Effects of Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, on Human Placental Cell Growth

Nilsson, Ulrika Wilhelmina; Johns, Terrance G.; Wilmann, T.; Kaitu’u-Lino, Tu’uhevaha J; Whitehead, Clare; Dimitriadis, Evdokia; Menkhorst, Ellen; Saglam, Burcu; Gao, Yan; Greenall, Sameer A.; Horne, Andrew W; Tong, Stephen

doi:10.1097/aog.0b013e3182a1ba56

Cited by 25 publications

(26 citation statements)

References 17 publications

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“…We have demonstrated effective management of women with non-tubal EPs and pretreatment hCGs as high as 48 558 IU/l by combining minimal doses of methotrexate with a short course of gefitinib. This co-treatment approach can achieve better treatment outcomes with lower overall drug exposure (Nilsson et al , 2013). …”

Section: Discussionmentioning

confidence: 99%

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Combination gefitinib and methotrexate treatment for non-tubal ectopic pregnancies: a case series

et al. 2014

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Non-tubal ectopic pregnancies are a rare subgroup of ectopic pregnancies implanted at sites other than the Fallopian tube. Mortality from non-tubal ectopic pregnancies is higher compared with that for tubal ectopic pregnancies, and they are becoming more common, partly due to the rising incidence of Caesarean sections and use of assisted reproductive technologies. Non-tubal ectopic pregnancies can be especially difficult to treat. Surgical treatment is complex, and follow-up after medical treatment is usually protracted. There is therefore a need for more effective medical therapies to resolve non-tubal ectopic pregnancies and reduce operative intervention. We have recently reported successful use of combination gefitinib (an orally available epidermal growth factor receptor inhibitor) and methotrexate for treatment of tubal pregnancies. To our knowledge, this combination has not been used to treat non-tubal pregnancies. Here we report the use of combination gefitinib and methotrexate to treat eight women with stable, non-tubal ectopic pregnancies at two tertiary academic teaching hospitals (Edinburgh, UK and Melbourne, Australia); five interstitial and three Caesarean section scar ectopic pregnancies. Pretreatment serum hCG levels ranged from 2458 to 48 550 IU/l, and six women had pretreatment hCG levels >5000 IU/l. The women were co-administered 1–2 doses of i.m. methotrexate (50 mg/m2 on Day 1, ± Day 4 or Day 7) with seven once daily doses of oral gefitinib (250 mg). The women were monitored until complete resolution of the ectopic pregnancy, defined as a serum hCG <15 IU/l. Time to resolution (days from first methotrexate dose until serum hCG <15 IU/l), safety and tolerability, complication rates and subsequent fertility outcomes were also recorded. All eight women were successfully treated with combination gefitinib and methotrexate. The most common side effects were transient acne/rash and diarrhoea, known side effects of gefitinib. All women promptly resumed menstruation and importantly, three women subsequently conceived spontaneously. Two have delivered a healthy infant at term and the third is currently in her second trimester of pregnancy. Hence, our case series supports a future clinical trial to determine the efficacy of combination gefitinib and methotrexate to treat non-tubal ectopic pregnancies.

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, we obtained preliminary data suggesting this combination may have a time to resolution which is 34% faster compared with treatment using methotrexate alone (Nilsson et al , 2013; Skubisz et al , 2013). This suggested adding gefitinib to methotrexate may improve on its efficacy in medically resolving ectopic pregnancies.…”

Section: Introductionmentioning

confidence: 91%

Combination gefitinib and methotrexate treatment for non-tubal ectopic pregnancies: a case series

et al. 2014

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“…However, we believe our preliminary observations on potential efficacy are considerably strengthened when considered together with our preclinical data. 14 We have generated laboratory data, both in vitro and in animal models, suggesting adding gefitinib to methotrexate enhances its ability to induce placental cell death. Therefore, the possibility that gefitinib may enhance the ability of methotrexate to resolve ectopic pregnancy is biologically plausible.…”

Section: Discussionmentioning

confidence: 99%

“…It has good oral bioavailability and often causes transient diarrhea and skin rash. 12,13 In preclinical studies, 14 we have found gefitinib supra-additively augments methotrexate-induced regression of placental tissue. Given the encouraging results obtained from the preclinical studies, 14 we translated our finding to humans, conducting a phase I trial to assess the safety, tolerability, and efficacy of combination gefitinib (once-daily 250 mg oral gefitinib taken up to 7 days) and intramuscular methotrexate to treat ectopic pregnancy.…”

Section: Level Of Evidence: IImentioning

confidence: 94%

Combination Gefitinib and Methotrexate Compared With Methotrexate Alone to Treat Ectopic Pregnancy

Skubisz

Horne

Johns

et al. 2013

Obstetrics &Amp; Gynecology

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“…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 8. To translate this into clinical care, we performed a phase I single-arm open-label dose-escalation study administering a combination of 250 mg oral gefitinib (one dose (n=3), three daily doses (n=3), seven daily doses (n=6)) and intramuscular MTX (50 mg/m 2 ) to 12 women with tEPs 9.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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IntroductionTubal 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 analysisWe 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 disseminationEthical 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 numberACTRN12611001056987.

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Effects of Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, on Human Placental Cell Growth

Abstract: Combining gefitinib with methotrexate potently inhibits placental cell growth in vitro and in mouse models. The combination may have potential in treating ectopic pregnancies.

Cited by 25 publications

References 17 publications

Combination gefitinib and methotrexate treatment for non-tubal ectopic pregnancies: a case series

Combination gefitinib and methotrexate treatment for non-tubal ectopic pregnancies: a case series

Combination Gefitinib and Methotrexate Compared With Methotrexate Alone to Treat Ectopic Pregnancy

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

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