ACRIN Breast Committee

1. ACRIN Breast Committee Fall Meeting 2010 6688 PHASE II STUDY OF FLUORINE-18 3'-DEOXY-3'-FLUOROTHYMIDINE (F-18-FLT) IN INVASIVE BREAST CANCER Lale Kostakoglu, MD, MPH David Mankoff, MD, PhD Fenghai Duan, PhD ACRIN Breast Committee

2. FLT structural analog of thymidine Although FLT is not incorporated into DNA, it is trapped in the cell through phosphorylation by TK1 FLT PET enables non-invasive imaging and quantification of tm proliferative activity in proportion to DNA synthesis rate FLT PET can be used as an imaging probe to assess impact of therapy ontmcell proliferation, especially using targeted drugs [F-18] FLT Background Buck AK, Methods 2009: 48:205

3. VIRGINIA COMMONWEALTH UNIVERSITY AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK ACRIN 6688 (amendment 6) PHASE II STUDY OF 3'-DEOXY-3'-18F FLUOROTHYMIDINE (FLT) IN INVASIVE BREAST CANCER

4. Protocol Investigators VCU Study ChairVCU Study Co-ChairVCU Study Co-Chair Paul R Jolles, MD Harry D Bear, MD, PhD Michael O Idowu, MD Dept Radiology Dept of Surgery Dept of Pathology Richmond, VA Richmond, VA Richmond, VA prjolles@vcu.eduhdbear@vcu.edumidowu@mcvh-vcu.edu ACRIN Study Co-ChairACRIN Study Co-Chair David Mankoff, MD, PhD Lale Kostakoglu, MD, MPH Professor of Radiology Professor of Radiology Seattle Cancer Care Alliance Mount Sinai School of Medicine Seattle, WA New York, NY 10029 dam@u.washington.edulale.kostakoglu@mssm.edu VCU Study StatisticianACRIN Study Statistician Donna K McClish, PhD Fenghai Duan, PhD Department of Biostatistics Ctr for Statistical Sciences Richmond, VA 23298 Brown University mcclish@mail2.vcu.edufduan@stat.brown.edu

5. To correlate the % change in SUVs between baseline (FLT1) and early-therapy (FLT2) with pCR (as a dichotoumous variable) to neoadjuvant chemotherapy of the primary tumor in LABC (Changed to early therapy from mid-therapy) Primary Objective

6. Obtain post-treatment proliferative Indices Obtain pre-treatment proliferative Indices Establish Eligibility Baseline Imaging Early therapy Imaging Post-therapy Imaging Surgical Resection Chemotherapy cycle 1 • Baseline organ function • Pathologically confirmed disease • Determine primary systemic Rx Ki-67, mitotic index on bx sample or re-biopsy (if available) 18FLT PET/CT (FLT-1) 18FLT PET/CT (FLT-2) 18FLT PET/CT (FLT-3) • Pathologic response, • Ki-67, mitotic index, surg. specimens [F-18] FLT Study Outline Chemotherapy last cycle

7. evaluate correlation or relationship between, FLT1 and FLT3 uptake parameters and proliferation markers FLT1, FLT2 and FLT3 uptake parameters and pCR of the primary tm and residual cancer burden (RCB) FLT1, FLT2 and FLT3 uptake parameters and non-response of the primary tm (SD or prog) FLT1, FLT2 and FLT3 uptake parameters and pCR in pts with regional disease in the LNs compare changes of, FLT2 and FLT3 uptake parameters to changes in tm sizes from other serial imaging modalities (mammogram, MRI, and US, as available) FLT2 and FLT3 uptake parameters to metabolic changes from FDG PET, as available monitor for potential safety issues and define any physiologic effects associated with FLT administration Secondary Objectives

8. Three imaging sessions pre-treatment (FLT-1), after one cycle (FLT-2), at completion (FLT-3) FLT-1 (baseline PET) must be completed within 4 wks prior to chemo initiation FLT-2 (early PET) must be performed 5-10 dys after initiation of the first chemo cycle FLT-3 (post therapy PET) will be performed after the completion of chemo and within 3 wks prior to surgery Timing of FLT PET Studies

9. There is no specific neoadjuvant chemo regimen required for this protocol Subjects for the study may be recruited from prospective neoadjuvant chemo trials, which may also include targeted agents, such as trastuzumab However, patients on neoadjuvant protocols using hormonal therapy alone are not eligible Neoadjuvant Therapy

10. Pathologically confirmed BC, a candidate for neoadjuvant therapy and for surgical resection of residual primary tm after neoadjuvant therapy Tumor size >2cm, measured on imaging or estimated by PE No obvious contraindications for primary chemotherapy Residual tumor planned to be removed surgically following completion of neoadjuvant therapy Age >18 ECOG Performance Status ≤ 2 (Karnofsky ≥ 60%) Normal organ and marrow function at 1st visit: -leukocytes ≥ 3,000/μl; -absolute neutrophil count ≥ 1,500/μl; -platelets ≥ 100,000/μl; -total bilirubin within N institutional limits; -AST(SGOT)/ALT(SGPT) ≤2.5 times institutional upper limit of N -creatinine within normal institutional limits; OR creatinine clearance ≥30 mL/min/1.73 m2 for pts with cr levels above normal; Inclusion Criteria determined to be

11. Prior treatment (any) to the involved breast Uncontrolled intercurrent illness Medically unstable Unable to lie still for 1.5 hrs, requirement of anesthesia History of allergic reactions attributed to compounds of similar chemical or biologic composition to FLT Pregnant or nursing or age<18 Previous malignancy, other than basal cell or squamous cell carcinoma of the skin or in situ ca of the cervix, from which the patient has been disease free for < 5 years Currently on hormone therapy as a primary therapy (aside from hormonal replacement therapy) Exclusion Criteria

12. Study Calendar

13. The participant will undergo [18F]FLT injection, immediately after injection a dynamic regional PET/CT imaging will be done for 60 minutes dynamic imaging will be followed by a static whole body image from top of head to upper thigh; 5-7 bed positions The preferred imaging sequence is to obtain dynamic PET imaging first, followed by the torso survey using static PET imaging, however, for patients  who are unable to tolerate lying in the scanner for dynamic imaging or for centers where scanner availability is limited, SUVs using static PET imaging starting 60 minutes after injection fulfills the needs of the study Analyses SUV30Patlak slope SUV30-60 FluxFLT SUV60 k3 Imaging Sessions

14. FLT Parameters Compared To Pre-Rx (FLT1) parameters Ki-67/mit index, biopsy Clinical Response Path. Response (pCR and RCB) After one cycle (FL2) parameters Clinical Response (absolute and % change from FLT1) Response from other imaging modalities (as available) Path Response (pCR and RCB) Post-therapy (FLT3) parameters Ki-67/mit index, surg specimen (absolute and % change from FLT1) Clinical Response Response from other imaging modalities (as available) Path. Response (pCR and RCB) Data Analysis

15. Pathologic Complete Response • pCR defined as the absence of viable invasive tm at histopathologic exam of post-therapy surgical specimen • This analysis will be performed at the local treating site and reviewed at the central site at VCU • Presence of residual non-invasive cancer (DCIS) in the absence of viable invasive cancer is still considered a pCR • Dichotomous response assessment; pCR vs non pCR • A secondary related measure will also be assessed, the residual cancer burden (RCB) as a more continuous variable which will be used for secondary objectives http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3

16. Accrual Goals • Enrollment Target • 54 cases in 18 months • Initial Sites: MSSM, UPENN, UW, VCU • Site enrollment expectations: 60 - 70 % of what site reported on application • Trial enrollment expectations: min 3 pts per mo • The ACRIN Biostatistics and Data Management Center (BDMC) will monitor participant accrual

17. Accrual Plot and Current Accrual Rate Last three months: Average 2 pts/month Last 3 months: Avg 2 pts/month

18. Participating Institutions and Accrual Status Opened Accrual

19. Research Radiopharmaceutical FLT will be purchased from a commercial vendor. The vendor must be authorized within the NCI IND (so far Cardinal and PETNET designated). FLT can only be synthesized on site if the chemistry manufacturing and control procedures are filed within the NCI IND (University of Washington is the inly site).

20. THANK YOU!