GnRHa + Letrozole in Progestin-insensitive Endometrial Cancer and Atypical Hyperplasia Patients

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

Detailed Description
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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. Considered there will be more thrombotic risks in obese patients using ethinylestradiol cyproterone, we use GnRHa plus letrozole in patients with BMI ≥ 30kg/m2 only. 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. Non-obese 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. And for obese patients,there will be only GnRHa + letrozole 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.

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

Conditions
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Endometrial Neoplasms, Atypical Endometrial Hyperplasia, Progesterone Resistance

Intervention / Treatment
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* Drug: GnRHa
* Drug: Letrozole 2.5mg
* Drug: Diane-35
* Drug: MET


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Non-obese group<br>Patients will be stratified into EEC group with 40 cases and EAH group with 40 cases. Each group will be randomized to GnRHa + Letrozole group and Diane-35 + metformin group.Then every 12 weeks, an hysteroscope will be used to evaluate the endometrial condition, and the pathological findings will be recorded. | Drug: GnRHa<br>* Gonadotropin-releasing hormone analogue, intramuscular injection of 3.75mg will be given every 4 weeks , and the maximum using courses will be 6.<br>* Other names: Triprorelin acetate;Drug: Letrozole 2.5mg<br>* 2.5mg po qd and no more than 24 weeks<br>Drug: Diane-35<br>* Periodic use. Patients will receive one pill po qd for 21 days, and next period should be started after 7 days.<br>* Other names: ethinylestradiol cyproterone;Drug: MET<br>* 500mg po tid<br>|
| Experimental: Obese group<br>Patients will be stratified into EEC group with 19 cases and EAH group with 19 cases. Interventional Study Model was Simon two-stage optimal design. Then every 12 weeks, an hysteroscope will be used to evaluate the endometrial condition, and the pathological findings will be recorded. | Drug: GnRHa<br>* Gonadotropin-releasing hormone analogue, intramuscular injection of 3.75mg will be given every 4 weeks , and the maximum using courses will be 6.<br>* Other names: Triprorelin acetate;Drug: Letrozole 2.5mg<br>* 2.5mg po qd and no more than 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rates within 28 weeks of treatment | 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. | From date of randomization until the date of CR, assessed up to 28 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 will be recorded, as well as incidence of adverse events. | From date of randomization until the date of CR or date of hysterectomy, assessed up to 28 weeks | 
| Time to achieve complete response | The median CR time will be calculated in two groups | From date of randomization until the date of CR or date of hysterectomy, assessed up to 28 weeks. | 
| Relapse rates |  | Up to 2 years after the treatment | 
| Rates of fertility outcomes | Including pregnancy and live-birth rates | Up to 2 years after the treatment | 
| 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. |