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

• ClinicalTrials.gov Identifier: NCT03926936
• Recruitment Status: Recruiting
• First Posted: April 25, 2019
• Last Update Posted: April 26, 2019
• Sponsor: Frederic Amant
• Collaborators: Kom Op Tegen Kanker; FWO Research Fund Flanders
• Information provided by (Responsible Party): Frederic Amant, University Hospital, Gasthuisberg

Tracking Information

• First Submitted Date: April 10, 2019
• First Posted Date: April 25, 2019
• Last Update Posted Date: April 26, 2019
• Actual Study Start Date: March 13, 2019
• Estimated Primary Completion Date: April 1, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 23, 2019)

Response rate [ Time Frame: week 24 ]

partial or complete response, as determined by RECIST v1.1 criteria

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 24, 2019)

• progression-free survival [ Time Frame: week 156 ]
  progression-free survival after 3 years
• clinical benefit [ Time Frame: week 24 ]
  Clinical benefit is defined as the number of patients having complete response, partial response or stable disease, as determined by RECIST v1.1 criteria
• duration of response [ Time Frame: up to week 156 ]
• number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: up to 56 days after stop study treatment ]
• EQ-5D quality of life assessment [ Time Frame: Quality of life questionnaires will be completed by the patients at baseline and thereafter 3-monthly up to week 156 ]
  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.
• EORTC QLQ-C30 quality of life assessment [ Time Frame: Quality of life questionnaires will be completed by the patients at baseline and thereafter 3-monthly up to week 156 ]
  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.

Original Secondary Outcome Measures (submitted: April 23, 2019)

• progression-free survival [ Time Frame: week 156 ]
  progression-free survival after 3 years
• clinical benefit [ Time Frame: week 24 ]
  complete response, partial response and stable disease, as determined by RECIST v1.1 criteria
• duration of response [ Time Frame: up to week 156 ]
• number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: up to 56 days after stop study treatment ]
• EQ-5D quality of life assessment [ Time Frame: Quality of life questionnaires will be completed by the patients at baseline and thereafter 3-monthly up to week 156 ]
  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.
• EORTC QLQ-C30 quality of life assessment [ Time Frame: Quality of life questionnaires will be completed by the patients at baseline and thereafter 3-monthly up to week 156 ]
  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.

Current Other Pre-specified Outcome Measures (submitted: April 23, 2019)

• Detection of ER expression by 18F-FES PET imaging [ Time Frame: up to week 156 ]
  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.
• Predicting response to Fulvestrant by sequential 18F-FES PET imaging [ Time Frame: up to week 156 ]
  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.
• Genomic analysis of blood and tumor biopsies [ Time Frame: up to week 156 ]
  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.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: FUlvestrant in Gynecological Cancers That Are Potentially Hormone Sensitive: the FUCHSia Study
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

Drug: Fulvestrant

intramuscular injection (2x 250mg), once every 2 weeks for the first month, and then monthly until completion of the study

Study Arms

• Experimental: Low-grade uterine sarcoma
  Intervention: Drug: Fulvestrant
• Experimental: low-grade endometrial carcinoma
  Intervention: Drug: Fulvestrant
• Experimental: sex cord stromal tumors
  Intervention: Drug: Fulvestrant
• Experimental: low-grade serous ovarian cancer
  Intervention: Drug: Fulvestrant

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 23, 2019): 200
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: April 1, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Frédéric Amant, MD PhD; +32 16 344273; frederic.amant@uzleuven.be

Contact: Sileny Han, MD PhD; sileny.han@uzleuven.be

• Listed Location Countries: Belgium

Administrative Information

• NCT Number: NCT03926936
• Other Study ID Numbers: S60857; 2017-005018-76 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Supporting Materials: Study Protocol

• Current Responsible Party: Frederic Amant, University Hospital, Gasthuisberg
• Original Responsible Party: Same as current
• Current Study Sponsor: Frederic Amant
• Original Study Sponsor: Same as current

Collaborators

• Kom Op Tegen Kanker
• FWO Research Fund Flanders

Investigators

• Principal Investigator: Frédéric Amant, MD PhD; UZ Leuven

• PRS Account: University Hospital, Gasthuisberg
• Verification Date: April 2019