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VIRGINIA COMMONWEALTH UNIVERSITY AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK ACRIN 6688

VIRGINIA COMMONWEALTH UNIVERSITY AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK ACRIN 6688 PHASE II STUDY OF 3'-DEOXY-3'-18F FLUOROTHYMIDINE (FLT) IN INVASIVE BREAST CANCER Agent Name : 3'-deoxy-3'-[F-18] fluorothymidine Agent NSC Number: 750184 IND Number: 71,260. Protocol Investigators

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VIRGINIA COMMONWEALTH UNIVERSITY AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK ACRIN 6688

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  1. VIRGINIA COMMONWEALTH UNIVERSITY AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK ACRIN 6688 PHASE II STUDY OF 3'-DEOXY-3'-18F FLUOROTHYMIDINE (FLT) IN INVASIVE BREAST CANCER Agent Name: 3'-deoxy-3'-[F-18] fluorothymidine Agent NSC Number: 750184 IND Number: 71,260

  2. Protocol Investigators VCU Study ChairVCU Study Co-ChairVCU Study Co-Chair Paul R Jolles, MD Harry D Bear, MD, PhD Michael O Idowu,MD,MPH 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

  3. FLT is a structural analog of thymidine Although FLT is not incorporated into DNA, it is trapped in the cell due to phosphorylation by TK Recently developed disease specific molecular agents induce cell cycle arrest (cytostatic effect) rather than tumor cell death (cytotoxic effect) Evaluating alterations in DNA metabolism may reflect response to treatment better than alterations in glucose utilization FLT PET can be used as an imaging probe to assess in vivo cellular proliferation in malignant tumors [F-18] FLT Background Buck AK, Methods 2009: 48:205

  4. Preliminary Studies Buck AK, Methods 2009: 48:205

  5. Non-Invasive detection and grading of malignant lymphoma using FLT PET as surrogate marker of tumor proliferation aggressive lymphoma Ki-67 labeling index: >90% Ki-67 labeling index: < 5% Low grade lymphoma Buck AK, Methods 2009: 48:205

  6. Reproducibility of [18F]FLT Parameters Kenny, EJNMMI 34:1339, 2007 Shields, AF, Clin Cancer Res. 2008;14:4463 Blood The box plot shows the mean percent error (horizontal line within the box), the 25th and 75th percentiles (bottom and top of box, respectively), and the range (bottom and top horizontal bars on vertical whiskers).

  7. Pre Therapy Post Therapy 7 dys post- therapy RESPONSE in a patient with grade II lobular ca NO RESPONSE in a patient with grade II IDC 7 dys post- therapy Kenny, EJNMMI 34:1339, 2007

  8. Primary Objective: To correlate the percentage change in SUVs between baseline (FLT-1) and mid-therapy (FLT-3) with pathologic complete response (pCR) to neoadjuvant chemotherapy of the primary tumor in patients with locally advanced breast cancer (LABC) Study Objectives

  9. Obtain post-treatment Proliferative Indices Obtain pre-treatment Proliferative Indices Baseline Imaging Early therapy Imaging Establish Eligibility Mid-therapy Imaging Surgical Resection Chemotherapy Chemotherapy • Baseline organ function • Pathologically confirmed disease • Determine primary systemic Rx • Ki-67 and 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 and mitotic index, surgical specimens [F-18] FLT Study Outline Chemotherapy

  10. Three imaging sessions pre-treatment (FLT-1), after one cycle (FLT-2), at mid-treatment (FLT-3) FLT-1 PET must be completed within 3 wks prior to beginning chemo FLT-2 PET must be performed 5-10 dys after initiation of first chemo cycle FLT-3 must be performed halfway through the therapy protocol and at least 5 dys after completion of the last chemo prior to the mid-point, and prior to the first chemo cycle after the midpoint For example, in a protocol consisting of 4 cycles of therapy this will be after cycle 2 and before cycle 3 and in a protocol consisting of 6 cycles, this would be after 3 cycles therapy and before cycle 4. In a regimen where a change of chemotherapy is planned, for example a change from doxorubicin-based therapy to taxane-based therapy, the midpoint would occur after the completion of the first type of chemotherapy and before the administration of the second type of chemotherapy. Imaging Protocol Timing of FLT PET Studies

  11. Secondary Objectives: evaluate the relationship between FLT-1, FLT-2 and FLT-3 uptake parameters and pCR and residual cancer burden (RCB) evaluate the relationship between FLT-1, FLT-2 and FLT-3 uptake parameters and non-response (SD or Prog disease) demonstrate correlation between FLT-1, FLT-2 and FLT-3 uptake parameters and tumor proliferation markers continue to monitor for potential safety issues and define any physiologic effects associated with [18F] FLT Study Objectives

  12. Secondary Objectives (cont’d): evaluate the relationship between FLT-1, and FLT-3 uptake parameters and pCR to neoadjuvant chemotherapy in patients with regional disease in the LNs compare the changes of FLT-2 and FLT-3 uptake parameters to changes in tm sizes from other serial imaging modalities such as mammograms, MRI, and US, as available compare changes of FLT-2 and FLT-3 uptake parameters to metabolic changes from FDG-PET, as available Study Objectives

  13. Pathologically confirmed breast cancer, determined to be a candidate for neoadjuvant therapy and for surgical resection of residual primary tm after neoadjuvant therapy. This includes all patients with locally advanced breast cancer (Stage IIIB and some IIIA), all patients with Stage IIIC disease (supraclavicular node involvement), and patients for whom neoadjuvant therapy is indicated to make breast conservation surgery feasible. The last group would be expected to have a median tumor diameter of approximately 4 cm Tumor size >2cm, measured on imaging or estimated by PE No obvious contraindications for primary Residual tumor planned to be removed surgically following completion of neoadjuvant therapy Age >18 Inclusion Criteria

  14. ECOG Performance Status ≤ 2 (Karnofsky ≥ 60%) Normal organ and marrow function, pre-chemotherapy: -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; -creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal; Able to lie still for 1.5 hours If female, postmenopausal for a min of one year, OR surgically sterile, OR not pregnant, confirmed by ß-HCG blood test, and willing to use adequate contraception Able to understand and willing to sign a written informed consent document and a HIPAA authorization in accordance with institutional guidelines Inclusion Criteria, con’t

  15. Prior treatment (chemo, RT or surgery) to involved breast Uncontrolled intercurrent illness. 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; History of allergic reactions attributed to compounds of similar chemical or biologic composition to F-18 FLT Pregnant or nursing. Pregnant women are excluded from this study because the effects of [18F]FLT in pregnancy are not known. Breastfeeding should be discontinued if the mother receives [18F]FLT. 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 No hormonal therapy is allowed Inclusion Criteria

  16. 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 Analyses SUV30 ∆SUV60-120 SUV60 Patlak slope SUV120 FluxFLT ∆SUV30-60 k3 Imaging Protocol Imaging Sessions

  17. [18F]FLT Parameters Compared To Pre-Rx (FLT-1) parameters Ki-67/mit index, biopsy Clinical Response CT Response Pathological Response (pCR and RCB) After one cycle (FLT-2) parameters Clinical Response (absolute values and % change from FLT-1) CT Response Mid-therapy (FLT-3) parameters Ki-67/mit index, surgical (absolute values and % change from FLT-1) Clinical Response CT Response Pathological Response (pCR and RCB) Imaging Protocol Imaging Sessions

  18. ParticipantAccrual • Enrollment Target • 54 cases in 18 months • Initial Sites: MSSM, UPENN, UW, VCU • Site Target: total # of sites ~10 • Site enrollment expectations: 60 - 70 percent of what site reported on application • Trial enrollment expectations: min 3 patients per month • The ACRIN Biostatistics and Data Management Center (BDMC) will monitor participant accrual

  19. The presence of any invasive tumor cells will be considered negative for pathologic complete response Following will be performed at the Core Lab at VCU/Dept of Pathology Ki-67 (MIB-1 antibody) Immunohistochemical staining Mitotic index Routine Clinical Histopathology Calculation of Residual Cancer Burden pCR is a dichotomous, but tm response is a continuous variable with non-response ranging from very small residual tm to resistant tms with progressing disease size of the tumor bed cellularity of residual primary tumor percentage of DCIS component number of positive nodes size of macrometastasis This tool is available at http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3 Therefore, continuous measures of residual cancer burden (RCB) would be expected to be more predictive of clinical outcome than simple dichotomous classification as currently practiced. RCB determined from routine pathologic materials may be a significant predictor of distant relapse-free survival (98). Different parameters will be collected and submitted to the data collection center for calculation of RCB and will include: The Residual Cancer Burden calculation will use clinical information obtained from participating institutions and pathological analysis at VCU. As the calculation of RCB is dependent on the parameters provided by participating institutions, the Core Laboratory at Virginia Commonwealth University will calculate the RCB as long as the parameters needed for the calculation are present in the reports. Tissue Specimen Analysis

  20. Participants who, are unable to complete chemotherapy and undego primary tumor surgery will be excluded from the primary analysis. Those who are able to complete the study to midpoint can be included in secondary analysis regardless of outcome are unable to complete study to midpoint because of therapy toxicity or disease progression will be removed experience any serious adverse event from the FLT PET imaging procedure as listed in Section 9.0 will be removed from the study deviate from planned therapy for lack of response or tumor progression will be excluded from primary cohort analysis Criteria for Removal from the Study

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