A Clinical Trial in Patients With Breast Cancer Susceptibility Gene (BRCA) Defective Tumours
Condition: Breast Cancer; Ovarian Cancer
MeSH terms: Breast Neoplasms
Intervention: 6-Mercaptopurine; Methotrexate
Intervention description: 6-Mercaptopurine (6MP) 55mg/m2 body surface area, administered orally (PO) once a day (od) in the morning 1 hour after eating, on a continuous schedule. One cycle is 28 days. Treatment is given continuously until disease progression.; Methotrexate (MTX) 15 mg/m2 taken orally, once a week, in the morning. One cycle is 28 days. Treatment is given continuously until disease progression.
Intervention MeSH terms: Methotrexate; Mercaptopurine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 74.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: BRCA defective

Summary:

      This study will evaluate the efficacy and safety of 6-mercaptopurine (6MP) in combination
      with methotrexate (MTX) in patients with breast or ovarian cancer who are known to have a
      BRCA (breast cancer gene) mutation.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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.

          2. 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.

          3. Age ≥18 years.

          4. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.

          5. Life expectancy >12 weeks.

          6. Written informed consent.

          7. Patient willing and able to comply with all protocol requirements.

          8. No prior anti-cancer treatment in previous 4 weeks, other than palliative radiotherapy
             (RT).

          9. 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

         10. Ascites and pleural effusions must be drained prior to therapy.

        Exclusion Criteria:

          1. 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.

          2. Patients found to have a Low/Low genotype on thiopurine methyltransferase (TPMT)
             testing will be excluded.

          3. Pregnant or breast-feeding women or women of childbearing potential unless highly
             effective methods of contraception are used.

          4. 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.

          5. Patients known or tested to be serologically positive for Hepatitis B, Hepatitis C or
             human immunodeficiency virus (HIV).

          6. 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.

          7. Patients who have received anticancer agent(s) or an investigational agent within 28
             days prior to study drug administration.

          8. 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.