Trial Outcomes & Findings for A Clinical Trial in Patients With Breast Cancer Susceptibility Gene (BRCA) Defective Tumours (NCT NCT01432145)

Last Updated: 2019-07-09

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

74 participants

Primary outcome timeframe

8 weeks after start of treatment

Results posted on

2019-07-09

Participant Flow

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.

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

Participant milestones

Participant milestones
Measure	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.
Overall Study STARTED	74
Overall Study COMPLETED	67
Overall Study NOT COMPLETED	7

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	6MP/MTX n=67 Participants 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.
Age, Continuous	55.9 years n=67 Participants
Age, Customized Age categorical · 18-64 years	54 Participants n=67 Participants
Age, Customized Age categorical · 65-84 years	13 Participants n=67 Participants
Age, Customized Age categorical · 85 years and over	0 Participants n=67 Participants
Sex: Female, Male Female	67 Participants n=67 Participants
Sex: Female, Male Male	0 Participants n=67 Participants
Region of Enrollment United Kingdom	67 participants n=67 Participants
Breast Cancer gene (BRCA) Status BRCA 1	40 Participants n=67 Participants
Breast Cancer gene (BRCA) Status BRCA 2	27 Participants n=67 Participants
Prior poly-Adenosine diphosphate (ADP) ribose polymerase (PARP) treatment Yes	26 Participants n=67 Participants
Prior poly-Adenosine diphosphate (ADP) ribose polymerase (PARP) treatment No	41 Participants n=67 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status PS 0	27 Participants n=67 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status PS 1	36 Participants n=67 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status PS 2	4 Participants n=67 Participants
Albumin levels	39.8 g/dl n=67 Participants
Thiopurine methyltransferase (TPMT)	88.3 mU/L n=67 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	6-Mercaptopurine and Methotrexate (6MP/MTX) n=67 Participants 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.
Objective Response Rate to 6-mercaptopurine and Methotrexate (6MP/MTX) in This Patient Population.	22 Participants

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome data not reported

Adverse Events

6MP/MTX

Serious events: 33 serious events

Other events: 46 other events

Deaths: 52 deaths

Serious adverse events

Serious adverse events
Measure	6MP/MTX n=67 participants at risk 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.
Vascular disorders Thromboembolic event	4.5% 3/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Investigations Neutrophil count decreased	9.0% 6/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Cardiac disorders Palpitations	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Blood and lymphatic system disorders Pancytopenia	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Blood and lymphatic system disorders Febrile neutropenia	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Nervous system disorders Ataxia	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
General disorders Fever	3.0% 2/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Abdominal pain	7.5% 5/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Ascites	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Colonic obstruction	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Constipation	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Nausea	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Pancreatitis	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Small intestinal obstruction	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Vomiting	3.0% 2/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Renal and urinary disorders Urinary tract obstruction	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Hepatobiliary disorders Obstruction	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Reproductive system and breast disorders Female genital tract fistula	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Reproductive system and breast disorders Vaginal haemorrhage	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Infections and infestations Anorectal infection	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Infections and infestations Infection	1.5% 1/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Infections and infestations Lung infection	4.5% 3/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Infections and infestations Sepsis	3.0% 2/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Infections and infestations Urinary tract infection	3.0% 2/67 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.

Other adverse events

Other adverse events
Measure	6MP/MTX n=67 participants at risk 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.
Investigations Neutrophil count decreased	35.8% 24/67 • Number of events 41 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Investigations Platelet count decreased	7.5% 5/67 • Number of events 8 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Investigations White blood cell count decreased	22.4% 15/67 • Number of events 21 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Blood and lymphatic system disorders Anaemia	32.8% 22/67 • Number of events 27 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
General disorders Fatigue	28.4% 19/67 • Number of events 24 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Ascites	4.5% 3/67 • Number of events 3 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Nausea	17.9% 12/67 • Number of events 15 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Vomiting	13.4% 9/67 • Number of events 11 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Hepatobiliary disorders Abdominal pain	11.9% 8/67 • Number of events 9 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Infections and infestations Urinary tract infection	4.5% 3/67 • Number of events 3 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Investigations Alanine Aminotransferase Increased	6.0% 4/67 • Number of events 9 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Metabolism and nutrition disorders Anorexia	4.5% 3/67 • Number of events 5 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Investigations Blood bilirubin increased	6.0% 4/67 • Number of events 6 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Diarrhoea	4.5% 3/67 • Number of events 5 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Respiratory, thoracic and mediastinal disorders Dyspnea	4.5% 3/67 • Number of events 4 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Investigations GGT increased	4.5% 3/67 • Number of events 5 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Nervous system disorders Headache	4.5% 3/67 • Number of events 3 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.
Gastrointestinal disorders Mucositis Oral	9.0% 6/67 • Number of events 6 • From start of treatment until end of follow-up, up to 2 years. For Adverse Events (AEs), Grade 3 and 4 AEs and Grade 2 Adverse Drug Reactions (ADRs) were collected.

Additional Information

Ms Heather House

University of Oxford Clinical Trials & Research Governance

Phone: 01865 572245

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PI Publication needs to be after the first study multip-centre publication and make reference to it.
Publication restrictions are in place

Restriction type: OTHER