Clinical Trial Results:
Phase II Clinical Trial of 6-Mercaptopurine(6MP)and low-dose Methotrexate In Patients With Known BRCA Defective Tumours.
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Summary
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EudraCT number |
2009-016846-16 |
Trial protocol |
GB |
Global end of trial date |
16 Feb 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Mar 2018
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First version publication date |
04 Mar 2018
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
OCTO-16
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Additional study identifiers
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ISRCTN number |
ISRCTN63150635 | ||
US NCT number |
NCT01432145 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University of Oxford
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Sponsor organisation address |
Clinical Trials & Research Governance, Joint Research Office, Block 60, Churchill Hospital, Old Road, Oxford, United Kingdom, OX3 7LJ
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Public contact |
Ms Heather House, Clinical Trials & Research Governance, University of Oxford
, 01865 572245, heather.house@admin.ox.ac.uk
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Scientific contact |
Ms Heather House, Clinical Trials & Research Governance, University of Oxford
, 01865 572245, heather.house@admin.ox.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
02 Oct 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
16 Feb 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Feb 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To determine the anti-cancer activity of 6MP with low dose Methotrexate in patients with breast, ovarian, fallopian tube or primary serous peritoneal cancer and a known BRCA mutation.
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Protection of trial subjects |
The trial received ethical and regulatory approval, and was run in compliance with the Medicines for Human Use (Clinical Trials) Regulations 2004, and amendments thereafter, the guidelines for Good Clinical Practice, and the applicable policies of the Sponsor, the University of Oxford. Together, these regulations implement the ethical principles of the Declaration of Helsinki (2008) and the regulatory requirements for clinical trials of an investigational medicinal product as set out in the European Union (EU) Directives 001/20/EC (Clinical Trials) and 2005/28/EC (GCP). Patients also were seen for study assessments up to 28 days post end of treatment and thereafter every 3 months for clinical assessment up to a total of 12 months.
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Background therapy |
BRCA1 and BRCA2 genes are critical in homologous recombination (HR) DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis. In a screen for novel drugs that selectively kill BRCA-defective cells, Helleday and colleagues identified 6-thioguanine (6TG). They demonstrated that 6TG induces DNA double-strand breaks that are repaired by HR. The defect in HR explains the hypersensitivity of BRCA-defective cells to 6TG. Furthermore, this pre-clinical study showed that 6TG is as efficient as the PARP inhibitor, AG014699, in selectively killing BRCA-defective tumours in a xenograft model. Importantly, 6TG also kills cisplatin-resistant or PARP inhibitor resistant BRCA- defective cells. The findings of Helledey and colleagues suggest that 6TG/6MP might be an effective treatment in BRCA deficient tumours even after developing resistance to PARP inhibitors or platinum drugs. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Jun 2011
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
12 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 67
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Worldwide total number of subjects |
67
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EEA total number of subjects |
67
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
54
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From 65 to 84 years |
13
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85 years and over |
0
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Recruitment
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Recruitment details |
74 patients were consented and registered from 14 UK 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. | ||||||
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Pre-assignment
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Screening details |
Over 130 patients with advanced ovarian or breast cancer were screened for eligibility from 14 UK sites between May 2011 and October 2014. | ||||||
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Period 1
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Period 1 title |
Baseline (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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6MP and methotrexate | ||||||
Arm description |
6MP 55mg/m2 per day, and methotrexate 15mg/m2 per week | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
6MP
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The dose of 6MP was 55mg/m2 body surface area, administered orally (PO) once a day (od) in the morning at least 1 hour after eating, on a continuous schedule. Tablets should have been taken at roughly the same time each day.
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Investigational medicinal product name |
Methotrexate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Methotrexate (15 mg/m2) was taken orally, once a week, in the morning.
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Baseline characteristics reporting groups
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Reporting group title |
Baseline
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
6MP and methotrexate
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Reporting group description |
6MP 55mg/m2 per day, and methotrexate 15mg/m2 per week | ||
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End point title |
Overall response rate [1] | ||||||
End point description |
Objective response defined as complete response, partial response and stable disease as measured by radiological disease response using RECIST criteria v1.1 (Appendix 3 of the protocol) with tumour size measured radiologically with computerised tomography (CT) and/or magnetic resonance imaging (MRI) (using the same at baseline and at follow-up).
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End point type |
Primary
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End point timeframe |
8 weeks after start of treatment
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Point estimate of proportion of patients responding to treatment at 8 weeks is 0.33 (95% CI 0.23-0.45). Tried to enter this result but EudraCT wouldn't accept it as a statistical analysis because it is not comparing two arms, but it is only a one armed trial. |
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| No statistical analyses for this end point | |||||||
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End point title |
Overall Survival | ||||||||
End point description |
Overall survival where length of survival is defined in whole days as the time from entry into the study until death from any cause. For those who are not observed to die during the course of the trial will be censored at their last known follow-up date.
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End point type |
Secondary
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End point timeframe |
Over two years of follow-up
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End point title |
Progression Free Survival | ||||||||
End point description |
Progression free survival where length of survival is defined in whole days as the time from entry into the study until progression or death from any cause. For those who are not observed to progress or die during the course of the trial will be censored at their last known progression-free follow-up date.
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End point type |
Secondary
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End point timeframe |
Over two years of follow-up.
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From start of treatment until end of follow-up.
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Adverse event reporting additional description |
Grade 3 and 4 Adverse events (AE)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4.0
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Reporting groups
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Reporting group title |
6MP and methotrexate
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Reporting group description |
6MP 55mg/m2 per day, and methotrexate 15mg/m2 per week | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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14 Oct 2011 |
Additional trial site and change of PI. |
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11 Nov 2011 |
Change of PI, plus:
To add fallopian tube and primary serous peritoneal cancers to the inclusion criteria.
To clarify the assessment of disease progression.
To clarify the samples required.
To clarify the populations for data analysis.
To include all generic forms of the drugs in the protocol. |
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21 Aug 2012 |
Addition of two new sites. |
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12 Oct 2012 |
Reduction of starting dose of both IMPs
Clarification of definition of objective response
Clarification of AE reporting period
Addition of study sites |
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24 Feb 2014 |
To adjust eligibility criteria; the exclusion of patients with low TPMT activity should be removed. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The EudraCT system will not allow us to enter the results of all secondary endpoints, i.e. Assessment of feasibility as a multi-centre study. Quality of life, a secondary endpoint, could not be analysed due to the low questionnaire completion rate. | |||
