Clinical trial NCT04823065: 4FMFES-PET Imaging of Endometrial and Ovarian Cancers
Official title: 4FMFES Positron Emission Tomography (PET) for Detection of Newly-diagnosed ER+ Endometrial and Ovarian Cancers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Endometrial Cancer
Ovarian Cancer
Keywords: PET
4FMFES
Endometrial cancer
Ovarian cancer
Lead sponsor: Centre de recherche du Centre hospitalier universitaire de Sherbrooke
Sponsor class: OTHER
Collaborators: name: Université de Sherbrooke
First posted: 2021-03-30
Enrollment: 53
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All recruited patients will undergo a 4FMFES-PET after biopsy confirmation of a ER+ endometrial cancer or suspicion of ovarian cancer. All patients are scanned prior to surgery.

Patients are then randomly distributed for 3 different interventions aiming to reduce the intestinal peristalsis in order to diminish abdominal background generated by 4FMFES radio-metabolites.

1. Control group: no intervention other than standard 4FMFES injection;
2. 4 mg loperamide, per os, 15 minutes prior to 4FMFES injection;
3. Repeated i.v. injection of 20 mg hyoscine-N-butylbromide at 0, 20 and 40 minutes after 4FMFES injection.
Primary purpose: DIAGNOSTIC

Brief summary: This project is about exploring a novel method to detect ovarian and uterine cancers earlier and better. More precisely, a high-performance radioactive estrogen analog will be used to visualize hormone-sensitive uterine and ovarian tumors using PET imaging. Not only this imaging methodology could improve the whole-body assessment of those diseases, but will also hint clinicians about the optimal course of therapy to undertake.

The lead investigator's team designed in the past years an innovative radioactive estrogen derivative tracer (4FMFES) for the medical imaging modality termed Positron Emission Tomography (PET). The compound was first shown to be safe for human use. Recently, a clinical trial demonstrated that 4FMFES-PET is superior to any existing comparable tracer for detection of hormone-sensitive breast cancer patients. 4FMFES is particularly useful to pinpoint unsuspected metastases early, which allowed better breast cancer patient management and staging. 4FMFES and standard FDG PET imaging were shown to be complementary in breast cancer, the use of both techniques together providing a detection rate nearing 100%. Since ovarian and uterine cancers are about as likely to be targeted by 4FMFES as breast cancer, the use of this novel precision imaging method will be adapted to those other indications.

In general, the sooner a cancer is diagnosed and treated, the better the outcome of a patient will be. Gynecological cancers lack precise screening and detection tools. In particular, while a majority of uterine cancers are relatively well managed, patients burdened with metastatic burden have a much worse prognosis, and precise and early detection of those lesions will greatly help clinicians to better treat those complicated cases. As for ovarian cancers, they are usually devoid of clinical symptoms until late onset, which partly explain the high mortality rate of this disease. Hence, for both diseases, a precision, whole-body imaging technique will allow earlier assessment, followed by earlier intervention, resulting in improved survival rate and better quality of life for patients.

Detailed description: Knowledge of estrogen receptor (ER) status is of paramount importance for breast cancer management. Mounting evidence supports an equally important role of ER status for uterine and ovarian cancers. Indeed, this prognostic factor was shown to stratify survival and progression-free rates, and to predict efficacy of ER-targeting adjuvant hormone therapy in those cancers. Between 70 and 80% of gynecological cancers expresses ER, akin to what is found in breast cancer. However, ER status is assessed by biopsy and hence is limited to primary lesions and to known, accessible metastases.

Commonly used diagnostic tools for gynecological cancers includes anatomical imaging modalities, such as echography, computed tomography (CT) and magnetic resonance imaging (MRI), with an increased role for metabolic \[18F\]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, all yielding suboptimal tumor detection rate and poor specificity. Studies explored combination of FDG-PET/CT with \[18F\]-16α-fluoroestradiol (FES) PET/CT imaging to obtain whole-body assessment of ER status of both uterine and ovarian cancers, with FDG/FES uptake ratio correlating with grade and stage of disease. However, FES has many shortcomings, including rapid hepatic metabolism and binding to plasma globulins, resulting in a strong blood pool and in high nonspecific uptake, both detrimental to tumor detection.

The investigator's research center have designed a novel ER-targeting PET tracer, 4-fluoro-11β-methoxy-16α-\[18F\] fluoroestradiol (4FMFES) that addresses those flaws; 4FMFES is 2.5-fold more resistant to metabolism and does not bind to globulins. A phase II study comparing FES with 4FMFES-PET in breast cancer patients showed significantly reduced background with 4FMFES, resulting in improved tumor contrast and in an increased tumor detection rate. Preliminary results showed that addition of 4FMFES-PET to the standard FDG-PET allowed upstaging of \~20% of the breast cancer patients studied so far. Those breast cancer derived data forebode the potential of combined FDG- and 4FMFES-PET for whole-body diagnosis and ER status assessment for uterine and ovarian cancers.

Aim: Launch a phase I/II clinical trial evaluating the use of FDG and 4FMFES PET in ER+ uterine and ovarian cancer patients to enhance diagnostic confidence and accuracy, and to assess whole-body ER status non-invasively.

Specific aims:

1. Optimize imaging protocol for abdomen 4FMFES imaging: 4FMFES is eliminated by hepatobiliary excretion and as such generates strong signals in the intestinal tract, which could induce strong background and even false positives. Appropriate timing between 4FMFES injection and scan would allow optimal tumor uptake and minimal unwanted signal in the peritoneal area. Separately, pre-treatment with cholecystokinine (to pre-empty the gallbladder) or with opioids (to prevent intestinal peristalsis) will be explored as alternate ways of optimizing the protocol. A cohort of patients will be constituted in order to explore the best strategy to undertake for the rest of the study.
2. Evaluate the use of combined FDG and 4FMFES-PET for diagnosis and staging of ER+ uterine and ovarian cancers: Two cohorts of both uterine and ovarian cancer patients will be monitored by FDG and 4FMFES-PET/CT in sequence. Tumor uptake for each tracer will be compared. Number of detected lesion per patient using this protocol will be compared to whatever findings CT, or FDG alone would have found, and % of upstaged patients will be reported.
3. Correlate FDG and 4FMFES-PET tumor uptake with biopsy-derived grade and status: Every known, accessible lesion will be biopsied, and tumor grade and receptor status will be assessed. Correlation between pathological characteristics, and FDG and 4FMFES PET-derived tumor uptake will be drawn.

The lack of sensitive and accurate imaging tools for uterine and ovarian cancer means that diagnosis is too often achieved at late onset of those diseases. Not only the validation of 4FMFES-PET combined with standard FDG-PET should yield more precise, whole-body diagnostic and staging, but also could predict prognosis and targeted therapy efficacy.

Eligibility criteria: Inclusion Criteria:

* Women who received a biopsy-confirmed diagnosis of a ER+ endometrial cancer, or;
* Women with a suspected ovarian cancer, or;
* Women with recurrent endometrial or ovarian cancer and with a ER+ primary tumor, and;
* Planned surgery, and;
* Stage 1A cancer and more, with primary more than 1 cm, and;
* Able to tolerate supine position, and;
* Written consent given by the patient.

Exclusion Criteria:

* Pregnancy, or;
* Replacement hormone therapy concomitant to 4FMFES-PET, or;
* Use of estrogen-based oral contraceptives concomitant to 4FMFES-PET, or;
* Anti-tumor hormone therapy that compete with estrogen receptors concomitant to 4FMFES-PET, such as tamoxifen and fulvestrant. Withdrawal of such therapies 8 weeks prior to the 4FMFES-PET scan will enable the patient to the imaging test, or;
* Cirrhosis, acute or chronic hepatitis, or any other hepatic problem that might impede the normal elimination of the PET tracer, or;
* Hypersentivity to either FDG or 4FMFES, or any of their consittuants.

Primary outcomes:
measure: Evaluate 4FMFES-PET diagnostic properties in endometrial and ovarian cancers
timeFrame: 48 months
measure: Compare 4FMFES-PET with standard FDG-PET in gynaecological cancers.
timeFrame: 48 months
measure: Use pharmaceutical intervention to slow down peristalsis to improve lower-abdomen 4FMFES-PET
timeFrame: 48 months
Secondary outcomes:
Other outcomes:
Locations:
city: Sherbrooke
country: Canada
facility: Centre de recherche du CHUS
state: Quebec
Study officials:
affiliation: Université de Sherbrooke
name: Éric Turcotte, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Paquette M, Espinosa-Bentancourt E, Lavallee E, Phoenix S, Lapointe-Milot K, Bessette P, Guerin B, Turcotte EE. 18F-4FMFES and 18F-FDG PET/CT in Estrogen Receptor-Positive Endometrial Carcinomas: Preliminary Report. J Nucl Med. 2022 May;63(5):702-707. doi: 10.2967/jnumed.121.262617. Epub 2021 Aug 19.