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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]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Clinically stable ectopic pregnancies

Condition category

Condition code

Reproductive Health and Childbirth

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]

Treatment: Drugs

Comparator / control treatment

None

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Cure of ectopic pregnancy, evidenced by serum quantitative human chorionic gonadotrophin (hCG) levels of zero.

Timepoint [1]

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]

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]

This will continue until there is final evidence of cure (hCG reaches zero).

Secondary outcome [1]

None

Timepoint [1]

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Monash Medical Centre - Clayton campus - Clayton

Recruitment outside Australia

Country [1]

United Kingdom

State/province [1]

Edinburgh

Funding & Sponsors

Funding source category [1]

Other Collaborative groups

Name [1]

Monash Institute of Medical Research

Address [1]

27-31 Wright St. Clayton 3168
Victoria

Country [1]

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]

Hospital

Name [1]

Southern Health

Address [1]

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]

Australia

Other collaborator category [1]

Individual

Name [1]

Dr Monika Skubisz

Address [1]

Department of Obstetrics and Gynaecology, Level 5, Monash Medical Centre, 246 Clayton Rd., Clayton 3168, Victoria

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Southern Health Human Research Ethics Committee B

Ethics committee address [1]

Research Directorate
Level 4, Main Block 
Monash Medical Centre
246 Clayton Rd,  
Clayton, 3168, 
Victoria

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

24/06/2010

Ethics approval number [1]

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

A/Prof Stephen Tong

Address

Translational Obstetrics Group
Department of Obstetrics & Gynaecology
University of Melbourne
Mercy Hospital for Women
163 Studley Road
Heidelberg, Victoria 3084

Country

Australia

Phone

+61 3 8458 4377

Fax

[email protected]

Contact person for public queries

Name

Monika Skubisz

Address

Department of Obstetrics and Gynaecology, Level 5, Monash Medical Centre, 246 Clayton Rd., Clayton 3168, Victoria

Country

Australia

Phone

+61395946666

Fax

[email protected]

Contact person for scientific queries

Name

Monika Skubisz

Address

Department of Obstetrics and Gynaecology, Level 5, Monash Medical Centre, 246 Clayton Rd., Clayton 3168, Victoria

Country

Australia

Phone

+61395946666

Fax

[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

Source	Title	Year of Publication	DOI
Embase	Oral vinorelbine to treat women with ectopic pregnancy: a phase 1 clinical safety and tolerability study.	2023	https://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.

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