A Clinical Trial in Patients With Breast Cancer Susceptibility Gene (BRCA) Defective Tumours

Inclusion Criteria

• Patients with proven BRCA1 or BRCA2 mutations and after appropriate exposure to standard treatment, as defined by:

Breast Cancer

• Patients with initially histologically or cytologically proven locally advanced or metastatic breast cancer who may have received up to 3 previous lines of chemotherapy in the locally advanced or metastatic breast cancer setting.
• Patients must have previously had a taxane and an anthracycline in either the adjuvant or metastatic setting, provided that these were not contraindicated.
• Patients with hormone responsive disease should have had at least 1 line of hormone therapy for metastatic disease.
• Prior treatment with a poly-Adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitor is permissible.

OR Ovarian Cancer

• Patients with initially histologically or cytologically proven ovarian cancer.
• Patients must have disease that is platinum resistant or in whom further platinum based therapy is inappropriate.
• Prior treatment with a PARP inhibitor is permissible.
• Patients must have measurable disease on computerized tomography (CT) or Magnetic resonance imaging (MRI) scan as defined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
• Age ≥18 years.
• Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
• Life expectancy >12 weeks.
• Written informed consent.
• Patient willing and able to comply with all protocol requirements.
• No prior anti-cancer treatment in previous 4 weeks, other than palliative radiotherapy (RT).
• Haematological and biochemical indices within the ranges shown below.
• Laboratory Test Value required
• Haemoglobin (Hb) > 10g/dL
• White Blood Count (WBC) > 3x109/L
• Platelet count > 100,000/μL
• Absolute Neutrophil count > 1.5x109/L;
• Serum bilirubin ≤ 2 x Upper limit normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) and alanine aminotransferase (ALT) or ALT ≤ 5 x ULN (liver metastasis)
• or ≤ 3 x ULN (no liver metastasis)
• Alkaline phosphatase ≤ 5 x ULN
• Serum creatinine ≤ 1.5 x ULN
• Ascites and pleural effusions must be drained prior to therapy.

Exclusion Criteria

• Patients with any of the following contra-indications to thiopurines (6MP or 6TG) or methotrexate:
• family history of severe liver failure;
• alcoholism;
• porphyria;
• diffuse infiltrative pulmonary or pericardial disease;
• known hypersensitivity to either trial agent.
• Patients found to have a Low/Low genotype on thiopurine methyltransferase (TPMT) testing will be excluded.
• Pregnant or breast-feeding women or women of childbearing potential unless highly effective methods of contraception are used.
• Other active malignancy, with the exception of adequately treated in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin.
• Patients known or tested to be serologically positive for Hepatitis B, Hepatitis C or human immunodeficiency virus (HIV).
• Patients with active central nervous system (CNS) lesions are excluded (i.e., those with radiographically unstable, symptomatic lesions). However, patients treated with stereotactic therapy or surgery and/or whole brain radiotherapy are eligible if the patient remains without evidence of disease progression in brain ≥ 3 months prior to registration date . They must also be off corticosteroid therapy for ≥ 3 weeks prior to registration date.
• Patients who have received anticancer agent(s) or an investigational agent within 28 days prior to study drug administration.
• Subjects who have not recovered to within one grade level (not to exceed grade 2) of their baseline following a significant adverse event or toxicity attributed to previous anticancer treatment are excluded.