysis. PK analyzes were performed for P and S at baseline and on cycle (C) 1 d15. Pharmacodynamic (PD) evaluations included dynamic contrast-enhanced magnetic resonance imaging. Results: 23 ptswere enrolled, M/F: 6/17, median age 55 yrs (29-75); PS: 0/1=16/7. The Table summarizes dose levels, DLTs, and the MTD. Ten pts at MTD required S dose reductions to 5/7 or QD dosing beyond C2. The most common toxicities were hand-foot skin reaction (HFSR) (17), alopecia (16), hypertension (HTN) (15), mucositis (12), and sensory neuropathy (10). Grade (Gr) 3/4 toxicities were HTN (7), HFSR (5), neutropenia (4), neuropathic pain (2) and mucositis (2), and 1 pt each with CVA, colon/bladder perforation, port-related DVT and P infusion reaction. Pts received a median of 5 cycles (1-19). One pt discontinued study in C1 due to CVA. Among 19 evaluable pts, 3 had CR (ovarian, endometrial, and urachal cancers), 8 PR (6 ovarian, 1 endometrial, 1 prostate), and 8 SD. Median response duration was 26 wks (10-58). PK analysis showed no significant interaction between P and S. Pretreatment Ktrans were higher in responders than nonresponders (p=0.03). Conclusions: While P+B+S was associated with increased toxicity, it demonstrated impressive efficacy across all dose levels. The recommended phase II dosing is P 80 mg/m2, B 5 mg/kg, and S 200 mg BID 5/7, based on data from the expansion cohort and long-term tolerability. Cohort (#pts) P (mg/m2) B (mg/kg) S (mg) # DLT DLT 1 (6) 80 5 200 BID 5/7 1 Gr 3 neutropenia > 7d 2 (MTD) (6) 80 5 200 BID 7/7 1 Gr 3 HTN 3 (2) 80 5 400 BID 5/7 2 Gr 3 HFSR × 2 2 (9) 80 5 200 BID 7/7 4 Gr 3 HFSR MTD expansion Gr 4 CVA + Gr 3 HTN Gr 3 neutropenia > 7 d S held >7d for Gr 2 HFSR Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Genentech, Roche Bayer, Genentech, Onyx