Monitoring HER2+ Breast Cancer Neoadjuvant Treatment With Advanced PET/MRI

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to see if using an investigational drug called [18F]FMISO with PET/MRI imaging can help monitor and predict the effect of trastuzumab (Herceptin) on chemotherapy in patients diagnosed with advanced HER2 positive breast cancer. This study is for imaging purposes only and is not a treatment study. The results of this study will not change a patient's clinical treatment plan but it may help physicians and researchers better understand how best to treat patients with breast cancer in the future.

Detailed Description
-----------------
There are 2 groups or cohorts in this study. The cohort patient's are in is based on their clinical treatment plan set by your physician. The number of imaging visits and timing of visits will be determined by what cohort they are in. If the patient is in cohort #1, they will make 4 visits to UAB. They will be scheduled for a pre-study or screening visit. During the pre-study visit, once consented, they will have a blood draw to determine kidney function, and a pregnancy test if they are a woman of childbearing potential. Their vital signs will be taken, they will be asked to fill out an MRI questionnaire, and they will have a PET/MRI fit test. If eligible for the study, they will be scheduled for the first PET imaging visit which will occur before they start chemotherapy. During this PET imaging visit, they will have a pregnancy test if they are a woman of childbearing potential. A plastic catheter will be placed into a vein in their arm and they will then be positioned in the PET/MRI scanner. Once positioned, they will be injected with the investigational radioactive drug, [18F]FMISO. They will then be imaged for up to 90 minutes during which time they will receive an FDA approved contrast agent called Prohance (gadoteridol). Once all the procedures are complete, the catheter will be removed and they may resume all normal activities. The patient will receive a follow-up phone call within 24-48 hours of your injection to be sure they are not experiencing any adverse events. Their second imaging visit will be scheduled after they receive therapy with Herceptin alone and within 10 days before their first cycle of combination therapy including Herceptin. During the second PET imaging visit, the same procedures will be followed as were performed during your first PET imaging visit. They will receive a follow-up phone call within 24-48 hours of your injection to be sure you are not experiencing any adverse events. Their third PET imaging visit will be scheduled after their first cycle of combination therapy including Herceptin and within 10 days before starting their second cycle of combination therapy including Herceptin. During the third PET imaging visit, the same procedures will be followed as were performed during their first and second PET imaging visits. The patient will receive a follow-up phone call within 24-48 hours of their injection to be sure they are not experiencing any adverse events. If the patients are in cohort #2, they will make 3 visits to UAB. The patients will be scheduled for a pre-study or screening visit. During the pre-study visit, once consented, they will have a blood draw to determine kidney function, and a pregnancy test if they are a woman of childbearing potential. Their vital signs will be taken, they will be asked to fill out an MRI questionnaire, and they will have a PET/MRI fit test. If eligible for the study, they will be scheduled for the first PET imaging visit which will occur before they start chemotherapy. During this visit, they will have a pregnancy test if they are a woman of childbearing potential. A plastic catheter will be placed into a vein in their arm and they will then be positioned in the PET/MRI scanner. Once positioned, the patient will be injected with the investigational radioactive drug, [18F]FMISO. They will then be imaged for up to 90 minutes during which time they will receive an FDA approved contrast agent called Prohance (gadoteridol). Once all the procedures are complete, the catheter will be removed and the patient may resume all normal activities. They will receive a follow-up phone call within 24-48 hours of your injection to be sure they are not experiencing any adverse events. Your second PET imaging visit will be scheduled after your first cycle of combination therapy including Herceptin and within 10 days before starting the second cycle of combination therapy including Herceptin. During the third PET imaging visit, the same procedures will be followed as were performed during the first PET imaging visits. The patient will receive a follow-up phone call within 24-48 hours of your injection to be sure they are not experiencing any adverse events. We will follow the patients every 6 months for 5 years by reviewing their medical records to see how they are doing.

Official Title
-----------------
Monitoring HER2+ Breast Cancer Neoadjuvant Treatment With Advanced PET/MRI

Conditions
-----------------
HER2-positive Breast Cancer

Intervention / Treatment
-----------------
* Drug: [18F]FMISO PET/MRI imaging


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must be ≥ 18 years old and ≤ 75 years old HER2+ breast cancer determined on primary tumor by a local pathology laboratory and defined as IHC score 3+ and/or positive by ISH (defined by ISH ratio of ≥ 2.0 for the number of HER2 gene copies to the number of chromosome 17 copies). Only one positive result is required for eligibility Locally advanced stage II-III HER2+ breast cancer patients eligible for neoadjuvant therapy who are naïve to beginning treatment Estimated life expectancy of greater than one year Patients must have one lesion with RECIST measurable disease (great than 1 cm in diameter) Exclusion Criteria: Inability to provide informed consent F Weight over 350 lbs., due to the scanner bore size Lactating, known or suspected pregnancy. Women with child-bearing potential must a have a negative serum β-hCG pregnancy test within 48 hours or a negative urine β-hCG pregnancy test within 48 hours of each PET imaging study. Contraindication for MRI study (e.g. non-removable metal implants or certain tattoos) Unable to lie still on the imaging table for one (1) hour contraindication for gadolinium-based contrast agent, ProHance (gadoteridol)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Herceptin monotherapy cohort<br>Herceptin monotherapy cohort. Locally advanced HER2+ breast cancer patients receiving neoadjuvant Herceptin monotherapy prior to combination therapy will undergo three contrast-enhanced [18F]FMISO PET/MRI scans. Each imaging session will be identical. Imaging session one will be after diagnosis and before beginning monotherapy. Imaging session two will be within 10 days prior to beginning combination therapy with targeted HER2 agents. Imaging session three will be within 10 days prior to beginning the second round of combination therapy with targeted HER2 agents. | Drug: [18F]FMISO PET/MRI imaging<br>* [18F]FMISO PET/MRI imaging<br>|
| Experimental: Combination therapy cohort<br>Locally advanced HER2+ breast cancer patients that receiving neoadjuvant combination therapy including Herceptin will undergo two contrast-enhanced [18F]FMISO PET/MRI imaging. Imaging session one will be after diagnosis and before beginning combination therapy. Imaging session two will be within 10 days prior to beginning the second round of combination therapy with targeted HER2 agents. | Drug: [18F]FMISO PET/MRI imaging<br>* [18F]FMISO PET/MRI imaging<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline measure of PET standardized uptake value (SUV). | Compare baseline metrics from PET/MRI | Baseline | 
| Baseline measure of apparent diffusion coefficient (ADC) in mm2/sec from MRI. | Compare baseline metrics from PET/MRI | Baseline | 
| Baseline measure of signal enhancement ratio (SER) from MRI. | Compare baseline metrics from PET/MRI | Baseline | 
| Changes in SER from MRI | Compare percent change of SER from imaging visit 3 to the baseline. | Baseline through 6 months | 
| Changes in ADC from MRI | Compare percent change of ADC (mm2/sec) from imaging visit 3 to the baseline. | Baseline through 6 months | 
| Changes in SUV from PET | Compare percent change of SUV from imaging visit 3 to the baseline. | Baseline through 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Follow-up | Compare changes in imaging metrics to neoadjuvant response (defined as pathological complete response, near-pathological response, residual disease). | Baseline through 5 years | 
| Follow-up | Compare changes in imaging metrics to clinical response (defined as disease free-survival or recurrence). | Baseline through 5 years | 
| Changes in ADC (mm2/sec) from MRI. | Compare percent change from imaging visit 2 to the baseline. | Baseline through 2 months | 
| Changes in SER from MRI. | Compare percent change from imaging visit 2 to the baseline. | Baseline through 2 months | 
| Changes in SUV from PET. | Compare percent change from imaging visit 2 to the baseline. | Baseline through 2 months |