Résumé
Background: AVE8062 is a Vascular Disrupting Agent, derivative of Combretastatin A4, which targets endothelium and causes shutdown of blood perfusion. Preclinical synergy between AVE8062 followed by docetaxel prompted clinical exploration of this combination. Methods: Objectives were to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and PK profile of intravenous AVE8062 on day 1 followed by D 75 mg/m2 on day 2 administered once every 3 weeks. Anti-tumor activity was assessed every 2 cycles. Results: Twenty-nine adult pts with advanced solid tumors (M/F 11/18), median age 51 (range 28–71), were enrolled and treated at AVE8062 dose levels of 11.5 mg/m2 (N=3), 15.5 mg/m2 (N=5), 20 mg/m2 (N=3), 25 mg/m2 (N=6), 30 mg/m2 (N=3), 35 mg/m2 (N=3) and 42 mg/m2 (N=6). Median number of cycles per patient was 3 (range 1–14). The most common tumor types were breast (n=10) and oesophagus (n=7). At 25 mg/m2 AVE8062, neutropenic infection at cycle 1 defined DLT in one patient (pt), whereas at 42 mg/m2 AVE8062 grade 3 headache and asthenia in two pts defined DLTs. Additional grade 3 or 4 study drug related adverse events (AE) included sepsis, febrile neutropenia and respiratory failure in one pt at 20 mg/m2 AVE8062, and nail toxicity in 1 pt at 25 mg/m2. The most common grade 3 or 4 haematological toxicity was neutropenia (11/29 pts). No other grade 3 or 4 adverse events were experienced by more than 2 pts. Grade ¾ related AEs were: grade 3 anemia, grade 4 sepsis, grade 3 respiratory failure, grade 4 febrile neutropenia, grade 3 neutropenic infection, grade 3 nail toxicity, grade 3 oesophageal fistula, grade 3 headache and grade 3 fatigue. The PK profile of AVE8062, its main metabolite RPR258063 and D were similar to those found in monotherapy studies. The MTD for the combination AVE8062/D was set at 35/75 mg/m2. Ten additional patients will be enrolled at this dose level then new dose levels of AVE8062 with D 100 mg/m2 will be studied. Among 23 evaluable pts, 3 had partial responses (breast cancer) and 13 had stable disease (mainly oesophageal cancer, head and neck, pancreatic adenocarcinoma, liver and unknown origin carcinoma). Conclusion: AVE8062 in combination with D was well tolerated. The recommended dose for this combination is 35 mg/m2 AVE8062 day 1 and 75 mg/m2 D day 2, every 3 weeks. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A15.