title: Phase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of a combination of gefitinib and methotrexate to treat tubal ectopic pregnancies (GEM II): study protocol.
abstract: BACKGROUND
  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/m(2)) 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.
  
  
  BACKGROUND
  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.
  
  
  BACKGROUND
  ACTRN12611001056987.
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Horne
authors.forename: Monika M
authors.initials: MM
authors.lastname: Skubisz
authors.forename: Ann
authors.initials: A
authors.lastname: Doust
authors.forename: W Colin
authors.initials: WC
authors.lastname: Duncan
authors.forename: Euan
authors.initials: E
authors.lastname: Wallace
authors.forename: Hilary O D
authors.initials: HO
authors.lastname: Critchley
authors.forename: Terrance G
authors.initials: TG
authors.lastname: Johns
authors.forename: Jane E
authors.initials: JE
authors.lastname: Norman
authors.forename: Siladitya
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Jill
authors.initials: J
authors.lastname: Mollison
authors.forename: Michael
authors.initials: M
authors.lastname: Rassmusen
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
keywords: Gynaecology; Reproductive Medicine