Abstract
Abstract Background: Vinflunine (VFL) is a new microtubule inhibitor of the vinca alkaloid class. VFL inhibits tubulin polymerization. Ixabepilone (IXA), a microtubule inhibitor, binds directly to -tubulin subunits, leading to suppression of microtubule dynamics. These agents have complementary mechanisms of action and relatively non-overlapping toxicities. This study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of an alternating regimen of VFL and IXA in patients (pts) with advanced cancer and to recommend a Phase 2 dose. Materials and Methods: This was an open-label Phase 1 doseescalation study of IXA and VFL in pts with advanced cancer. IXA was administered as a 3-hour infusion alternating every 3 weeks (wks) with VFL administered as a 20-minute infusion. A cycle was defined as 6 wks (42 days), with DLT assessment during Cycle 1. Doses started at 30 mg/m2 IXA and 250 mg/m2 VFL (IXA30+VFL250). VFL doses were first escalated to a maximum of 320 mg/m2. Once an intolerable dose or the maximum dose of VFL was reached, IXA was to be escalated with a maximum dose level of IXA 40 mg/m2. A standard 3+3 escalation design was used. The MTD was defined as the dose level below which ≥2/6 pts experienced a DLT. Results: This was the first clinical study to evaluate vinflunine and ixabepilone as an alternating regimen. Nine pts were enrolled and treated; 3 each at IXA30+VFL250, IXA30+VFL280, and IXA30+VFL320. Further enrollment and dose escalation was stopped when the study was closed due to termination of VFL development at BMS. The treated pts consisted of 8 males / 1 female, 3 with SCLC, 4 with NSCLC, and 2 with sarcomas. The majority of pts were white (8 of 9). Median Age was 63 years (range 38–85). ECOG performance status was 0 (n=1) or 1 (n=8). Adverse events were summarized by treatment. Of interest, 3 pts experienced grade 1 peripheral neuropathy (1 IXA, 2 VFL); 5 pts with grade 3/4 neutropenia (2 IXA, 2 VFL, 1 IXA/VFL); 2 pts with grade 2 constipation (2 VFL). Serious adverse events (SAEs) were reported in 3 of 9 treated pts. The SAEs of pyrexia grade 2, neutropenia grade 2, and leucopenia grade 3 were considered related to study drug in 1 patient. None of the SAEs or non-serious AEs led to discontinuation of study treatment. Two pts experienced progression of disease which resulted in death. Antitumor activity (as defined by RECIST and assessed by the investigator) was observed: confirmed partial response in 1 pt with NSCLC (IXA30+VFL320 dose level) and stable disease lasting from 2.5 to 9 months in 3 pts (2 with SCLC in IXA30+VFL250 and 1 with NSCLC in IXA30+VFL280). Conclusions: There were no DLTs observed in the dose levels examined and the MTD was not reached due to termination of study. The toxicity of the alternating regimen was manageable. Antitumor activity was observed in all dose cohorts. The alternating regimen of vinflunine and ixabepilone may warrant further investigation. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C237.
