Phase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of combination gefitinib and methotrexate to treat ectopic pregnancies (GEM II): study protocol

Andrew W. Horne; Monika M Skubisz; Ann Doust; W Colin Duncan Duncan; Euan Wallace; Hilary O D Critchley; Terence G Johns; Jane E Norman; Siladitya Bhattacharya; Jill Mollison; Michael  Rassmusen; Stephen Tong

doi:10.1136/bmjopen-2013-002902

Phase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of combination gefitinib and methotrexate to treat ectopic pregnancies (GEM II): study protocol

Andrew W. Horne, Monika M Skubisz, Ann Doust, W Colin Duncan Duncan, Euan Wallace, Hilary O D Critchley, Terence G Johns, Jane E Norman, Siladitya Bhattacharya, Jill Mollison, Michael Rassmusen, Stephen Tong

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Abstract

Introduction Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels <1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate (MTX). TEPs with hCG >1000 IU/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000–10 000 IU/L

Methods and analysis We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000–10 000 IU/L). We intend to give a single dose of intramuscular MTX (50 mg/m2) and oral gefitinib (250 mg) daily for 7 days. Our primary outcome is the resolution of EP to non-pregnant hCG levels <15 IU/L without requirement of surgery. Our secondary outcomes are comparison of time to resolution against historical controls given MTX only, and safety and tolerability as determined by clinical/biochemical assessment.

Ethics and dissemination Ethical approval has been obtained from Scotland A Research Ethics Committee (MREC 11/AL/0350), Southern Health Human Research Ethics Committee B (HREC 11180B) and the Mercy Health Human Research Ethics Committee (R12/25). Data will be presented at international conferences and published in peer-reviewed journals.

Trial registration number ACTRN12611001056987.

Original language	English
Article number	e002902
Journal	BMJ Open
Volume	3
Issue number	7
DOIs	https://doi.org/10.1136/bmjopen-2013-002902
Publication status	Published - 18 Jul 2013

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Horne, A. W., Skubisz, M. M., Doust, A., Duncan, W. C. D., Wallace, E., Critchley, H. O. D., Johns, T. G., Norman, J. E., Bhattacharya, S., Mollison, J., Rassmusen, M., & Tong, S. (2013). Phase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of combination gefitinib and methotrexate to treat ectopic pregnancies (GEM II): study protocol. BMJ Open, 3(7), [e002902]. https://doi.org/10.1136/bmjopen-2013-002902

Phase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of combination gefitinib and methotrexate to treat ectopic pregnancies (GEM II) : study protocol. / Horne, Andrew W.; Skubisz, Monika M; Doust, Ann et al.

In: BMJ Open, Vol. 3, No. 7, e002902, 18.07.2013.

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

Horne, AW, Skubisz, MM, Doust, A, Duncan, WCD, Wallace, E, Critchley, HOD, Johns, TG, Norman, JE, Bhattacharya, S, Mollison, J, Rassmusen, M & Tong, S 2013, 'Phase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of combination gefitinib and methotrexate to treat ectopic pregnancies (GEM II): study protocol', BMJ Open, vol. 3, no. 7, e002902. https://doi.org/10.1136/bmjopen-2013-002902

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abstract = "Introduction Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels <1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate (MTX). TEPs with hCG >1000 IU/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000–10 000 IU/LMethods and analysis We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000–10 000 IU/L). We intend to give a single dose of intramuscular MTX (50 mg/m2) and oral gefitinib (250 mg) daily for 7 days. Our primary outcome is the resolution of EP to non-pregnant hCG levels <15 IU/L without requirement of surgery. Our secondary outcomes are comparison of time to resolution against historical controls given MTX only, and safety and tolerability as determined by clinical/biochemical assessment.Ethics and dissemination Ethical approval has been obtained from Scotland A Research Ethics Committee (MREC 11/AL/0350), Southern Health Human Research Ethics Committee B (HREC 11180B) and the Mercy Health Human Research Ethics Committee (R12/25). Data will be presented at international conferences and published in peer-reviewed journals.Trial registration number ACTRN12611001056987.",

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AU - Horne, Andrew W.

AU - Skubisz, Monika M

AU - Doust, Ann

AU - Duncan, W Colin Duncan

AU - Wallace, Euan

AU - Critchley, Hilary O D

AU - Johns, Terence G

AU - Norman, Jane E

AU - Bhattacharya, Siladitya

AU - Mollison, Jill

AU - Rassmusen, Michael

AU - Tong, Stephen

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N2 - Introduction Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels <1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate (MTX). TEPs with hCG >1000 IU/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000–10 000 IU/LMethods and analysis We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000–10 000 IU/L). We intend to give a single dose of intramuscular MTX (50 mg/m2) and oral gefitinib (250 mg) daily for 7 days. Our primary outcome is the resolution of EP to non-pregnant hCG levels <15 IU/L without requirement of surgery. Our secondary outcomes are comparison of time to resolution against historical controls given MTX only, and safety and tolerability as determined by clinical/biochemical assessment.Ethics and dissemination Ethical approval has been obtained from Scotland A Research Ethics Committee (MREC 11/AL/0350), Southern Health Human Research Ethics Committee B (HREC 11180B) and the Mercy Health Human Research Ethics Committee (R12/25). Data will be presented at international conferences and published in peer-reviewed journals.Trial registration number ACTRN12611001056987.

AB - Introduction Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels <1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate (MTX). TEPs with hCG >1000 IU/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000–10 000 IU/LMethods and analysis We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000–10 000 IU/L). We intend to give a single dose of intramuscular MTX (50 mg/m2) and oral gefitinib (250 mg) daily for 7 days. Our primary outcome is the resolution of EP to non-pregnant hCG levels <15 IU/L without requirement of surgery. Our secondary outcomes are comparison of time to resolution against historical controls given MTX only, and safety and tolerability as determined by clinical/biochemical assessment.Ethics and dissemination Ethical approval has been obtained from Scotland A Research Ethics Committee (MREC 11/AL/0350), Southern Health Human Research Ethics Committee B (HREC 11180B) and the Mercy Health Human Research Ethics Committee (R12/25). Data will be presented at international conferences and published in peer-reviewed journals.Trial registration number ACTRN12611001056987.

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DO - 10.1136/bmjopen-2013-002902

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JO - BMJ Open

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Phase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of combination gefitinib and methotrexate to treat ectopic pregnancies (GEM II): study protocol

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