Study of 18F-FFNP Breast PET/MRI

Study Overview
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Brief Summary
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This clinical trial will investigate an estrogen-regulated parameter as an early measure of endocrine therapy response: progesterone receptor (PR) protein with a progestin-based radioligand, 18F-fluorofuranylnorprogesterone (18F-FFNP). The overall purpose of this research is to test the efficacy of 18F-FFNP PET/MRI for predicting response to presurgical endocrine therapy and to determine the quantitative reliability of 18F-FFNP breast PET/MRI in patients with newly diagnosed ER+/PR+/HER2- primary breast cancer.

Detailed Description
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Primary Objective • Determine the diagnostic accuracy of 18F-FFNP PET/MRI for predicting response to presurgical endocrine therapy. Secondary Objectives Determine the repeatability of quantitative assessment of tumor 18F-FFNP uptake. Determine the intra- and inter-observer variability of quantitative assessment of tumor 18F-FFNP uptake. Assess the safety and tolerability of 18F-FFNP. Exploratory Objectives Define the parent and metabolite fractions of 18F-FFNP over the time course of the scan. Assess the association between tumor 18F-FFNP uptake with serum progesterone, estradiol, and corticosteroid binding globulin levels. Compare changes in 18F-FFNP breast PET/MRI parameters with changes in PR immunohistochemistry in therapy responders and non-responders. Assess the association between tumor 18F-FFNP uptake with disease recurrence. Determine whether MRI parameters improve the predictive value of FFNP PET alone.

Official Title
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Phase II Study of 18F-FFNP Breast PET/MRI in the Assessment of Early Response of Breast Cancer to Presurgical Endocrine Therapy

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: 18F-fluorofuranylnorprogesterone
* Device: Positron Emissions Tomography / Magnetic Resonance Imaging
* Drug: Anastrozole
* Other: Blood Sampling
* Drug: Gadobenate dimeglumine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal status defined by either prior bilateral oophorectomy age greater than or equal to 60 years of age age less than 60 years of age and amenorrheic for 12 or more months in the absence of prior chemotherapy, tamoxifen, toremifene or ovarian suppression and FSH and estradiol in the postmenopausal range per local normal range Diagnosis of biopsy-proven invasive breast cancer measuring at least 1.0 cm in diameter by any imaging modality Biopsy-proven ER-positive, PR-positive, HER2-negative invasive breast cancer Breast MRI planned or performed before surgery Definitive surgical excision of the primary tumor planned without neoadjuvant therapy; defined as therapy (chemotherapy, targeted therapy, radiation therapy or endocrine therapy) given to decrease the size of the tumor prior to planned surgery. Exclusion Criteria: Inability or unwillingness to provide informed consent to the study PR and Ki67 IHC slides or FFPE tissue blocks from clinical breast biopsy not available Patients who have completed neoadjuvant chemotherapy, endocrine therapy, targeted therapy, surgical resection, or radiation for the current biopsy-proven malignancy Patients who are planning to undergo anastrozole as standard of care neoadjuvant therapy Patients who are currently taking aromatase inhibitors or ER antagonists (tamoxifen, raloxifene) Patients with breast expanders Patients who are pregnant or lactating Patients whose girth exceeds the bore of the PET/MRI scanner Patients with a contraindication to gadolinium-based contrast agents, including allergy or impaired renal function (per UW Health Guidelines) Patients with a history of allergic reaction attributable to compounds of similar chemical or biologic composition to 18F-FFNP Patients with history of allergic reaction to anastrozole Patients in liver failure as judged by the patient's physician Patients with standard contraindications to MRI (per UW Health Guidelines) Patients requiring conscious sedation for imaging are not eligible; patients requiring mild, oral anxiolytics for the clinical MRI scan will be allowed to participate as long as the following criteria are met: The patient has their own prescription for the medication The informed consent process is conducted prior to the self-administration of the medication. The patient comes to the research visit with a driver. Patients unable to lie prone for 45 minutes for imaging Patients taking hormone replacement therapy or over-the-counter products/supplements/herbal preparation with potential estrogenic effects who are unwilling to discontinue these agents during the timeframe of the study until surgery.

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: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Window of Opportunity
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Metabolite Analysis<br>participants will undergo venous blood sampling during the PET/MRI scan | Drug: 18F-fluorofuranylnorprogesterone<br>* 18F-FFNP will be given by a slow infusion (approximately 2 minutes), and the dose administered will be approximately 7 mCi.<br>* Other names: FFNP;Device: Positron Emissions Tomography / Magnetic Resonance Imaging<br>* Breast specific PET/MRI data will be acquired using a 3T simultaneous PET/MRI scanner (Signa PET/MR, GE Healthcare)<br>* Other names: PET/MRI;Other: Blood Sampling<br>* Venous blood samples will be collected at multiple timepoints (e.g., 5, 10, 20, 30, and 45 min after 18F-FFNP injection to determine parent and metabolite fractions<br>Drug: Gadobenate dimeglumine<br>* FDA-approved gadolinium-based intravenous contrast agent used for the MRI portion of this study<br>* Other names: MultiHance;|
| Experimental: Group 2: Pre-surgical Treatment<br>participants will undergo PET/MRI scans before and after 2 weeks treatment with anastrozole | Drug: 18F-fluorofuranylnorprogesterone<br>* 18F-FFNP will be given by a slow infusion (approximately 2 minutes), and the dose administered will be approximately 7 mCi.<br>* Other names: FFNP;Device: Positron Emissions Tomography / Magnetic Resonance Imaging<br>* Breast specific PET/MRI data will be acquired using a 3T simultaneous PET/MRI scanner (Signa PET/MR, GE Healthcare)<br>* Other names: PET/MRI;Drug: Anastrozole<br>* hormone based chemotherapy that reduces estrogen, 1 mg anastrozole once daily by mouth for a minimum of 14 days<br>Drug: Gadobenate dimeglumine<br>* FDA-approved gadolinium-based intravenous contrast agent used for the MRI portion of this study<br>* Other names: MultiHance;|
| Experimental: Group 3: Test-Retest<br>participants will undergo baseline and repeat PET/MRI scans without intervening treatment to determine repeatability | Drug: 18F-fluorofuranylnorprogesterone<br>* 18F-FFNP will be given by a slow infusion (approximately 2 minutes), and the dose administered will be approximately 7 mCi.<br>* Other names: FFNP;Device: Positron Emissions Tomography / Magnetic Resonance Imaging<br>* Breast specific PET/MRI data will be acquired using a 3T simultaneous PET/MRI scanner (Signa PET/MR, GE Healthcare)<br>* Other names: PET/MRI;Drug: Gadobenate dimeglumine<br>* FDA-approved gadolinium-based intravenous contrast agent used for the MRI portion of this study<br>* Other names: MultiHance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change in 18F-FFNP uptake between baseline and follow-up PET/MRI scans | Tumor uptake values of 18F-FFNP will be obtained from the attenuation corrected PET component of the simultaneous breast 18F-FFNP PET/MRI research scan according to the procedures detailed in the imaging manual and the FDA IND. | up to 4 weeks on study and up to 7 weeks on study | 
| Percentage change in tumor Ki67 proliferation score, as a surrogate measure of endocrine sensitivity | Baseline Ki67 proliferation immunohistochemistry score will be obtained from the existing clinical standard-of-care breast biopsy. Post-treatment K67 proliferation immunohistochemistry score will be obtained from the surgical specimen after excision. Treatment response is defined as a reduction in Ki67 score of greater than or equal to 60 percent. Treatment nonresponse is defined as a reduction of less than 60 percent. | up to 4 weeks on study and up to 7 weeks on study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Qualitative Analysis of 18F-FFNP uptake | 18F-FFNP uptake will be visually evaluated qualitatively with the following grading scale: no uptake (tumor < background), minimal uptake (tumor = background), mild (tumor slightly > background), moderate uptake (tumor >> background), and intense uptake (tumor >>> background). Tumor uptake will also be dichotomized as increased (mild, moderate, or intense uptake) or absent (no uptake, minimal). | imaging takes up to 2 hours during a visit and will take place up to 4 weeks and up to 6 weeks for the test-retest Group 3 | 
| Intra- and Inter-Observer Variability of Quantitative Assessment of Tumor 18F-FFNP uptake | For the test-retest portion of the clinical trial, the mixed effects model framework will be utilized to determine the intra- and interobserver variability of quantitative assessment of tumor 18F-FFNP uptake via a parametric bootstrapping approach. | imaging takes up to 2 hours during a visit and will take place up to 4 weeks and up to 6 weeks for the test-retest Group 3 | 
| Quantitative Assessment of Tumor 18F-FFNP: Standardized Uptake Values (SUV) | Differences in repeatability of the different SUV measures (SUVmax, SUVpeak, and SUVmean) and their respective methods of normalization will be assessed by comparing the variances of the relative test-retest differences, using the Pitnam-Morgan test for correlated variances. | imaging takes up to 2 hours during a visit and will take place up to 4 weeks and up to 6 weeks for the test-retest Group 3 | 
| Test-Retest Variability of Quantitative Assessment of Tumor 18F-FFNP uptake | For the test-retest portion of the clinical trial, the mixed effects model framework will be utilized to determine the test-retest variability of quantitative assessment of tumor 18F-FFNP uptake via a parametric bootstrapping approach. | imaging takes up to 2 hours during a visit and will take place up to 4 weeks and up to 6 weeks for the test-retest Group 3 | 
| NCIC Adverse Events Version 5.0 Frequency Tables | Safety and tolerability of 18F-FFNP by NCIC Adverse Events Version 5.0 will be assessed by frequency tables and possible relationship to study drug as assessed by the investigators. | up to 7 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-, PR+, ER+