FUlvestrant in Gynecological Cancers That Are Potentially Hormone Sensitive: the FUCHSia Study

Study Overview
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Brief Summary
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In this phase 2 clinical trial, the aim is to evaluate the efficacy of the ER-antagonist Fulvestrant in women with estrogen receptor positive (ER+) low grade gynecological cancers. The primary objective of the study is to determine the response rate (RR) upon Fulvestrant treatment, comprising either partial or complete response, as determined by RECIST v1.1 criteria for each tumor type. The secondary objectives are to: (1) determine progression-free survival (PFS) upon Fulvestrant treatment, after 3 years, in each tumor type group (2) assess clinical benefit (CB) upon Fulvestrant treatment, comprising complete response, partial response and stable disease, as determined by RECIST v1.1 criteria, in each tumor type group (3) assess duration of response in each tumor type group (4) assess safety and tolerability of Fulvestrant administration in each tumor type group (5) assess quality of life (QoL) and symptoms in each tumor type group. As exploratory objectives, the aim is to: (1) evaluate the feasibility of 16α-18F-fluoro-17β-estradiol (18F-FES) PET imaging for detection of ER expression (2) determine the value of sequential 18F-FES PET scans in predicting response to Fulvestrant (3) collect tumor biopsies and cf-DNA from patients enrolled in the trial. These samples will be subsequently characterized at the genetic level, to identify adaptive response mechanisms to Fulvestrant treatment.

Official Title
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An Open-label, Single Arm, Prospective, Multi-center, Tandem Two Stage Designed, Phase II Study to Evaluate the Efficacy of Fulvestrant in Women With Recurrent/Metastatic Estrogen Receptor Positive Gynecological Malignancies

Conditions
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Endometrial Stromal Sarcoma, Adenosarcoma of Uterus, Leiomyosarcoma Uterus, Endometrial Cancer, Sex Cord Stromal Tumor, Serous Ovarian Tumor

Intervention / Treatment
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* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent prior admission to the study Age ≥ 18 years at the moment of signing the informed consent Recurrent or metastatic low grade uterine sarcomas (low grade endometrial stromal sarcoma, low grade adenosarcoma without sarcomatous overgrowth and low grade leiomyosarcoma), low-grade endometrial carcinomas, sex cord stromal tumors (granulosa cell tumors...) and low grade serous ovarian cancer Measurable disease, according to RECIST v1.1 criteria, assessed by CT scans ER-positive tumors based on immunohistochemistry, assessed using the Allred scoring system (based on intensity and percentage of positive cells, see Appendix 4), and archival tissue available At least and maximum of 1 prior line of hormonal therapy (tamoxifen, progestins and/or aromatase inhibitors). Response on 1st line hormonal therapy must have lasted for at least 3 months. Eastern Cooperative Oncology Group (ECOG) performance status: 0-2 Demonstrate adequate organ function: platelets > 100 x 10E9/L, serum total bilirubin < 1.5x Upper Limit of Normal (ULN) (patients with confirmed Gilbert's syndrome may be included in the study), alanine transaminase or aspartate transaminase < 2.5x ULN if no demonstrable liver metastases or < 5x ULN in presence of liver metastases Post-menopausal status as defined by (i) age 60 or more, or (ii) age 45-59 and satisfying the following criteria: amenorrhea for at least 12 months and FSH in postmenopausal range, or (iii) ≥ 18 years of age and having had a bilateral oophorectomy Be willing to receive 18F-FES PET scan. Exceptions will be made in case of (i) patients living far from one of the imaging centers and for whom travelling would be a too high burden for their physical conditions; (ii) patients who received tamoxifen within 8 weeks prior to study Day 1. These patients will be enrolled, but they will not receive a FES PET scan Be willing to donate a core tumor biopsy if technically feasible Exclusion Criteria: Any other active malignancy or primary malignancy diagnosed within the previous 5 years, except for adequately treated squamous or basal cell carcinoma of the skin or in situ cervical carcinoma Patients currently receiving (and unwilling to discontinue) any estrogen replacement therapy. Patients participating in a study or having participated in a study of an investigational agent and received study therapy (or used an investigational device) within 4 weeks prior to study Day 1 Patients who received prior chemo- or targeted therapy within 4 weeks prior to study Day 1 or who has not recovered from adverse events (i.e., adverse event not resolved to ≤ Grade 1 or baseline), due to a previously administered agent Patients with no archival tissue available, except for patients from whom an additional fresh core biopsy can be obtained for ER assessment Any other disease, metabolic dysfunction, physical examination or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interfere with obtaining informed consent. Any condition not permitting compliance with the study protocol

Ages Eligible for Study
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Minimum Age: 18 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: Low-grade uterine sarcoma<br> | Drug: Fulvestrant<br>* intramuscular injection (2x 250mg), once every 2 weeks for the first month, and then monthly until completion of the study<br>|
| Experimental: low-grade endometrial carcinoma<br> | Drug: Fulvestrant<br>* intramuscular injection (2x 250mg), once every 2 weeks for the first month, and then monthly until completion of the study<br>|
| Experimental: sex cord stromal tumors<br> | Drug: Fulvestrant<br>* intramuscular injection (2x 250mg), once every 2 weeks for the first month, and then monthly until completion of the study<br>|
| Experimental: low-grade serous ovarian cancer<br> | Drug: Fulvestrant<br>* intramuscular injection (2x 250mg), once every 2 weeks for the first month, and then monthly until completion of the study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | partial or complete response, as determined by RECIST v1.1 criteria | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival | progression-free survival after 3 years | week 156 | 
| clinical benefit | Clinical benefit is defined as the number of patients having complete response, partial response or stable disease, as determined by RECIST v1.1 criteria | week 24 | 
| duration of response |  | up to week 156 | 
| number of participants with treatment-related adverse events as assessed by CTCAE v5.0 |  | up to 56 days after stop study treatment | 
| EQ-5D quality of life assessment | Quality of life as measured by the EQ-5D questionnaire. EQ-5D has 2 parts-the EQ-5D descriptive system and the EQ visual analog scale (EQ VAS). The descriptive system comprises 5 health states (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), which will be converted into a summary index according to the EQ-5D user guide. The EQ VAS records the self-rated health on an analog scale. For both EQ-5D index and EQ VAS, a higher score indicates a better health status. Descriptive statistics of the subscores and the summary score at each visit and the difference with baseline will be reported. | Quality of life questionnaires will be completed by the patients at baseline and thereafter 3-monthly up to week 156 | 
| EORTC QLQ-C30 quality of life assessment | Quality of life as measured by the EORTC-QLQ-C30 questionnaire. For EORTC QLQ-C30, functional scores (emotional, role, cognitive, physical, and social) will be pooled and a summary score will be calculated according to Giesinger et al. A higher score indicates better health for functioning and global health status, whereas for the symptom scales a lower score indicates a lower level of symptom burden. Descriptive statistics of the subscores and the summary score at each visit and the difference with baseline will be reported. | Quality of life questionnaires will be completed by the patients at baseline and thereafter 3-monthly up to week 156 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fulvestrant, low-grade gynecological cancer, efficacy