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 languageEnglish
Article numbere002902
JournalBMJ Open
Volume3
Issue number7
DOIs
Publication statusPublished - 18 Jul 2013

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Ectopic Pregnancy
Methotrexate
Multicenter Studies
Chorionic Gonadotropin
Clinical Trials
Research Ethics Committees
Epidermal Growth Factor Receptor
Tubal Pregnancy
Ambulatory Monitoring
Health
Scotland
Serum
Gynecology
Ethics
gefitinib
Safety
Pregnancy
Therapeutics

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

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

Research output: Contribution to journalArticle

Horne, Andrew W. ; Skubisz, Monika M ; Doust, Ann ; Duncan, W Colin Duncan ; Wallace, Euan ; Critchley, Hilary O D ; Johns, Terence G ; Norman, Jane E ; Bhattacharya, Siladitya ; Mollison, Jill ; Rassmusen, Michael ; Tong, Stephen. / 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. In: BMJ Open. 2013 ; Vol. 3, No. 7.
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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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T1 - 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)

T2 - study protocol

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.

U2 - 10.1136/bmjopen-2013-002902

DO - 10.1136/bmjopen-2013-002902

M3 - Article

VL - 3

JO - BMJ Open

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SN - 2044-6055

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