OBJECTIVE: To determine the safety, tolerability, and efficacy of combination gefitinib and methotrexate to treat ectopic pregnancy.
METHODS: We performed a phase I, single-arm (nonrandomized), open-label study. Twelve women with ectopic pregnancies were administered methotrexate (50 mg/m2, intramuscular) and 250 mg oral gefitinib in a dose-escalation protocol: one dose (day 1) n=3; three doses (days 1–3) n=3; seven doses (days 1–7) n=6. Efficacy was examined by comparing human chorionic gonadotrophin (hCG) decline and time to resolution with historic controls administered methotrexate only.
RESULTS: Common side effects were transient acneiform rash in 67% (8/12) and diarrhea in 42% (5/12) of participants. There was no clinical or biochemical evidence of serious pulmonary, renal, hepatic, or hematologic toxicity. Of six participants with a pretreatment serum hCG level between 1,000 and 3,000 international units/L, hCG levels declined significantly faster than in the control group. Median serum hCG levels by day 7 after treatment were less than one fifth of levels observed among 71 historic controls treated with methotrexate alone (median [interquartile range] hCG in participants 261 [55–1,445] international units/L compared with controls 1,426 [940–2,573]; P=.008). Median time for the ectopic pregnancies to resolve with combination therapy was 34% shorter compared with methotrexate alone (21 days compared with 32 days; P=.018).
CONCLUSION: Combination gefitinib and methotrexate has potential as a treatment for ectopic pregnancy but is commonly associated with minor side effects such as transient rash and diarrhea. The treatment requires validation of safety and efficacy in a larger trial.
CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, www.anzctr.org, AC'TRN12610000684022.
LEVEL OF EVIDENCE: II
The combination of gefitinib and methotrexate has potential as a treatment for ectopic pregnancy, although minor side effects are common.
Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, and the Ritchie Centre and the Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia; and the MRC Centre for Reproductive Health, the Queen's Medical Research Institute, Edinburgh, United Kingdom.
Corresponding author: Stephen Tong, PhD, Translational Obstetrics Group, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia; e-mail: firstname.lastname@example.org.
Supported by National Health and Medical Research Council of Australia (NHMRC) Project Grants #606611 (S.T. and T.G.J.) and #1008276 (S.T., E.M.W., and T.G.J.); NHMRC Career Development Fellowship #1050765 (S.T.); The Monash Institute of Medical Research Flagship Grant (S.T., T.G.J., E.M.W.); Medical Research Council Clinician Science Fellowship (A.W.H.); Medical Research Council Centenary Award #G0802808 (A.W.H.); The Helen MacPherson Trust (S.T.); and The Victorian Government's Operational Infrastructure Support Program (M.S., T.G.J., and E.M.W.).
Financial Disclosure Drs. Johns, Nilsson, and Tong are joint holders of patents that relate to the use of Epidermal Growth Factor Receptor inhibition in treating ectopic pregnancies. The other authors did not report any potential conflicts of interest.
The authors thank Ms. Ann Doust for recruiting participants in Edinburgh and Professors Susan Walker and Peter Rogers for input into trial management.
Presented at The Society for Gynecological Investigation annual meeting, March 22–24, 2012, San Diego, California.