Phase II Study of Fluorine-18 3'-Deoxy-3'-Fluorothymidine (F-18-FLT) in Invasive Breast Cancer

3'-Deoxy-3'-18F Fluorothymidine PET/CT in Predicting Response To Chemotherapy Before Surgery in Patients With Locally Advanced Breast Cancer

This phase II trial studies how well 3'-deoxy-3'-18F fluorothymidine (18F-FLT) positron emission tomography (PET)/computed tomography (CT) works in predicting response in patients receiving chemotherapy and undergoing surgery for breast cancer that has spread from where it started to nearby tissue or lymph nodes. Diagnostic procedures, such as 18F-FLT PET/CT, may help in learning how well chemotherapy works to kill breast cancer cells before surgery and help doctors plan the best treatment.

Study Overview

• Status: Completed
• Conditions: Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIB Breast Cancer; Stage IIIC Breast Cancer
• Intervention / Treatment: Procedure: CT; Drug: 18F-FLT; Procedure: PET

Detailed Description

PRIMARY OBJECTIVES:

I. To correlate the percentage change in standardized uptake value at 60 minutes (SUV60) between baseline (FLT-1) and early-therapy (FLT-2) with pathologic complete response to neoadjuvant chemotherapy of the primary tumor in patients with locally advanced breast cancer.

SECONDARY OBJECTIVES:

I. To demonstrate correlation between FLT-1 and post-therapy (FLT-3) uptake parameters and tumor proliferation markers in locally advanced breast cancer.

II. To evaluate the relationship between FLT-1, FLT-2 and FLT-3 uptake parameters and pathologic complete response of the primary tumor and residual cancer burden (RCB).

III. To evaluate the relationship between FLT-1, FLT-2 and FLT-3 uptake parameters and non-response of the primary tumor (stable or progressive disease) to therapy.

IV. To evaluate the relationship between FLT-1, FLT-2 and FLT-3 uptake parameters and pathologic complete response to neoadjuvant chemotherapy in patients with regional disease in the lymph nodes in patients with locally advanced breast cancer.

V. To compare the changes of FLT-2 and FLT-3 uptake parameters to changes in tumor sizes from other serial imaging modalities such as mammograms, magnetic resonance imaging (MRI), and ultrasound.

VI. To compare the changes of FLT-2 and FLT-3 uptake parameters to metabolic changes from [18F] fludeoxyglucose (FDG)-PET, as available.

VII. To continue to monitor for potential safety issues and define any physiologic effects associated with 18F FLT administration.

OUTLINE:

Patients undergo 18F-FLT PET/CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Scottsdale Medical Imaging Limited
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
  • Florida
    • Clearwater, Florida, United States, 33756
      • Morton Plant Hospital
    • Dunedin, Florida, United States, 34695
      • Morton Plant Mease
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center Jefferson
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Washington University
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Youngstown, Ohio, United States, 44512
      • Radiology Consultants Inc
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Milton S Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania School of Medicine
    • Philadelphia, Pennsylvania, United States, 19103
      • American College of Radiology Imaging Network
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77042
      • Westchase Oncology Center
    • Houston, Texas, United States, 77042
      • Excel Diagnostics
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Pathologically confirmed breast cancer, determined to be a candidate for primary systemic (neoadjuvant) therapy and for surgical resection of residual primary tumor following completion of neoadjuvant therapy
• Locally advanced breast cancer, not stage IV, and with a tumor size >= 2 cm (as measured on imaging or estimated by physical exam)
• No obvious contraindications for primary chemotherapy
• Residual tumor planned to be removed surgically following completion of neoadjuvant therapy
• Able to lie still for 1.5 hours for PET scanning
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Leukocytes >= 3,000/ul
• Absolute neutrophil count >= 1,500/ul
• Platelets >= 100,000/ul
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times the institutional upper limit of normal
• Creatinine within normal institutional limits OR creatinine clearance >= 30 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• If female, postmenopausal for a minimum of one year, OR surgically sterile, OR not pregnant, confirmed by institutional standard of care (SOC) pregnancy test, and willing to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation
• Able to understand and willing to sign a written informed consent document and a Health Insurance Portability and Accountability Act (HIPAA) authorization in accordance with institutional guidelines

Exclusion Criteria:

• Previous treatment (chemotherapy, radiation, or surgery) to involved breast; including hormone therapy
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Medically unstable
• Condition requiring anesthesia for PET scanning and/or unable to lie still for 1.5 hours
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to F-18 fluorothymidine
• Pregnant or nursing
• Previous malignancy, other than basal cell or squamous cell carcinoma of the skin or in situ carcinoma of the cervix, from which the patient has been disease free for less than 5 years
• Currently on hormone therapy as the primary systemic neoadjuvant therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Diagnostic (18F-FLT); Patients undergo 18F-FLT PET /CT at baseline (prior to chemotherapy, FLT-1), early therapy (5-10 days after the initiation of the first course of chemotherapy, FLT-2), and post therapy (within 3 weeks prior to surgery, FLT-3). Patients undergo standard surgical resection of residual tumor following completion of neoadjuvant chemotherapy.

Procedure: CT; Undergo 18F-FLT PET/CT; Other Names: CAT; CAT Scan; Computerized Axial Tomography; Computerized Tomography; tomography; CT SCAN; Computed Tomography; Drug: 18F-FLT; Undergo 18F-FLT PET/CT; Other Names: 3'-deoxy-3'-[18F]fluorothymidine; 3'-deoxy-3'-(18F) fluorothymidine; fluorothymidine F 18; Fluorothymidine F-18; Procedure: PET; Undergo 18F-FLT PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; PET SCAN; Positron Emission Tomography

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
%Change in FLT Uptake Between the Baseline (Pre-therapy) and the Early-therapy Imaging Studies to Predict Pathological Complete Response	The primary statistical evaluation will be based on the percent change in FLT SUV60 between baseline (pre-therapy, FLT-1) and the early-therapy imaging (5-10 days after chemotherapy, FLT-2) studies	Baseline (FLT-1) to early therapy (5-10 days after chemotherapy, FLT-2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation Between SUVmax and Ki-67 LI at FLT1(Baseline PET)	For the purposes of reporting, SUVmax @ FLT1 will be considered the outcome. the correlation is measured between the fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) and SUVmax at FLT1 . Ki-67 labeling index (LI) was calculated as the number of Ki-67 positive tumor cells per one thousand tumor cells.	Baseline (FLT-1)
Correlation Between SUVmax and Ki-67 LI at FLT3 (Post-NAC)	For the purposes of reporting, SUVmax @ FLT-3 will be considered the outcome. correlation between the fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) and SUVmax at FLT-3 Ki-67 labeling index (LI) was calculated as the number of Ki-67 positive tumor cells per one thousand tumor cells.	Post-NAC (FLT3)
SUVmax at FLT-1 Comparison Between Residual Cancer Burden (RCB) 0/I and RCB II/III	While normally RCB (or other final determination) would be considered the outcome, since this is a predictive question, we will consider the Standardized Uptake Values the measurement of interest and report those values herein. Mean Standard Uptake Values (max) at Baseline (FLT-1) were compared for Participants with Residual Cancer Burden 0/I vs Residual Cancer Burden of II/III	Baseline (FLT-1)
SUVmax at FLT-2 Comparison Between Residual Cancer Burden (RCB) 0/I and RCB II/III	While normally RCB (or other final determination) would be considered the outcome, since this is a predictive question, we will consider the uptake values the measurement of interest and report those values herein. Mean Standard Uptake Values (max) after one cycle of NAC (FLT2) were compared for Participants with Residual Cancer Burden (RCB) 0/I vs RCB II/III	early treatment (FLT2)
SUVmax at FLT-3 Comparison Between Residual Cancer Burden (RCB) 0/I and RCB II/III	The Standard Uptake Values (max) after completion of NAC (FLT-3) were compared for Participants with Residual Cancer Burden 0/I vs Residual Cancer Burden of II/III While normally RCB (or other final determination) would be considered the outcome, since this is a predictive question, we will consider the mean of the uptake values the measurement of interest and report those values herein.	post-NAC (FLT-3)
Change in Uptake Between FLT1 and FLT3 to Predict Pathologic Complete Response (pCR) of the Primary Tumor	To evaluate the relationship between the change in uptake between FLT1 and FLT3 and pathologic complete response, an ROC curve will be estimated and the area under the curve (AUC), along with its 90% confidence interval, will be determined. For the purposes of reporting, we will consider the percent change in uptake between FLT1 and FLT3 to be the outcome. Reported values in the Outcome Measure table represent Change in uptake between FLT1 and FLT3, i.e., percentage change of SUVmax. The relationship between the change in uptake between FLT1 and FLT3 and pathological complete response was assessed by using ROC analysis. The Area Under the ROC Curve is reported in the Statistical Analysis section	Baseline (FLT-1) and post-NAC (FLT-3)
%Change SUVmax From FLT1-FLT2 to Predict Lymph Node Status at Surgery	Reported values in the Outcome Measure table represent %Change in uptake between FLT1 and FLT2, i.e., percentage change of SUVmax. The relationship between the change in uptake between FLT1 and FLT2 and lymph node (LN) status. For the purposes of reporting, the % Change in SUV will be considered the outcome.	Baseline (FLT-1) and Early Therapy (FLT-2)
%Change SUVmax From FLT1-FLT3 to Predict Lymph Node Status at Surgery	%change in SUVmax from FLT1-FLT3 will be compared by lymph node status at surgery For the purposes of reporting, %change in SUVmax from FLT1-FLT3 will be consider the outcome.	Baseline (FLT-1) and post-NAC (FLT-3)

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Lale Kostakoglu, American College of Radiology Imaging Network

Publications and helpful links

General Publications

• Kostakoglu L, Duan F, Idowu MO, Jolles PR, Bear HD, Muzi M, Cormack J, Muzi JP, Pryma DA, Specht JM, Hovanessian-Larsen L, Miliziano J, Mallett S, Shields AF, Mankoff DA; ACRIN 668 Investigative Team. A Phase II Study of 3'-Deoxy-3'-18F-Fluorothymidine PET in the Assessment of Early Response of Breast Cancer to Neoadjuvant Chemotherapy: Results from ACRIN 6688. J Nucl Med. 2015 Nov;56(11):1681-9. doi: 10.2967/jnumed.115.160663. Epub 2015 Sep 10.

Helpful Links

• A Phase II Study of [(18)F]-3'Deoxy-3'-Fluorothymidine Positron Emission Tomography (FLT-PET) in The Assessment of Early Response of Breast Cancer to Neoadjuvant Chemotherapy: Results From ACRIN 6688

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: December 11, 2007
• First Submitted That Met QC Criteria: December 11, 2007
• First Posted (Estimate): December 13, 2007

Study Record Updates

• Last Update Posted (Estimate): December 30, 2016
• Last Update Submitted That Met QC Criteria: December 28, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites; Alovudine; Dideoxynucleosides
• Other Study ID Numbers: NCI-2009-00266 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); ACRIN 6688 (Other Identifier: American College of Radiology Imaging Network); 8029 (Other Identifier: CTEP); N01CM27165 (Other Identifier: US NIH Grant/Contract Award Number)