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Trial registered on ANZCTR


Registration number
ACTRN12610000684022
Ethics application status
Approved
Date submitted
22/07/2010
Date registered
19/08/2010
Date last updated
25/02/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
Combination Gefitinib and Methotrexate to Medically Treat Ectopic Pregnancies: A Phase I Clinical Toxicity Trial.
Scientific title
Combination Gefitinib and Methotrexate to Medically Treat Ectopic Pregnancies: A Phase I Clinical Toxicity Trial.
Secondary ID [1] 252274 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Clinically stable ectopic pregnancies 257797 0
Condition category
Condition code
Reproductive Health and Childbirth 257969 257969 0 0
Other reproductive health and childbirth disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 256859 0
Treatment: Drugs
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 258834 0
Cure of ectopic pregnancy, evidenced by serum quantitative human chorionic gonadotrophin (hCG) levels of zero.
Timepoint [1] 258834 0
Serum hCG is a biomarker of ectopic pregnancy viability. Levels of serum hCG will be measured at days 4, day 7 and then measured weekly through to zero.
Primary outcome [2] 258835 0
Documentation of tolerability (ie side effects) and toxiciy.

This will be assessed by:
History taking by a medical practitioner (at least daily for the first three days, then at weekly clinic visits)
Examination of participants undertaken by a medical practitioner (at least daily for the first three days then weekly clinic visits).

Investigations:
Day 4 and 7 blood tests: liver function test, renal function test (U/E/C), full blood test (FBE).
Timepoint [2] 258835 0
This will continue until there is final evidence of cure (hCG reaches zero).
Secondary outcome [1] 264947 0
None
Timepoint [1] 264947 0
None

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
45 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participant will be recruited through Monash Medical Centre's Emergency Department and Gynaecology outpatient clinics. Participant's duration of once daily 250mg gefitinib treatment will be decided by their order of recruitment, i.e. the first 3 women will receive a once-off 250mg dose on day 1 in combination with methotrexate, the next 3 will receive 250mg orally for three days and the last 6 participants recruited will receive 250mg gefitinib orally for seven days.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
4/11/2010
Actual
4/11/2010
Date of last participant enrolment
Anticipated
Actual
26/09/2011
Date of last data collection
Anticipated
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 2141 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment outside Australia
Country [1] 2775 0
United Kingdom
State/province [1] 2775 0
Edinburgh

Funding & Sponsors
Funding source category [1] 257323 0
Other Collaborative groups
Name [1] 257323 0
Monash Institute of Medical Research
Country [1] 257323 0
Australia
Primary sponsor type
Individual
Name
Dr Stephen Tong
Address
Department of Obstetrics and Gynaecology, Level 5, Monash Medical Centre, 246 Clayton Rd., Clayton 3168, Victoria
Country
Australia
Secondary sponsor category [1] 256564 0
Hospital
Name [1] 256564 0
Southern Health
Address [1] 256564 0
Professor Euan Wallace, Director of Maternity Services, Department of Obstetrics and Gynaecology, Level 5, Monash Medical Centre, 246 Clayton Rd., Clayton 3168, Victoria
Country [1] 256564 0
Australia
Other collaborator category [1] 251440 0
Individual
Name [1] 251440 0
Dr Monika Skubisz
Address [1] 251440 0
Department of Obstetrics and Gynaecology, Level 5, Monash Medical Centre, 246 Clayton Rd., Clayton 3168, Victoria
Country [1] 251440 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259348 0
Southern Health Human Research Ethics Committee B
Ethics committee address [1] 259348 0
Research Directorate
Level 4, Main Block
Monash Medical Centre
246 Clayton Rd,
Clayton, 3168,
Victoria
Ethics committee country [1] 259348 0
Australia
Date submitted for ethics approval [1] 259348 0
Approval date [1] 259348 0
24/06/2010
Ethics approval number [1] 259348 0
10142B

Summary
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.
Trial website
Trial related presentations / publications
Combination gefitinib and methotrexate compared with methotrexate alone to treat ectopic pregnancy. Skubisz MM, Horne AW, Johns TG, Nilsson UW, Duncan WC, Wallace EM, Critchley HO, Tong S. Obstet Gynecol. 2013 Oct;122(4):745-51. doi: 10.1097/AOG.0b013e3182a14cfb.
Public notes

Contacts
Principal investigator
Name 31423 0
A/Prof Stephen Tong
Address 31423 0
Translational Obstetrics Group
Department of Obstetrics & Gynaecology
University of Melbourne
Mercy Hospital for Women
163 Studley Road
Heidelberg, Victoria 3084
Country 31423 0
Australia
Phone 31423 0
+61 3 8458 4377
Fax 31423 0
Email 31423 0
[email protected]
Contact person for public queries
Name 14670 0
Monika Skubisz
Address 14670 0
Department of Obstetrics and Gynaecology, Level 5, Monash Medical Centre, 246 Clayton Rd., Clayton 3168, Victoria
Country 14670 0
Australia
Phone 14670 0
+61395946666
Fax 14670 0
Email 14670 0
[email protected]
Contact person for scientific queries
Name 5598 0
Monika Skubisz
Address 5598 0
Department of Obstetrics and Gynaecology, Level 5, Monash Medical Centre, 246 Clayton Rd., Clayton 3168, Victoria
Country 5598 0
Australia
Phone 5598 0
+61395946666
Fax 5598 0
Email 5598 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseOral vinorelbine to treat women with ectopic pregnancy: a phase 1 clinical safety and tolerability study.2023https://dx.doi.org/10.1016/j.fertnstert.2023.05.161
N.B. These documents automatically identified may not have been verified by the study sponsor.