GnRHa + Letrozole vs Diane-35 + Metformin in Progestin-insensitive Endometrial Cancer and Atypical Hyperplasia Patients

Sponsor

Xiaojun Chen (Other)

Overall Status

Recruiting

CT.gov ID

NCT05316935

Collaborator

(none)

Enrollment

Location

Arms

32.6

Anticipated Duration (Months)

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To investigate the efficacy of GnRHa plus letrozole vs Diane-35 plus metformin in progestin-insensitive early-stage endometrial cancer (EEC) and atypical hyperplasia(EAH) patients asking for conservative treatment.

Condition or Disease	Intervention/Treatment	Phase
Endometrial Neoplasms Atypical Endometrial Hyperplasia Progesterone Resistance	Drug: GnRHa Drug: Letrozole 2.5mg Drug: Diane-35 Drug: MET	Phase 2/Phase 3

Detailed Description

There were more and more women with early endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (EAH) who want to preserve fertility. Approximately 70% to 80% of females who meet the criteria for conservation treatment are able to achieve CR after progestin therapy, with a median time of 6-7 months, but about 20% to 30% of patients get no response or need to take longer time to achieve remission (over one year). With long duration of treatment, there will be more side effects such as weight gain, impaired liver function, endometrial injury, ovarian reserve inhibition etc. which will decrease the efficacy of conservative treatment. Previous researches had shown that GnRHa plus letrozole or ethinylestradiol cyproterone plus metformin could be a better second-line treatment for progestin-insensitive patients. Till now, no similar studies were found, so we design this study to explore the efficacy of GnRHa plus letrozole and ethinylestradiol cyproterone plus metformin in progestin-insensitive EEC and EAH patients to provide new evidences for improving conservative treatment efficacy.

This will be a single-centred prospective pilot study. Patients diagnosed as progestin-insensitive EAH or EEC by dilatation and curettage (D&C) or hysteroscopy will be enrolled. Patients will be stratified by pathological diagnosis (EEC or EAH) and then they will be randomly assigned (1:1) to two arms. One will be GnRHa + letrozole group and another will be ethinylestradiol cyproterone + metformin group.

The primary endpoint is cumulative complete response (CR) rate at 28 weeks of treatment. The secondary endpoints include adverse events, duration of complete response, recurrent rate, pregnancy rate and quality of life of patients.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Gonadotropin-releasing Hormone Agonist (GnRHa) Plus Letrozole vs Ethinylestradiol Cyproterone Plus Metformin in Progestin-insensitive Early-stage Endometrial Cancer and Atypical Hyperplasia Patients With Conservative Treatment

Actual Study Start Date :

Jul 13, 2022

Anticipated Primary Completion Date :

Mar 30, 2025

Anticipated Study Completion Date :

Mar 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GnRHa + letrozole group Patients will be stratified into EEC group and EAH group. Then every 12 weeks, an hysteroscope will be used to evaluate the endometrial condition, and the pathological findings will be recorded.	Drug: GnRHa Gonadotropin-releasing hormone analogue, intramuscular injection of 3.75mg will be given every 4 weeks , and the maximum using courses will be 6. Other Names: Triprorelin acetate Drug: Letrozole 2.5mg 2.5mg po qd and no more than 24 weeks
Experimental: Diane-35 + metformin group Patients will be stratified into EEC group and EAH group. Then every 12 weeks, an hysteroscope will be used to evaluate the endometrial condition, and the pathological findings will be recorded.	Drug: Diane-35 Periodic use. Patients will receive one pill po qd for 21 days, and next period should be started after 7 days. Other Names: ethinylestradiol cyproterone Drug: MET 500mg po tid

Arm

Intervention/Treatment

Experimental: GnRHa + letrozole group

Patients will be stratified into EEC group and EAH group. Then every 12 weeks, an hysteroscope will be used to evaluate the endometrial condition, and the pathological findings will be recorded.

Drug: GnRHa

Gonadotropin-releasing hormone analogue, intramuscular injection of 3.75mg will be given every 4 weeks , and the maximum using courses will be 6.

Other Names:

Triprorelin acetate

Drug: Letrozole 2.5mg

2.5mg po qd and no more than 24 weeks

Experimental: Diane-35 + metformin group

Patients will be stratified into EEC group and EAH group. Then every 12 weeks, an hysteroscope will be used to evaluate the endometrial condition, and the pathological findings will be recorded.

Drug: Diane-35

Periodic use. Patients will receive one pill po qd for 21 days, and next period should be started after 7 days.

Other Names:

ethinylestradiol cyproterone

Drug: MET

500mg po tid

Outcome Measures

Primary Outcome Measures

Complete response rates within 28 weeks of treatment [From date of randomization until the date of CR, assessed up to 28 weeks]
The cumulative 28-week CR rates will be calculated in two groups. Patients will be evaluated with an hysteroscopy every 12 weeks. For some may delay the evaluation as personal reasons, we define the primary outcome measure as complete response rates within 28 weeks of treatment.

Secondary Outcome Measures

Adverse events [From date of randomization until the date of CR or date of hysterectomy, assessed up to 28 weeks]
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 will be recorded, as well as incidence of adverse events.
Time to achieve complete response [From date of randomization until the date of CR or date of hysterectomy, assessed up to 28 weeks.]
The median CR time will be calculated in two groups
Relapse rates [Up to 2 years after the treatment]
Rates of fertility outcomes [Up to 2 years after the treatment]
Including pregnancy and live-birth rates
Compliance [Data on treatment and hysteroscopy management will be collected, and deviations from study protocol will be recorded in writing. For example, the time of drug interruptions due to related toxicities or AEs, and delay of hysteroscopy for personal reasons.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Have a confirmed initial pathological diagnosis based upon hysteroscopy: histologically prove EAH or well-differentiated EEC G1 without myometrial invasion
No signs of suspicious extrauterine involvement on enhanced magnetic resonance imaging (MRI) or enhanced computed tomography (CT) or ultrasound
Using progestin, any of the following therapy, as first-line treatment:

Megestrol acetate ≥ 160 mg qd using, combined with Levonorgestrel Lntrauterine System (LNG-IUS) inserted or not
Medroxyprogesterone acetate ≥ 250 mg qd using, combined with LNG-IUS inserted or not
LNG-IUS inserted

Progestin-insensitive:

remained with stable disease after 7 months of progestin use
did not achieve CR after 10 months of progestin use

Have a desire for remaining reproductive function or uterus
Good compliance with adjunctive treatment and follow-up

Exclusion Criteria:

Combined with severe medical disease or severely impaired liver and kidney function
Pathologically confirmed as endometrial cancer with suspicious myometrial invasion or extrauterine metastasis
Patients with other types of endometrial cancer or other malignant tumors of the reproductive system
Patients with breast cancer or other hormone- dependent tumors or diseases that cannot be used with Diane-35, GnRHa, Letrozole or MET
Strong request for uterine removal or other conservative treatment
Known or suspected pregnancy
Acute severe disease such as stroke or heart infarction or a history of thrombosis disease
Smoker(>15 cigarettes a day)