A dose-finding and pharmacokinetic study of IV vinflunine in combination with doxorubicin as first line treatment of metastatic breast cancer

Abstract #6124 Background: VFL is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class. In a phase II study in anthracycline and taxane pretreated MBC patients (pts), an ORR of 30% observed. Given activity shown by DXR or VFL in MBC, we conducted a phase I study of the combination, define maximum tolerated dose (MTD), recommended dose (RD), safety (NCI CTC 2.0), PK interaction and efficacy (Recist).
 Methods: 2 schedules investigated (VFL D1 with DXR D1, every 3 weeks and VFL Ds 1 and 8, with DXR Ds 1 and 8, every 3 weeks). Eligibility: Pts with MBC, previously untreated for metastatic disease; could have received adj/neoadjuvant with anthracycline-containing regimen, cumulative doses Results: 32 patients were enrolled (15 patients in schedule 1 and 17 in schedule 2) and received escalating doses of VFL and DXR.
 In schedule 1, 2 dose levels (DL) were investigated; At DL VFL250/DXR50, 8 pts were treated with 6 patients evaluable for DLT, where 2 DLTs were identified consisting of neutropenia 9 /l > 3 days and a neutropenic infection; then this DL was considered MTD; at the DL VFL250/DXR40, 7 pts were treated without developing DLTs then considered RD. 73 cycles were administered (median 6); Most frequent haematological toxicity was neutropenia, gr 3 in 1 pt and gr 4 in 11 pts. Main non-haematological adverse events were: nausea 80%, fatigue 73.3%, constipation 40%, vomiting 40%, anorexia 33.3%, stomatitis 20%, dyspnea 13.3%. Clinical activity: 7 pts (46.7%) had PR, and 4 pts (26.7%) SD. No PK interaction was detected.
 In schedule 2, at DL VFL150/DXR25, 6 of 9 pts were evaluable in whom 2 Gr 4 neutropenia > 7 days occurred, (DL considered as MTD). In the DL below VFL120/DXR25, 6 of 8 pts were evaluable, only 1 Gr 4 neutropenia > 7 days occurred, (DL considered RD). A total of 89 cycles (median 6) were administered; neutropenia was the main haematological toxicity, with Gr ¾ in 14 pts (82.4%); main non-haematological toxicities: fatigue 82.4%, constipation 76.5%, nausea 76.5%, vomiting 64.7%, stomatitis 41.2%, dyspnea 41.2%, anorexia 35.3%; no episode of Gr 4 occurred.
 Among 17 treated pts, 8 (47.1%) had PR and 6 (35.3%) SD. PK analysis ongoing.
 Conclusion: RD for schedule 1 is VFL250/DXR40 on day 1, Q3W, for schedule 2, VFL120/DXR25 on days 1 and 8, Q3W. Overall VFL/DXR combination is feasible and toxicity was manageable, where haematological toxicity was frequent but reversible. Promising antitumour activity was detected. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6124.