[6124] A dose-finding and pharmacokinetic study of I.V. vinflunine in combination with doxorubicin as first line treatment of metastatic breast cancer.

Machiels JP, Chollet P, Taleb A, Baurain JF, Humblet Y, Mazzeo F, Zaman K, Kasiborski F, Bauer J Cliniques Universitaires UCL Saint-Luc, Brussels, Belgium; Centre Jean Perrin, Clermont-Ferrand, France; Institut de Recherche Pierre Fabre, Boulogne-Billancourt, France; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

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 < 250 mg/m for DXR, 450 mg/m for EPI. Dose escalation used 3+3 design; PK samples were obtained for VFL and DXR to investigate potential interaction.

	iv VFL (mg/m) on day 1 Q 3 weeks	DXR (mg/m) on day1 Q 3 weeks
Schedule 1 / Dose levels	250	50
	250	40
	iv VFL(mg/m) on days 1 and 8 Q 3 weeks	DXR (mg/m) on days 1 and 8 Q 3 weeks
Schedule 2/ Dose levels	150	25
	120	25

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 < 0.1x10⁹/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 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.

Sunday, December 14, 2008 7:00 AM

Poster Session VI: Treatment: Advanced Chemotherapy (7:00 AM-9:00 AM)