Combination gefitinib and methotrexate to medically treat ectopic pregnancy: a phase I clinical trial. (#76)
Between 1-2% of all pregnancies are ectopic. Methotrexate is used to treat ectopic pregnancies where serum ßhCG<3000IU/L; the majority (~75%) require surgical excision.1 The Epidermal Growth Factor Receptor [EGFR] is highly expressed in placenta.2 Pre-clinical studies by our group showed combination gefitinib (EGFR Inhibitor) and methotrexate treatment is supra-additive in regressing placental tissue in vitro and in vivo. We sought to translate these findings into the clinic by treating humans with ectopic pregnancies with combination gefitinib and methotrexate.
We undertook a phase I study, recruiting twelve women with stable ectopic pregnancies eligible for current methotrexate-only treatment. We co-administered methotrexte 50mg/m2 intramuscularly on day 1 and 250mg of oral daily gefitinib in a dose-escalation protocol: day 1 (n=3); days 1-3 (n=3) and days 1-7 (n=6). Participants were reviewed clinically, weekly until resolution (ßhCG<5IU/L). Toxicity was monitored by history, examination and biochemical tests. Combination treatment was well tolerated: a transient acneiform rash occurred in 8/12 and mild diarrhoea was experienced by 6/12 participants. These were mild and resolved spontaneously after completion of treatment. All women promptly resumed menstruation.
We also performed a sub-cohort analysis where serum ßhCGs were between 1000-3000IU/L, comparing rate of serum ßhCG decline and time to resolution with a contemporaneous cohort treated with single-agent methotrexate, to assess the efficacy of combination treatment. ßhCG levels were significantly lower in participants compared to controls at days 4 and 7 (p<0.05); time to resolution was 11 days shorter (median 21 [25-75%:17-27.25] versus 32 days [25-48.5]. One participant, successfully treated for an ectopic pregnancy in her only fallopian tube, subsequently conceived naturally and delivered a healthy infant at term.
In summary, combination gefitinib and methotrexate is safe and well tolerated and appears to be a more efficacious treatment for ectopic pregnancy compared to methotrexate alone.
- Jurkovic D, Wilkinson H. Diagnosis and management of ectopic pregnancy. BMJ. 2011;342:d3397. Epub 2011/06/15.
- EGFR (epidermal growth factor receptor) [database on the Internet]. The Scripps Research Institute. 2011 [cited 22/12/2011]. Available from: http://biogps.org/ - goto=genereport&id=1956.