6MP: A Clinical Trial in Patients With Breast Cancer Susceptibility Gene (BRCA) Defective Tumours

• Sponsor: University of Oxford (Other)
• Overall Status: Completed
• CT.gov ID: NCT01432145
• Collaborator: (none)
• Enrollment: 74
• Location: 1
• Arm: 1
• Duration (Months): 48
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Ovarian Cancer	Drug: 6-Mercaptopurine; Drug: Methotrexate	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 74 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Clinical Trial Of 6-Mercaptopurine (6MP) and Low-Dose Methotrexate In Patients With Known BRCA Defective Tumours
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 6MP/MTX 6-Mercaptopurine 55mg/m2 per day, and methotrexate 15mg/m2 per week

Drug: 6-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.; Other Names: 6MP ; Drug: Methotrexate; 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.; Other Names: MTX

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts 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.

1. 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.

2. Age ≥18 years.

3. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.

4. Life expectancy >12 weeks.

5. Written informed consent.

6. Patient willing and able to comply with all protocol requirements.

7. No prior anti-cancer treatment in previous 4 weeks, other than palliative radiotherapy (RT).

8. 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

1. 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.

1. Patients found to have a Low/Low genotype on thiopurine methyltransferase (TPMT) testing will be excluded.

2. Pregnant or breast-feeding women or women of childbearing potential unless highly effective methods of contraception are used.

3. 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.

4. Patients known or tested to be serologically positive for Hepatitis B, Hepatitis C or human immunodeficiency virus (HIV).

5. 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.

6. Patients who have received anticancer agent(s) or an investigational agent within 28 days prior to study drug administration.

7. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Churchill Hospital	Oxford		United Kingdom	OX3 7LJ

Sponsors and Collaborators

• University of Oxford

Investigators

• Principal Investigator: Shibani Nicum, University of Oxford

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Oxford
• ClinicalTrials.gov Identifier: NCT01432145
• Other Study ID Numbers: OCTO_016
• First Posted: Sep 12, 2011
• Last Update Posted: Jul 9, 2019
• Last Verified: Jun 1, 2018

• Keywords provided by University of Oxford: BRCA defective
• Additional relevant MeSH terms: Breast Neoplasms; Methotrexate; Mercaptopurine

Study Results

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 Detail	No wash out or run-in periods. No enrolled participants were excluded from the study before assignment.

Arm/Group Title	6MP/MTX
Arm/Group Description	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.
Period Title: Overall Study
STARTED	74
COMPLETED	67
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	6MP/MTX
Arm/Group Description	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.
Overall Participants	67
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	55.9
Age, Customized (Count of Participants)
18-64 years	54 80.6%
65-84 years	13 19.4%
85 years and over	0 0%
Sex: Female, Male (Count of Participants)
Female	67 100%
Male	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United Kingdom	67 100%
Breast Cancer gene (BRCA) Status (Count of Participants)
BRCA 1	40 59.7%
BRCA 2	27 40.3%
Prior poly-Adenosine diphosphate (ADP) ribose polymerase (PARP) treatment (Count of Participants)
Yes	26 38.8%
No	41 61.2%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
PS 0	27 40.3%
PS 1	36 53.7%
PS 2	4 6%
Albumin levels (g/dl) [Mean (Full Range) ]
Mean (Full Range) [g/dl]	39.8
Thiopurine methyltransferase (TPMT) (mU/L) [Mean (Full Range) ]
Mean (Full Range) [mU/L]	88.3

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate to 6-mercaptopurine and Methotrexate (6MP/MTX) in This Patient Population.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	6-Mercaptopurine and Methotrexate (6MP/MTX)
Arm/Group Description	6-Mercaptopurine: 6MP 75mg/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: Methotrexate 20mg/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.
Measure Participants	67
Count of Participants [Participants]	22 32.8%

2. Secondary Outcome

Title	Quality of Life - EuroQol Group, Five Dimensions, Three-level (EQ-5D-3L) Standardized Instrument for Measuring Generic Health Status
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	6-Mercaptopurine and Methotrexate (6MP/MTX)
Arm/Group Description	6-Mercaptopurine: 6MP 75mg/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: Methotrexate 20mg/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.
Measure Participants	0

Adverse Events

Time Frame	From start of treatment until end of follow-up, up to 2 years.
Adverse Event Reporting Description	For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Arm/Group Title	6MP/MTX
Arm/Group Description	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 (see table below) 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 (see table below) until disease progression.
All Cause Mortality
	6MP/MTX
	Affected / at Risk (%)	# Events
Total	52/67 (77.6%)
Serious Adverse Events
	6MP/MTX
	Affected / at Risk (%)	# Events
Total	33/67 (49.3%)
Blood and lymphatic system disorders
Pancytopenia	1/67 (1.5%)
Febrile neutropenia	1/67 (1.5%)
Cardiac disorders
Palpitations	1/67 (1.5%)
Gastrointestinal disorders
Abdominal pain	5/67 (7.5%)
Ascites	1/67 (1.5%)
Colonic obstruction	1/67 (1.5%)
Constipation	1/67 (1.5%)
Nausea	1/67 (1.5%)
Pancreatitis	1/67 (1.5%)
Small intestinal obstruction	1/67 (1.5%)
Vomiting	2/67 (3%)
General disorders
Fever	2/67 (3%)
Hepatobiliary disorders
Obstruction	1/67 (1.5%)
Infections and infestations
Anorectal infection	1/67 (1.5%)
Infection	1/67 (1.5%)
Lung infection	3/67 (4.5%)
Sepsis	2/67 (3%)
Urinary tract infection	2/67 (3%)
Investigations
Neutrophil count decreased	6/67 (9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	1/67 (1.5%)
Nervous system disorders
Ataxia	1/67 (1.5%)
Renal and urinary disorders
Urinary tract obstruction	1/67 (1.5%)
Reproductive system and breast disorders
Female genital tract fistula	1/67 (1.5%)
Vaginal haemorrhage	1/67 (1.5%)
Vascular disorders
Thromboembolic event	3/67 (4.5%)
Other (Not Including Serious) Adverse Events
	6MP/MTX
	Affected / at Risk (%)	# Events
Total	46/67 (68.7%)
Blood and lymphatic system disorders
Anaemia	22/67 (32.8%)	27
Gastrointestinal disorders
Ascites	3/67 (4.5%)	3
Nausea	12/67 (17.9%)	15
Vomiting	9/67 (13.4%)	11
Diarrhoea	3/67 (4.5%)	5
Mucositis Oral	6/67 (9%)	6
General disorders
Fatigue	19/67 (28.4%)	24
Hepatobiliary disorders
Abdominal pain	8/67 (11.9%)	9
Infections and infestations
Urinary tract infection	3/67 (4.5%)	3
Investigations
Neutrophil count decreased	24/67 (35.8%)	41
Platelet count decreased	5/67 (7.5%)	8
White blood cell count decreased	15/67 (22.4%)	21
Alanine Aminotransferase Increased	4/67 (6%)	9
Blood bilirubin increased	4/67 (6%)	6
GGT increased	3/67 (4.5%)	5
Metabolism and nutrition disorders
Anorexia	3/67 (4.5%)	5
Nervous system disorders
Headache	3/67 (4.5%)	3
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/67 (4.5%)	4

Limitations/Caveats

Quality of life, a secondary endpoint, could not be analysed due to the low questionnaire completion rate.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI Publication needs to be after the first study multip-centre publication and make reference to it.