Combination gefitinib and methotrexate to treat ectopic pregnancy: early phase clinical trials

2017-02-23T01:52:58Z (GMT) by Skubisz, Monika Michalina
This body of work examines novel diagnostics and therapeutics for ectopic pregnancy. The incidence of ectopic pregnancy is 1-2% of pregnancies, where implantation occurs outside of the endometrial cavity. It remains a leading cause of maternal death in early pregnancy. The management of ectopic pregnancy is predominantly surgical; this is mandated when rupture has occurred, however, only 5% of women present this way. The medical treatment option, consisting of single-dose methotrexate, has limited efficacy in treating more advanced ectopic pregnancies, so that only 25-30% of diagnosed women benefit from it. The introduction of epidermal growth factor receptor inhibitors such as gefitinib into the pharmaceutical lexicon has created a potentially novel approach to the treatment of trophoblastic tissue disorders. Pre-clinical experiments have shown that combining gefitinib with methotrexate effects significant, supra-additive regression of trophoblastic cells and tissues. The main aim of this PhD is to translate these findings into clinical practice, thereby improving the medical management of ectopic pregnancy. In a phase I dose-escalation toxicity study, we established the safety of combination gefitinib and methotrexate in 12 women with ectopic pregnancies currently eligible for medical management; combination treatment effected a more rapid decline in serum human chorionic gonadotrophin (hCG) levels and shortened the time to resolution compared to controls. We then applied combination treatment to larger and more complex non-tubal ectopic pregnancies; in a case series of 8 women, all were successfully treated with no undue toxicity caused. Subsequently, in a phase II study of 28 women, we confirmed combination gefitinib and methotrexate to be safe, well tolerated and effective at treating an extended range of ectopic pregnancies. To further improve diagnosis and management of ectopic pregnancy, we identified and investigated two novel biomarkers – adrenomedullin and macrophage inhibitory cytokine-1 (MIC-1). We could not confirm altered adrenomedullin expression in ectopic pregnancy, and correspondingly, it was not a useful biomarker of the condition. MIC-1 was able to exclude ectopic pregnancy above a certain threshold, demonstrating potential to form part of a panel of biomarkers for the diagnosis of the condition. We also validated that an early falling serum hCG is predictive of medical treatment success after single-dose methotrexate for ectopic pregnancy: in two studies examining 251 women, a fall in hCG between days 1-4 of treatment was 85-88% predictive of treatment success. Finally, we examined the potential of combination gefitinib and methotrexate to improve treatment of persistent gestational trophoblastic disease (pGTD), a rare form of pregnancy with malignant progression; in a separate phase I dose-escalation toxicity study, we found the combination to again be safe and well tolerated in 6 women, despite higher doses of methotrexate administered. Collectively, this work has contributed new approaches to the diagnosis and treatment of ectopic pregnancy and pGTD. It provides proof-in-principle evidence that combination gefitinib and methotrexate may be more effective in the treatment of ectopic pregnancy, underpinning future funding and investigation. It is my hope that this work will minimise the suffering of women diagnosed with these conditions.