Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours

Corran Roberts; Victoria Y. Strauss; Sylwia Kopijasz; Charlie Gourley; Marcia Hall; Ana Montes; Jacinta Abraham; Andrew Clamp; Richard Kennedy; Susana Banerjee; Lisa K. Folkes; Michael Stratford; Shibani Nicum

doi:10.1038/s41416-019-0674-4

Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours

Corran Roberts, Victoria Y. Strauss, Sylwia Kopijasz, Charlie Gourley, Marcia Hall, Ana Montes, Jacinta Abraham, Andrew Clamp, Richard Kennedy, Susana Banerjee, Lisa K. Folkes, Michael Stratford, Shibani Nicum^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Background

Tumour cells with BRCA1/2 gene mutations demonstrate increased sensitivity to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. 6-mercaptopurine (6MP) was found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AG014699, even after these cells acquired resistance to a PARP inhibitor or cisplatin.

Methods

This phase II single-arm trial investigated the activity of 6MP 55–75 mg/m2 per day, and methotrexate 15–20 mg/m2 per week in advanced breast or platinum-resistant ovarian cancer patients with a BRCA1/2 germline mutation, who had progressed after ≥1 previous line of chemotherapy. The primary outcome was objective response including stable disease (SD) as an assessment of clinical benefit rate (CBR), at 8 weeks, by RECIST v1.1. Secondary outcomes included overall survival (OS) and progression-free survival (PFS).

Results

In total, 67 evaluable patients were recruited; 55 ovarian and 11 breast cancer patients. In total, 21 patients had SD (31%), one had a partial response (1.5%); CBR was 33% at 8 weeks. In total, 12/67 patients (18%) had SD at 16 weeks. In total, five ovarian cancer patients had SD for over 200 days. Median OS was 10.3 months (95% CI 6.9–14.5), median PFS 1.9 months (1.7–2.8).

Conclusions

The overall activity of 6MP and methotrexate in these patients was low; however, there was a small group of patients who appeared to derive longer-term clinical benefit.

Original language	English
Pages (from-to)	483-490
Number of pages	8
Journal	British Journal of Cancer
Volume	122
Issue number	4
Early online date	09 Dec 2019
DOIs	https://doi.org/10.1038/s41416-019-0674-4
Publication status	Published - 18 Feb 2020

Bibliographical note

Funding Information:
Funding information The trial was sponsored by the University of Oxford, with funding from Cancer Research UK’s Clinical Trials Award and Advisory Committee (CTAAC) who approved a full funding application on 26th October 2010 (grant no: C1488/A12447), and this work was supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health’s National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. VS was funded by Cancer Research UK (grant no. C5527/A16895).

Funding Information:
legislation were observed in conducting the 6MP study; namely, the study complied with the ethical principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical trials of an IMP under the European Union Clinical Trials Directive. Subjects provided their informed consent to participate in the study. The study was approved by the National Research Ethics Committee South Central–Oxford B (REC reference 10/H0605/79).

Funding Information:
Competing interests S.N. has received honoraria from AstraZeneca, Tesaro, Clovis and Roche and has provided consultancy for AstraZeneca, Clovis, Tesaro and Roch, and has received research funding from AstraZeneca. C.G. has received honoraria from AstraZeneca, Tesaro, Cor2Ed and Medscape; has provided consultancy for AstraZeneca, Clovis, Nucana, Tesaro, Roche, Foundation One and Cor2Ed; his institution receives research funding from AstraZeneca, Aprea AB, Nucana and Tesaro. R.K. receives payment as medical director for Almac Diagnostics. J.A. has received honorarium in the past 24 months, which has included travel expenses for advisory roles from Novartis and Genomic Health. S.B. has received research funding from Astrazeneca and has served on advisory boards for Astrazeneca, Tesaro and Clovis. All other authors jointly declare that they have no competing interests.

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours
Copyright 2022 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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Cite this

Roberts, C., Strauss, V. Y., Kopijasz, S., Gourley, C., Hall, M., Montes, A., Abraham, J., Clamp, A., Kennedy, R., Banerjee, S., Folkes, L. K., Stratford, M., & Nicum, S. (2020). Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours. British Journal of Cancer, 122(4), 483-490. https://doi.org/10.1038/s41416-019-0674-4

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title = "Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours",

abstract = "BackgroundTumour cells with BRCA1/2 gene mutations demonstrate increased sensitivity to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. 6-mercaptopurine (6MP) was found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AG014699, even after these cells acquired resistance to a PARP inhibitor or cisplatin.MethodsThis phase II single-arm trial investigated the activity of 6MP 55–75 mg/m2 per day, and methotrexate 15–20 mg/m2 per week in advanced breast or platinum-resistant ovarian cancer patients with a BRCA1/2 germline mutation, who had progressed after ≥1 previous line of chemotherapy. The primary outcome was objective response including stable disease (SD) as an assessment of clinical benefit rate (CBR), at 8 weeks, by RECIST v1.1. Secondary outcomes included overall survival (OS) and progression-free survival (PFS).ResultsIn total, 67 evaluable patients were recruited; 55 ovarian and 11 breast cancer patients. In total, 21 patients had SD (31%), one had a partial response (1.5%); CBR was 33% at 8 weeks. In total, 12/67 patients (18%) had SD at 16 weeks. In total, five ovarian cancer patients had SD for over 200 days. Median OS was 10.3 months (95% CI 6.9–14.5), median PFS 1.9 months (1.7–2.8).ConclusionsThe overall activity of 6MP and methotrexate in these patients was low; however, there was a small group of patients who appeared to derive longer-term clinical benefit.",

author = "Corran Roberts and Strauss, {Victoria Y.} and Sylwia Kopijasz and Charlie Gourley and Marcia Hall and Ana Montes and Jacinta Abraham and Andrew Clamp and Richard Kennedy and Susana Banerjee and Folkes, {Lisa K.} and Michael Stratford and Shibani Nicum",

note = "Funding Information: Funding information The trial was sponsored by the University of Oxford, with funding from Cancer Research UK{\textquoteright}s Clinical Trials Award and Advisory Committee (CTAAC) who approved a full funding application on 26th October 2010 (grant no: C1488/A12447), and this work was supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health{\textquoteright}s National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. VS was funded by Cancer Research UK (grant no. C5527/A16895). Funding Information: legislation were observed in conducting the 6MP study; namely, the study complied with the ethical principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical trials of an IMP under the European Union Clinical Trials Directive. Subjects provided their informed consent to participate in the study. The study was approved by the National Research Ethics Committee South Central–Oxford B (REC reference 10/H0605/79). Funding Information: Competing interests S.N. has received honoraria from AstraZeneca, Tesaro, Clovis and Roche and has provided consultancy for AstraZeneca, Clovis, Tesaro and Roch, and has received research funding from AstraZeneca. C.G. has received honoraria from AstraZeneca, Tesaro, Cor2Ed and Medscape; has provided consultancy for AstraZeneca, Clovis, Nucana, Tesaro, Roche, Foundation One and Cor2Ed; his institution receives research funding from AstraZeneca, Aprea AB, Nucana and Tesaro. R.K. receives payment as medical director for Almac Diagnostics. J.A. has received honorarium in the past 24 months, which has included travel expenses for advisory roles from Novartis and Genomic Health. S.B. has received research funding from Astrazeneca and has served on advisory boards for Astrazeneca, Tesaro and Clovis. All other authors jointly declare that they have no competing interests. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41416-019-0674-4",

language = "English",

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Roberts, C, Strauss, VY, Kopijasz, S, Gourley, C, Hall, M, Montes, A, Abraham, J, Clamp, A, Kennedy, R, Banerjee, S, Folkes, LK, Stratford, M & Nicum, S 2020, 'Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours', British Journal of Cancer, vol. 122, no. 4, pp. 483-490. https://doi.org/10.1038/s41416-019-0674-4

TY - JOUR

T1 - Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours

AU - Roberts, Corran

AU - Strauss, Victoria Y.

AU - Kopijasz, Sylwia

AU - Gourley, Charlie

AU - Hall, Marcia

AU - Montes, Ana

AU - Abraham, Jacinta

AU - Clamp, Andrew

AU - Kennedy, Richard

AU - Banerjee, Susana

AU - Folkes, Lisa K.

AU - Stratford, Michael

AU - Nicum, Shibani

N1 - Funding Information: Funding information The trial was sponsored by the University of Oxford, with funding from Cancer Research UK’s Clinical Trials Award and Advisory Committee (CTAAC) who approved a full funding application on 26th October 2010 (grant no: C1488/A12447), and this work was supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health’s National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. VS was funded by Cancer Research UK (grant no. C5527/A16895). Funding Information: legislation were observed in conducting the 6MP study; namely, the study complied with the ethical principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical trials of an IMP under the European Union Clinical Trials Directive. Subjects provided their informed consent to participate in the study. The study was approved by the National Research Ethics Committee South Central–Oxford B (REC reference 10/H0605/79). Funding Information: Competing interests S.N. has received honoraria from AstraZeneca, Tesaro, Clovis and Roche and has provided consultancy for AstraZeneca, Clovis, Tesaro and Roch, and has received research funding from AstraZeneca. C.G. has received honoraria from AstraZeneca, Tesaro, Cor2Ed and Medscape; has provided consultancy for AstraZeneca, Clovis, Nucana, Tesaro, Roche, Foundation One and Cor2Ed; his institution receives research funding from AstraZeneca, Aprea AB, Nucana and Tesaro. R.K. receives payment as medical director for Almac Diagnostics. J.A. has received honorarium in the past 24 months, which has included travel expenses for advisory roles from Novartis and Genomic Health. S.B. has received research funding from Astrazeneca and has served on advisory boards for Astrazeneca, Tesaro and Clovis. All other authors jointly declare that they have no competing interests. Publisher Copyright: © 2019, The Author(s).

PY - 2020/2/18

Y1 - 2020/2/18

N2 - BackgroundTumour cells with BRCA1/2 gene mutations demonstrate increased sensitivity to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. 6-mercaptopurine (6MP) was found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AG014699, even after these cells acquired resistance to a PARP inhibitor or cisplatin.MethodsThis phase II single-arm trial investigated the activity of 6MP 55–75 mg/m2 per day, and methotrexate 15–20 mg/m2 per week in advanced breast or platinum-resistant ovarian cancer patients with a BRCA1/2 germline mutation, who had progressed after ≥1 previous line of chemotherapy. The primary outcome was objective response including stable disease (SD) as an assessment of clinical benefit rate (CBR), at 8 weeks, by RECIST v1.1. Secondary outcomes included overall survival (OS) and progression-free survival (PFS).ResultsIn total, 67 evaluable patients were recruited; 55 ovarian and 11 breast cancer patients. In total, 21 patients had SD (31%), one had a partial response (1.5%); CBR was 33% at 8 weeks. In total, 12/67 patients (18%) had SD at 16 weeks. In total, five ovarian cancer patients had SD for over 200 days. Median OS was 10.3 months (95% CI 6.9–14.5), median PFS 1.9 months (1.7–2.8).ConclusionsThe overall activity of 6MP and methotrexate in these patients was low; however, there was a small group of patients who appeared to derive longer-term clinical benefit.

AB - BackgroundTumour cells with BRCA1/2 gene mutations demonstrate increased sensitivity to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. 6-mercaptopurine (6MP) was found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AG014699, even after these cells acquired resistance to a PARP inhibitor or cisplatin.MethodsThis phase II single-arm trial investigated the activity of 6MP 55–75 mg/m2 per day, and methotrexate 15–20 mg/m2 per week in advanced breast or platinum-resistant ovarian cancer patients with a BRCA1/2 germline mutation, who had progressed after ≥1 previous line of chemotherapy. The primary outcome was objective response including stable disease (SD) as an assessment of clinical benefit rate (CBR), at 8 weeks, by RECIST v1.1. Secondary outcomes included overall survival (OS) and progression-free survival (PFS).ResultsIn total, 67 evaluable patients were recruited; 55 ovarian and 11 breast cancer patients. In total, 21 patients had SD (31%), one had a partial response (1.5%); CBR was 33% at 8 weeks. In total, 12/67 patients (18%) had SD at 16 weeks. In total, five ovarian cancer patients had SD for over 200 days. Median OS was 10.3 months (95% CI 6.9–14.5), median PFS 1.9 months (1.7–2.8).ConclusionsThe overall activity of 6MP and methotrexate in these patients was low; however, there was a small group of patients who appeared to derive longer-term clinical benefit.

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DO - 10.1038/s41416-019-0674-4

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AN - SCOPUS:85076555407

SN - 0007-0920

VL - 122

SP - 483

EP - 490

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 4

ER -

Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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