Clinical trial NCT05316935: GnRHa + Letrozole in Non-obese Progestin-insensitive Endometrial Cancer and Atypical Hyperplasia Patients
Official title: Gonadotropin-releasing Hormone Agonist (GnRHa) Plus Letrozole in Non-obese Progestin-insensitive Early-stage Endometrial Cancer and Atypical Hyperplasia Patients With Conservative Treatment
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Endometrial Neoplasms
Atypical Endometrial Hyperplasia
Progesterone Resistance
Lead sponsor: Fudan University
Sponsor class: OTHER
First posted: 2022-04-07
Enrollment: 80
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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. Considered there will be more thrombotic risks in obese patients using ethinylestradiol cyproterone, we enrolled patients with BMI \< 30kg/m2 only in this study.

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.

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.

Eligibility criteria: Inclusion Criteria:

* Have a confirmed initial pathological diagnosis based upon hysteroscopy: histologically prove EAH or well-differentiated EEC G1 without myometrial invasion
* BMI\<30kg/m2
* 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:

  1. Megestrol acetate ≥ 160 mg qd using, combined with Levonorgestrel Lntrauterine System (LNG-IUS) inserted or not
  2. Medroxyprogesterone acetate ≥ 250 mg qd using, combined with LNG-IUS inserted or not
  3. LNG-IUS inserted
* Progestin-insensitive:

  1. remained with stable disease after 7 months of progestin use
  2. 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)

Primary outcomes:
measure: Complete response rates within 28 weeks of treatment
timeFrame: From date of randomization until the date of CR, assessed up to 28 weeks
Secondary outcomes:
measure: Adverse events
timeFrame: From date of randomization until the date of CR or date of hysterectomy, assessed up to 28 weeks
measure: Time to achieve complete response
timeFrame: From date of randomization until the date of CR or date of hysterectomy, assessed up to 28 weeks.
measure: Relapse rates
timeFrame: Up to 2 years after the treatment
measure: Rates of fertility outcomes
timeFrame: Up to 2 years after the treatment
measure: Compliance
timeFrame: 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.
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Obstetrics and Gynecology Hospital, Fudan University
state: Shanghai
city: Shanghai
country: China
facility: Tenth People's Hospital of Tongji University
state: Shanghai
Study officials:
References:
citation: Zhou S, Xu Z, Yang B, Guan J, Shan W, Shi Y, Chen X. Characteristics of progestin-insensitive early stage endometrial cancer and atypical hyperplasia patients receiving second-line fertility-sparing treatment. J Gynecol Oncol. 2021 Jul;32(4):e57. doi: 10.3802/jgo.2021.32.e57.