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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Endometrial Cancer; Endometrial Stromal Sarcoma; Sex Cord Stromal Tumor; Adenosarcoma of Uterus; Leiomyosarcoma Uterus; Serous Ovarian Tumor
• Intervention / Treatment: Drug: Fulvestrant

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Frédéric Amant, MD PhD; Phone Number: +32 16 344273; Email: frederic.amant@uzleuven.be
• Study Contact Backup: Name: Sileny Han, MD PhD; Email: sileny.han@uzleuven.be

Study Locations

• Belgium
  • Edegem, Belgium, 2650
    • Not yet recruiting
    • UZ Antwerp
    • Contact: Peter Van Dam, MD PhD; Email: peter.van.dam@uza.be
    • Principal Investigator: Peter Van Dam, MD PhD
  • Gent, Belgium, 9000
    • Recruiting
    • UZ Gent
    • Contact: Lore Lapeire, MD PhD; Email: lore.lapeire@ugent.be
    • Principal Investigator: Lore Lapeire, MD PhD
  • Mechelen, Belgium, 2800
    • Recruiting
    • AZ Sint Maarten
    • Contact: Karin Leunen, MD PhD; Email: karin.leunen@emmaus.be
    • Principal Investigator: Karin Leunen, MD PhD
    • Sub-Investigator: Patrick Berteloot, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-grade uterine sarcoma	Drug: Fulvestrant; intramuscular injection (2x 250mg), once every 2 weeks for the first month, and then monthly until completion of the study
Experimental: low-grade endometrial carcinoma	Drug: Fulvestrant; intramuscular injection (2x 250mg), once every 2 weeks for the first month, and then monthly until completion of the study
Experimental: sex cord stromal tumors	Drug: Fulvestrant; intramuscular injection (2x 250mg), once every 2 weeks for the first month, and then monthly until completion of the study
Experimental: low-grade serous ovarian cancer	Drug: Fulvestrant; intramuscular injection (2x 250mg), once every 2 weeks for the first month, and then monthly until completion of the study

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detection of ER expression by 18F-FES PET imaging	16α-18F-fluoro-17β-estradiol (18F-FES) positron emission tomography (PET) technique uses a radiolabeled estrogen derivative and allows non-invasive, repetitive imaging of the ER receptor, mainly the α subtype. This technique has been validated for measurement of ER expression in breast cancer. PET parameters will be derived from the PET data at baseline and will be correlated to the treatment response and the survival of the patients (PFS and OS). Liver metastases will not be included in the analysis due to high physiologic background uptake.	up to week 156
Predicting response to Fulvestrant by sequential 18F-FES PET imaging	16α-18F-fluoro-17β-estradiol (18F-FES) positron emission tomography (PET) uses a radiolabeled estrogen derivative and allows non-invasive, repetitive imaging of the ER, mainly the α subtype. This technique has been validated for measurement of ER in breast cancer and it has been shown that lesions with no or limited reduction of 18F-FES uptake are at risk for early progression and thus therapy failure. The relationship between the absolute value of the PET parameters, and their change between baseline and Week 4, will be correlated to treatment response and survival of the patients. The hypothesis is that responding patients will have a median reduction of FES uptake on pre- and post-fulvestrant 18F-FES-PET (at Week 4) of >75% (based on SUVmax). All patients with CR or PR according to RECIST will be classified as having responded to Fulvestrant treatment. The response rate is hypothesized to be higher in the 18F-FES responder group than in the 18F-FES non-responder group.	up to week 156
Genomic analysis of blood and tumor biopsies	Core biopsies and blood from patients will be collected and stored in a biobank. cf-DNA will be isolated from plasma and copy number alterations will be measured by shallow whole-exome sequencing. DNA will be extracted form core biopsies and will be subject to ER/chromatin analysis, shallow whole-exome sequencing and targeted sequencing.	up to week 156

Collaborators and Investigators

• Sponsor: Frederic Amant
• Collaborators: Kom Op Tegen Kanker; FWO Research Fund Flanders
• Investigators: Principal Investigator: Frédéric Amant, MD PhD, UZ Leuven

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2019
• Primary Completion (Anticipated): April 1, 2022
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: April 10, 2019
• First Submitted That Met QC Criteria: April 23, 2019
• First Posted (Actual): April 25, 2019

Study Record Updates

• Last Update Posted (Actual): April 26, 2019
• Last Update Submitted That Met QC Criteria: April 24, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: efficacy; fulvestrant; low-grade gynecological cancer
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Neoplasms, Complex and Mixed; Sarcoma; Neoplasms, Muscle Tissue; Neoplasms, Gonadal Tissue; Endometrial Stromal Tumors; Endometrial Neoplasms; Leiomyosarcoma; Sex Cord-Gonadal Stromal Tumors; Adenosarcoma; Sarcoma, Endometrial Stromal; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Fulvestrant
• Other Study ID Numbers: S60857; 2017-005018-76 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No