Methotrexate in Metastatic Colorectal Cancer With MSH2 Deficiency

A Non-randomised Phase II Trial of Methotrexate in Metastatic Colorectal Cancer With MSH2 Deficiency

To assess the efficacy of methotrexate in a genetically selected population of patients with advanced colorectal cancer, who have loss of a particular gene, MSH2. The efficacy of methotrexate will be evaluated by the proportion of cases that have a significant response to treatment (objective response rate).

The study will involve treating 29 subjects with methotrexate given intravenously. All subjects will receive treatment; there is no control arm or randomisation. The subjects will be known to have deficiency of MSH2, or a mutation (genetic change) in MSH2 that stops it functioning normally. This can either be demonstrated by testing for loss of MSH2 protein in the tumour itself, or by the demonstration of a mutation in the MSH2 gene in the subject's blood.

Inclusion Criteria:

• Confirmed diagnosis of metastatic or locally recurrent colorectal carcinoma
• Aged 18 years or older
• Paraffin embedded histological material available for analysis
• Either confirmed loss of expression of MSH2 on immunohistochemistry IHC or confirmed mutation in MSH2 on gene sequencing
• Life expectancy of > 3 months

Exclusion Criteria:

• Previous treatment with methotrexate, either for malignant or non-malignant disease, except when methotrexate was given at low dose with other drugs to modify their effects
• Concomitant uncontrolled medical conditions
• Concomitant metastatic malignancy apart from non-melanotic skin cancers and carcinoma in situ of the uterine cervix in the last 10 years
• Any contraindication to treatment with methotrexate (as this will affect safety)