None listed
Conditions
Brief summary
BACKGROUND: Ectopic pregnancies are conceptuses that implant outside the womb, mainly the fallopian tube. They are life threatening since they can erode through major blood vessels causing fatal bleeding. While very small ectopic pregnancies can be treated medically (single injection of a chemotherapeutic agent ‘methotrexate’). The mainstay of treatment is surgery. We have undertaken 20 months of laboratory work to show placental tissue can be efficiently killed with the combination of two drugs: methotrexate and ‘gefitinib’. Gefitinib is an epidermal growth factor receptor (EGFR) inhibitor, never previously proposed to be used to treat ectopics. The EGFR pathway is used by the placenta an important survival signal. Thus using gefitinib to block EGFR activation can affect the viability of the ectopic pregnancy. Importantly, we have shown in preclinical studies that combining both drugs is supra-additive (i.e. the killing effects of adding both is stronger than the sum of each individual treatment). Importantly, the safety profile of each drug is known. Methotrexate is already used for small ectopic pregnancies where its toxicity profile is known. We plan using this exact same protocol that is used clinically (co-administered with gefitinib). Gefitinib is already used clinically in cancer treatment. After a primary lung cancer is treated, gefitinib tablets are taken once daily for life. It is thus not a traditional chemotherapeutic agent. It is well tolerated, but can cause a skin rash. Thus, we believe that combination treatment with methotrexate and gefitinib could be used to treat ectopic pregnancies. We now propose moving this idea into the clinic, starting phase I clinical trial toxicity studies. METHODS: The aim of this trial will be to determine whether a single injection of methotrexate and seven tablets of gefitinib is safe, and well tolerated. We propose recruiting 12 women presenting with a small stable ectopic pregnancy at Monash Medical Centre, Clayton. Treatment: Each participant will receive a single intramuscular injection of methotrexate (50mg/m2) on day 1, as per standard medical management of ectopic pregnancy. In addition, participants will receive one 250mg tablet of gefitinib daily for increasing amounts of time in subsequent cohorts: the first three women recruited (cohort one), will receive a single dose of 250mg gefitinib on day 1, the next three participants (cohort two), will receive three daily doses of 250mg gefitinib from day 1 to day 3. After review by the Human Research Ethics Committee (HREC) of an interim report on the first six participants and permission to proceed, the final six women recruited (cohort three), will receive seven daily doses of 250mg gefitinib orally from day 1 to day 7. Monitoring of toxicity: We will admit participants for up to seven days where they will be reviewed medically on a daily basis. Medical history and examination will be taken to monitor potential side effects (e.g. rash, diarrhoea, and respiratory symptoms). We will also look for any potential signs that the ectopic pregnancy has ruptured. If there are any such suspicions, we will offer prompt surgery. We will stop the medication if any significant side effects are noted. We will do regular blood tests to monitor potential toxicity to the renal, liver and haematological (blood) systems. Monitoring of treatment success: We will monitor human chorionic gonadotrophin (hCG) levels in the blood. This is a sensitive marker of placental cell mass. Thus, blood levels can tell clinicians whether the ectopic is disappearing (declining hCG levels). An hCG of zero would mean the women has been cured of their ectopic. Thus we will measure hCG regularly until it reaches zero. Expected outcome: Combination methotrexate and gefitinib is safe and well tolerated. We will generate critical toxicity data to justify a phase II trial to determine whether this proposed treatment can cure most ectopic pregnancies.
Interventions
Day 1:One dose of methotrexate 50mg/m2 intramuscularly PLUS n=3 250 mg oral gefitinib taken on day 1 n=3 250 mg oral gefitinib taken on days 1-3 n=6 250 mg oral gefitinib taken on days 1-7 i.e. escalation of dosage schedule of gefitinib on the background of the same dose of methotrexate. All cohorts will consist of women diagnosed with unruptured ectopic pregnancies, which meet criteria for current medical management i.e. have a quantitative serum human chorionic gonadotrophin hormone of equal o
Day 1:One dose of methotrexate 50mg/m2 intramuscularly PLUS n=3 250 mg oral gefitinib taken on day 1 n=3 250 mg oral gefitinib taken on days 1-3 n=6 250 mg oral gefitinib taken on days 1-7 i.e. escalation of dosage schedule of gefitinib on the background of the same dose of methotrexate. All cohorts will consist of women diagnosed with unruptured ectopic pregnancies, which meet criteria for current medical management i.e. have a quantitative serum human chorionic gonadotrophin hormone of equal or less than 3000, ultrasound findings of a gestational sac size of up to 4cm and no suspicion of rupture. There will be no control for this phase 1 toxicity trial.
Sponsors
Dr Stephen Tong
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
Women diagnosed with stable ectopic pregnancy, with an hCG of less than 3000 IU/L and an ultrasound showing a gestational sac of under 3 cms.
Exclusion criteria
Haemodynamic instability, women of Japanese ethnicity, chronic lung problems/lung cancer history, severe dermatological and gastrointestinal disease history, liver or renal dysfunction, allergy to gefitinib/methotrexate.
Outcome results
None listed