Trial Information

The MAX Study: A Randomised Phase II/III Study to Evaluate the Role of 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.