Background

Tivozanib (T, AV-951) is a potent and selective oral small molecule tyrosine kinase inhibitor (TKI) of VEGFR-1, -2, and -3; its high specificity for the receptor may afford improved activity over multi-targeted TKIs. This phase 1b open-label, multicenter study investigated the safety and tolerability, pharmacokinetics (PK), activity, and vascular reactivity (VR) of T in combination with weekly paclitaxel (P) in metastatic breast cancer (MBC).

Methods

Eligible patients (pts) had evaluable MBC with normal organ function and ECOG PS 0-2. Up to 4 prior lines of chemotherapy were allowed for MBC, including taxanes, with no limit on prior endocrine or biologic therapies. Prior exposure to bevacizumab (B) was permitted; however, prior treatment with VEGFR TKIs was not. Unstable brain metastases, grade >1 baseline neuropathy, uncontrolled hypertension (HTN), and symptomatic heart failure were excluded. A standard 3+3 dose escalation scheme was used offering P 90 mg/m2 3 weeks out of 4 (28 days=1 cycle) with escalation cohorts (C) of T: C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg; treatment was preceded by a Day -5 dose of T. Toxicity was graded per CTCAE v3.0, and dose reductions were available for toxicity. Maximum tolerated dose (MTD) was defined as the maximum dose at which ≥1 of 6 pts experienced dose-limiting toxicity (DLT). Response was assessed after every 2 cycles. PK were evaluated after the Day -5 lead-in dose and during Cycles 1-2; VR was evaluated by arterial ultrasound at baseline and at Day 1 of each cycle.

Results

A total of 18 pts enrolled in this study: median age was 48 years (32-65); median ECOG PS was 0 (0-1). 56% were hormone receptor-positive; 22% were HER2-positive. Median number of prior lines of therapy in the metastatic setting was 2 (0-4). All pts had prior taxane exposure, 72% as adjuvant therapy and 28% for MBC; 56% had prior B exposure. Therapy was generally well tolerated; toxicities (all grades) occurring in ≥20% of pts in all cohorts included neuropathy (61%), fatigue (56%), diarrhea (44%), nausea (28%), and neutropenia (22%). Grade 3 toxicities included neutropenia, diarrhea, and fatigue (11% each); no grade 4 toxicity was observed. HTN occurred in 33% of pts; 2 pts developed grade 3 HTN, leading to dose reduction in 1 pt, and both pts were subsequently well controlled with anti-HTN medication. Two episodes of DLT were observed, in C1 (grade 1 palpitations) and C3 (grade 2 asymptomatic pneumoperitoneum), leading to cohort expansion. Fifteen pts were evaluable for response. Median number of cycles received was 5 (0-12+), with 5 pts receiving ongoing therapy. Four pts (27%) had partial response as best response, 2 with prior B exposure. An additional 6 pts (40%) had stable disease ≥16 weeks. PK and VR analyses are ongoing. Conclusions

The combination of T and weekly P was tolerable at all dose levels; the MTD was identified as T 1.5 mg daily with P 90 mg/m2. Notable toxicities included neuropathy, nausea, diarrhea, fatigue, neutropenia, and HTN; serious unanticipated toxicity did not occur. A response rate of 27% was observed in this small population, most with prior taxane and B exposure. Further studies of this combination at the MTD dose level are warranted.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-10.