Clinical trial NCT01686126: Improving the Treatment for Women With Early Stage Cancer of the Uterus
Official title: A Phase II Randomised Clinical Trial of Mirena® ± Metformin ± Weight Loss Intervention in Patients With Early Stage Cancer of the Endometrium
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Complex Endometrial Hyperplasia With Atypia
Grade 1 Endometrial Endometrioid Adenocarcinoma
Keywords: endometrial hyperplasia
endometrial adenocarcinoma
Gynecological Cancer
Lead sponsor: Queensland Centre for Gynaecological Cancer
Sponsor class: OTHER_GOV
Collaborators: name: The University of Queensland
name: Queensland University of Technology
First posted: 2012-09-17
Enrollment: 165
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Currently the standard treatment for early stage endometrial cancer or endometrial hyperplasia with atypia is a total hysterectomy (an operation to remove the uterus) and removal of both ovaries. While highly effective, this surgery carries significant side effects for:

* young women who still wish to have children and would lose fertility; and
* women with one or more disorders (or diseases) in addition to the early stage endometrial cancer or endometrial hyperplasia with atypia and/or morbid obesity who are at risk for surgical complications making surgery unsafe.

This study will access a new approach to the treatment of endometrial cancer to spare women of having to undergo major surgery that may be unwanted or unnecessary.

Mirena is approved in Australia for contraception, to treat heavy bleeding, and to prevent thickening of the lining of the uterus (endometrial hyperplasia) during oestrogen replacement therapy (HRT). However it is not approved to treat early stage endometrial cancer or endometrial hyperplasia with atypia. This research project will test to see if Mirena is an effective treatment for early stage endometrial cancer and endometrial hyperplasia with atypia.

Metformin is approved in Australia to treat Diabetes. However it is not approved to treat early stage endometrial cancer or endometrial hyperplasia with atypia. Therefore, it is an experimental treatment for early stage endometrial cancer and endometrial hyperplasia with atypia. This means that it must be tested to see if it is an effective treatment for early stage endometrial cancer and endometrial hyperplasia with atypia.

Weight loss interventions are feasible and safe, and already being implemented by gynaecologic oncologist to make women eligible for surgery. Weight loss of 7% body weight induces a large biological effect (for example reduces incidence of diabetes by 58%, and hypertension by 26%).


Eligibility criteria: Inclusion Criteria:

1. Females with a BMI \> 30 kg/m2 wishing to retain fertility or females who are at high risk of surgical complications due to co-morbidities or obesity
2. Over 18 years of age at time of randomisation
3. Histologically confirmed complex endometrial hyperplasia with atypia or grade 1 endometrioid endometrial adenocarcinoma on a curette or endometrial biopsy
4. CT or MRI scan of pelvis, abdomen and chest (or chest X-Ray) suggesting the absence of extrauterine disease
5. Myometrial invasion on MRI of not more than 50%, for women with histologically confirmed Endometrial Cancer only (for women who are unable to fit into an MRI machine inclusion into trial is at investigators discretion)
6. No lymph vascular invasion on curetting or pipelle, if able to be assessed on sample
7. Serum CA125 ≤ 30 U/mL
8. No hypersensitivity or contraindications for Mirena
9. Ability to comply with endometrial biopsies at specified intervals
10. Negative serum or urine pregnancy test in pre-menopausal women and women \< 2 years after the onset of menopause
11. Creatinine \< 150µmol/L (1.7 mg/dL) to be randomised into Mirena + Metformin arm (can still be eligible to be randomised to Mirena only or Mirena + Weight Loss, see section 5.4 Other Eligibility Criteria Considerations)

Exclusion Criteria:

1. ECOG performance status \> 3
2. Grade 1 endometrioid adenocarcinoma of the endometrium with myometrial invasion deeper than 50% on MRI or any patients with grade 2 or grade 3 endometrioid adenocarcinoma
3. Histological (cell) type other than endometrioid adenocarcinoma (sarcomas or high risk endometrial e.g. papillary serous, clear cell)
4. Pregnant or planning to become pregnant during trial period
5. Has had prior treatment or undergoing current treatment for EAC or EHA
6. Patients with a history of pelvic or abdominal radiotherapy
7. Unwilling to have additional endometrial biopsies or curettes and unable to attend three monthly clinical assessments
8. Unable to provide informed consent
9. Unable or unwilling to complete questionnaires
10. Evidence of extrauterine spread on medical imaging
11. Congenital or acquired uterine anomaly which distorts the uterine cavity
12. Acute pelvic inflammatory disease
13. Conditions associated with increased susceptibility to infections with microorganisms (e.g., AIDS, leukaemia, IV drug abuse) according to the patients Medical History
14. Genital actinomycosis
15. Current other cancer, except low grade malignancies that do not require any systemic treatment or treatment to the pelvis
16. Breastfeeding mothers
17. Mirena inserted greater than 12 weeks before randomisation/enrolment
18. Previous use of Mirena within the last 5 years from randomisation/enrolment
19. Contraindications to both Metformin and weight loss

Primary outcomes:
measure: Pathological complete response
timeFrame: 6 months
Secondary outcomes:
measure: Predict the response to treatment
timeFrame: 6 months
Other outcomes:
Locations:
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Auchenflower
country: Australia
facility: The Wesley Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Greenslopes
country: Australia
facility: Greenslopes Private Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Mater Health Services, Brisbane
state: Queensland
city: South Brisbane
country: Australia
facility: Mater Private Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast Hospital
state: Queensland
city: Townsville
country: Australia
facility: Townsville Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Carlton
country: Australia
facility: Royal Women's Hospital
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Perth
country: Australia
facility: King Edward Memorial Hospital for Women
state: Western Australia
city: Subiaco
country: Australia
facility: St John of God Hospital
state: Western Australia
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Women's Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
Study officials:
affiliation: Queensland Centre for Gynaecological Cancer
name: Andreas Obermair
role: STUDY_CHAIR
References:
citation: Janda M, Robledo KP, Gebski V, Armes JE, Alizart M, Cummings M, Chen C, Leung Y, Sykes P, McNally O, Oehler MK, Walker G, Garrett A, Tang A, Land R, Nicklin JL, Chetty N, Perrin LC, Hoet G, Sowden K, Eva L, Tristram A, Obermair A. Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial. Gynecol Oncol. 2021 Apr;161(1):143-151. doi: 10.1016/j.ygyno.2021.01.029.