The MAX Study: Mitomycin C, Avastin and Xeloda in Patients With Untreated Metastatic Colorectal Cancer

Aims - The phase II stage of the study aims to determine the relative toxicity of the combination of capecitabine and bevacizumab and the combination of capecitabine, mitomycin C (MMC) and bevacizumab with that of capecitabine monotherapy and to assess tumour response rate (RECIST criteria) for each arm For Phase III stage the primary objective is to compare progression-free survival (PFS) on the three arms. Secondary objectives are to determine treatment related toxicity; to determine tumour response rates (RECIST criteria); to determine overall survival for each treatment arm; to compare disease related symptoms and Quality of life and to determine cost effectiveness of bevacizumab containing treatments. Research Plan Synopsis - Trial Design: Randomised, stratified multicentre phase II/III study. The study will proceed in 2 phases, initially a randomised phase II stage evaluating safety after 60 patients (approx 20 per arm) and 150 patients (approx 50 per arm) have completed at least 6 weeks' treatment. This will continue with a randomised phase III stage evaluating activity, toxicity and quality of life measures. Treatments: Patients will be randomised to treatment in either one of the three arms: I) Capecitabine as monotherapy ; 2) Capecitabine and bevacizumab; or 3) Capecitabine and bevacizumab and MMC. Drug administration: Arm 1: Capecitabine 2500mg/m2/d (in 2 divided doses) d1-14 q3weekly. Arm 2: Capecitabine administered as per Arm 1 plus Bevacizumab 7.5 mg/kg q3weekly. Arm 3: Capecitabine and Bevacizumab administered as per Arm 2 plus Mitomycin C 7 mg/m2 q 6weekly (maximum dose 14 mg, maximum 4 treatments). Analysis: A total sample size of 333 patients (111 per group) will be required to detect an improvement of at least 3.1 months in progression free survival from 5.5 to 8.6 months using a 2-tailed comparison, 2.5% level of significance, 3-year accrual and 1-year follow-up. The 12-month survival rate for patients on capecitabine alone is 50%. A sample size of 111 per arm will have 80% power to detect an increase of 17% in the 1-year rate from 50% to 67% based on a significance level of 2.5%, 3-year accrual and 1-year follow-up. For both endpoints (PFS and survival) the difference between capecitabine alone and the regimen containing MMC is expected to be greater (in the order of 4.5 months) which will yield \> 80% power to detect the difference in PFS. Whilst not a primary comparison, the study will nevertheless still have 80% power to detect a 5.5 month difference between the two experimental arms as a secondary comparison based on a level of significance of 1.7%. Secondary endpoints include treatment related toxicity. Toxicity analyses will include treatment-received population, which includes all patients who received at least 1 dose of study treatment. Toxicity will be described by tabulating the proportions of patients with a worst toxicity grade of 0, 1, 2, 3, or 4 for each of the relevant NCI CTC AE scales. Phase II: Confidence intervals for the difference in the incidence of bevacizumab and MMC associated grade 3/4 toxicities on the three arms will be calculated. If the incidence of these toxicities in the triple combination regimen (Capecitabine/MMC/ bevacizumab) exceeds the rate of toxicity experienced in the capecitabine/bevacizumab combination by more than 20% then consideration will be given to dose adjustment or stopping recruitment into the triple combination arm. Phase III: The PFS for capecitabine chemotherapy alone is expected to be about 5.5 months and this is expected to increase to 9 months with the addition of bevacizumab, which is considered to be clinically meaningful. Using an overall 95% confidence level and 80% power and a 2.5% significance level for each comparison 111 patients per arm are required to detect differences based on a 36-month accrual and 12-month follow-up. Outcomes and Significance - This randomised phase II/III study aims to compare capecitabine monotherapy with capecitabine plus bevacizumab and capecitabine plus bevacizumab plus MMC in patients with previously untreated metastatic colorectal cancer. The use of either MMC or bevacizumab to 5FU based chemotherapy appears to result in improved activity without substantial increases in toxicity. Thus regimens incorporating these agents could have significant activity and be well tolerated. These regimens could be suitable as a low toxicity palliative regimen for a broad range of the population of patients with metastatic colorectal cancer including older patients with co-morbidities. As it is anticipated that rates of acute toxicity with each regimen will be lower than those observed with oxaliplatin or CPT-11-based regimens, the target population may be more broad ranging than most other studies. Thus, it may include older patients, patients with limited performance status (PS2), patients with co-morbidities or patients in whom there are concerns relating to toxicity with oxaliplatin or CPT-11-based combination chemotherapy. However, it is not restricted to this population and younger, fitter patients may also be enrolled in the study as a lower rate of side effects is likely to be associated with improved quality of life.