International multi-centre randomised Phase II/III study of Capecitabine (Cap), bevacizumab (Bev) and mitomycin C (MMC) as first-line treatment for metastatic colorectal cancer (mCRC): Final safety analysis of the AGITG MAX trial

4029 Background: Fluoropyrimidine (FU) monotherapy combined with Bev has activity and is less toxic than standard combination chemotherapy. MMC also has the potential to improve efficacy of FU monotherapy. MAX is a randomised phase II/III trial designed to evaluate Cap alone compared with Cap in combination with Bev±MMC aiming to develop an active but low toxicity combination regimen, potentially suitable for a broad range of patients. Patients with mCRC considered suitable for single agent FU chemotherapy were randomised to Cap, CapBev or to CapBev + MMC (MCapBev). The primary outcome is PFS, with safety an important secondary outcome. Methods: Patients with mCRC who had not received prior chemotherapy or for whom 6 mths had elapsed since adjuvant chemotherapy, ECOG PS<2 were randomised to either Arm A (Cap 2,000 or 2,500 mg/m2 in 2 divided doses, 14 days, q3w), Arm B (Cap+Bev 7.5mg/kg q3w) or Arm C (MMC 7 mg/m2, capped at 14mg and limit 4 doses, q6w + CapBev). Randomisation was stratified by centre, PS and Cap dose. Final safety analysis of 471 patients is presented. Results: Recruitment was from 7/05 to 7/07. Sex, ECOG status, median age and Cap dose was balanced. Two thirds of patients received Cap dose 2,000 mg/m2. 60 day all-cause mortality was Arm A 4.5%, Arm B 5.7%, Arm C 2.5%. Rates of stomatitis, hepatic toxicity, febrile neutropenia & thrombocytopenia were < 5% in all 3 arms. Grade 3/4/5 AEs are summarised in table below. There were 2 patients in Arm C who had manageable, but delayed onset (10 & 11 mths after last dose MMC) haemolytic ureamic syndrome. Conclusions: All treatment arms were well tolerated and addition of either Bev or Bev and MMC to Cap was associated with little additional grade 3/4 toxicity, apart from higher rates of grade 3 HFS in the CapBev & MCapBev arms. Acceptable rates of grade 3/4 HT, VTE, haemorrhage & perforation was seen in the Bev arms. Efficacy results will be presented ASCO 2009. Toxicity %Gd 3/4/5 Arm A (156) Arm B (157) Arm C (158) Diarrhoea 11% 15% 14% Nausea/Vomiting 5%/5% 5%/5% 4%/3% Fatigue 9% 10% 13% Hand foot syndrome (HFS) 15% 25% 26% Proteinuria/HT <1%/<1% 3%/3% 7%/5% Venous thromboembolic (VTE) 8% 8% 10% Cardiac/arterial event 0/0 3%/0 1%/2% Haemorrhage 3% 1% 4% Perforation <1% 2% 0 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche Roche Roche