Breast Cancer, Ovarian Cancer
Conditions
Keywords
BRCA defective
Brief 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.
Detailed description
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. 6MP is used instead of thioguanine(6TG) as it is converted to the same cytotoxic moiety as 6TG, ie. thioguanine nucleotides, but with reduced toxic effects. Low dose methotrexate is used in combination with 6MP as it promotes the formation of thioguanine nucleotides.
Interventions
DRUG6-Mercaptopurine
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.
DRUGMethotrexate
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.
Sponsors
University of Oxford
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate to 6-mercaptopurine and Methotrexate (6MP/MTX) in This Patient Population. | 8 weeks after start of treatment | 1st stage: If less than 3/30 evaluable patients respond at 8 weeks the trial will be stopped for futility. If 3 or more out of 30 evaluable patients respond then a further 35 patients will be recruited (2nd stage) - this was met. The proportion of patients responding to treatment (complete response, partial response or stable disease) at the second stage will be presented per Response Evaluation Criteria In Solid Tumours (RECIST) criteria version 1.1 measured radiologically with computerised tomography (CT) and/or magnetic resonance imaging (MRI); the same method is used at baseline and at follow-up: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Patients who yield progressive disease (PD) are classed as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life - EuroQol Group, Five Dimensions, Three-level (EQ-5D-3L) Standardized Instrument for Measuring Generic Health Status | At the end of treatment or 12 months | Evaluated using the EQ-5D-3L questionnaire at baseline, 3 and 6 months, and at the end of treatment or 12 months, as well as using the ECOG performance status measure after each cycle |
Countries
United Kingdom
Participant flow
Recruitment details
74 patients were consented and registered from 14 sites between May 2011 and October 2014, and 67 of these registered patients were found to be evaluable. This is larger than the planned sample size of 65 patients, to compensate for unevaluable patients.
Pre-assignment details
No wash out or run-in periods. No enrolled participants were excluded from the study before assignment.
Participants by arm
| Arm | Count |
|---|---|
| 6MP/MTX 6-Mercaptopurine: The dose of 6MP will be 75mg/m2 body surface area, administered orally (PO) once a day (od) in the morning 1 hour after eating, on a continuous schedule. Tablets should be taken at roughly the same time each day. One cycle is 28 days. Treatment is given continuously until disease progression.
Methotrexate: Methotrexate (20 mg/m2) will be taken orally, once a week, in the morning. One cycle is 28 days. Treatment is given continuously until disease progression.
Update: These original doses were reduced following an Urgent Safety Measure in August 2012 due to a large proportion of patients requiring a dose reduction or treatment delay due to incidences of myelo-suppression.
The reduced doses were 55mg/m2 of 6MP orally once a day, and 15mg/m2 of Methotrexate orally once a week. | 67 |
| Total | 67 |
Baseline characteristics
| Characteristic | 6MP/MTX | — |
|---|---|---|
| Age, Continuous | 55.9 years | — |
| Age, Customized Age categorical 18-64 years | 54 Participants | — |
| Age, Customized Age categorical 65-84 years | 13 Participants | — |
| Age, Customized Age categorical 85 years and over | 0 Participants | — |
| Albumin levels | 39.8 g/dl | — |
| Breast Cancer gene (BRCA) Status BRCA 1 | 40 Participants | — |
| Breast Cancer gene (BRCA) Status BRCA 2 | 27 Participants | — |
| Eastern Cooperative Oncology Group (ECOG) Performance Status PS 0 | 27 Participants | — |
| Eastern Cooperative Oncology Group (ECOG) Performance Status PS 1 | 36 Participants | — |
| Eastern Cooperative Oncology Group (ECOG) Performance Status PS 2 | 4 Participants | — |
| Prior poly-Adenosine diphosphate (ADP) ribose polymerase (PARP) treatment No | 41 Participants | — |
| Prior poly-Adenosine diphosphate (ADP) ribose polymerase (PARP) treatment Yes | 26 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United Kingdom | 67 participants | — |
| Sex: Female, Male Female | 67 Participants | — |
| Sex: Female, Male Male | 0 Participants | — |
| Thiopurine methyltransferase (TPMT) | 88.3 mU/L | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 52 / 67 |
| other Total, other adverse events | 46 / 67 |
| serious Total, serious adverse events | 33 / 67 |
Outcome results
Primary
Objective Response Rate to 6-mercaptopurine and Methotrexate (6MP/MTX) in This Patient Population.
1st stage: If less than 3/30 evaluable patients respond at 8 weeks the trial will be stopped for futility. If 3 or more out of 30 evaluable patients respond then a further 35 patients will be recruited (2nd stage) - this was met. The proportion of patients responding to treatment (complete response, partial response or stable disease) at the second stage will be presented per Response Evaluation Criteria In Solid Tumours (RECIST) criteria version 1.1 measured radiologically with computerised tomography (CT) and/or magnetic resonance imaging (MRI); the same method is used at baseline and at follow-up: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Patients who yield progressive disease (PD) are classed as non-responders.
Time frame: 8 weeks after start of treatment
Population: Evaluable patients are those patients who complete at least 4 out of 8 weeks of trial medication and are assessed for response as per RECIST v1.1 at 8 weeks. Patient who stop trial medication early due to disease progression are also fully evaluable as they have reached an end point.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 6-Mercaptopurine and Methotrexate (6MP/MTX) | Objective Response Rate to 6-mercaptopurine and Methotrexate (6MP/MTX) in This Patient Population. | 22 Participants |
Secondary
Quality of Life - EuroQol Group, Five Dimensions, Three-level (EQ-5D-3L) Standardized Instrument for Measuring Generic Health Status
Evaluated using the EQ-5D-3L questionnaire at baseline, 3 and 6 months, and at the end of treatment or 12 months, as well as using the ECOG performance status measure after each cycle
Time frame: At the end of treatment or 12 months
Population: Quality of life could not be analysed due to the low questionnaire completion rate; only two patients (3%) completed the baseline and 12 month follow up QoL questionnaires, , but data could not be reported in the Outcome Measure due to confidentiality issues.