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ACRIN 6688 PHASE II STUDY OF 3'-DEOXY-3'-18F FLUOROTHYMIDINE (FLT) IN INVASIVE BREAST CANCER Principal Investigator: Lale Kostakoglu, MD 9/30/10.

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Presentation on theme: "ACRIN 6688 PHASE II STUDY OF 3'-DEOXY-3'-18F FLUOROTHYMIDINE (FLT) IN INVASIVE BREAST CANCER Principal Investigator: Lale Kostakoglu, MD 9/30/10."— Presentation transcript:

1 ACRIN 6688 PHASE II STUDY OF 3'-DEOXY-3'-18F FLUOROTHYMIDINE (FLT) IN INVASIVE BREAST CANCER Principal Investigator: Lale Kostakoglu, MD 9/30/10

2  Recent advances in cancer treatment occurred in the development of disease specific molecular agents, many of which induce cell cycle arrest (cytostatic effect) inhibiting cell proliferation and tumor growth  Evaluating alterations in DNA metabolism may reflect therapy response better than changes in glucose utilization  FDG reflects tm proliferation only in part and associated with FPs due to tracer retention in inflammatory processes [F-18] FLT Background

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  FLT PET enables non-invasive imaging and quantification of the tm proliferative fraction in proportion to DNA synthesis rate  FLT PET can be used as an imaging probe to assess in vivo cellular proliferation in malignant tumors, especially with targeted drugs Buck AK, Methods 2009: 48:205 [F-18] FLT Background

4  Because of lower overall tm uptake and high bckg activity in the liver and bone marrow, FLT is not expected to have the same sensitivity as FDG for tumor detection across all organs  FLT-PET is considered a potentially powerful tool to  provide additional diagnostic specificity for proliferating tissues  Provide important biological info that could have implications in treatment selection or monitoring Salskov A, Semin Nucl Med 2007;37:429 [F-18] FLT Background

5 Preliminary Studies proliferation dependent accumulation of FLT The high cc’s observed between FLT uptake and Ki67 measurements implicate that cellular uptake of FLT is predominantly caused by proliferative activity Buck AK, Methods 2009: 48:205

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

7 SUVmax in CR/PRSUVmax in SD Kenny, EJNM 34:1339, 2007 FLT in BREAST CANCER Aim: a. determine FLT-PET response at 1 wk in pts treated with chemo b.determine the reproducibility of serial scans 17 discrete lesions in 13 stage II–IV breast ca pts Imaging prior to and at 1 wk after treatment with chemo Clinical response assessed 60 dys after commencing chemo 6 pts had a significant clinical response at day 60; these pts also had a significant reduction in FLT uptake at 1 wk Decrease in SUV at 1 wk discriminated btw clinical response and SD (p=0.02) FLT response generally preceded tm size changes

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

9 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). Shields, AF, Clin Cancer Res. 2008;14:4463 Kenny, EJNMMI 34:1339, 2007 Reproducibility of [18F]FLT Parameters

10 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

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

12 Primary Objective: To correlate the percentage change in SUVs between baseline (FLT-1) and early-therapy (FLT-2) with pCR (as a dichotoumous variable) to neoadjuvant chemotherapy of the primary tumor in patients with locally advanced breast cancer (LABC) Changed to early therapy from mid-therapy Study Objective

13 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 to neoadjuvant 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

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

15  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

16  There is no specific neoadjuvant chemo regimen required for this protocol  Several neoadjuvant therapy protocols are currently used at participating institutions and 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

17  Pathologically confirmed breast cancer, determined to be 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 1 st 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 m 2 for pts with cr levels above normal; Inclusion Criteria

18  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

19  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

20 Study Calendar <4 wks Pre- Study Pre- therapy Imaging (FLT-1) After 1 wk (5-10 dys) (FLT-2) Post- therapy Imaging (FLT-3) Surger y FLT PET/CT XXX Informed Consent X DemographicsX Medical History XX HeightXX WeightXXXXX PEX CBC w/diff, Plts X Serum Chemistry X AE Evaluation XXX

21 Visit 1: Screening visit -screening assessment will occur to determine eligibility -signed consent form will be obtained prior to study trial -CBC with differential and serum chemistry, and platelets. -If data available from clinical records in the appropriate time window, they need not be repeated for pre-study evaluation. -medical history, demographics, height, weight, and PE -tissue samples/slides from bx will be sent to VCU Pathology Visit 2: FLT PET Imaging Studies (FLT1) -baseline FLT PET scan; within 4 wks prior to chemo Visit 3: FLT PET Imaging Studies (FLT2) -early therapy FLT PET;5-10 dys after the initiation of 1 st cycle Visit 4: FLT PET Imaging Studies (FLT-3) -post therapy FLT PET;after chemo & within 3wks prior to surgery Visit 5: Surgery -After neoadjuvant chemo, surgical resection of residual tm -A portion of residual tm sample/slides will be sent for to VCU Core Pathology for pathologic analysis and proliferation assays within 2 wks post surgery - If no viable tumor remains, a pCR will be documented Study Procedures

22  The participant will undergo [ 18 F]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 for the is to obtain the dynamic PET imaging first, then 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/scheduling is limited, the acquisition of the SUV using static PET imaging starting 60 minutes after injection fulfills the needs of the study.  Analyses SUV 30 Patlak slope SUV 30-60 Flux FLT SUV 60 k 3 Imaging Sessions

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

24  pCR is defined as the absence of viable invasive tumor at histopathologic examination of the 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 other than pCR  A secondary related measure will also be assessed, the residual cancer burden (RCB) which will be used for secondary objectives (described in the protocol) Pathologic Complete Response

25  Clinical Response as per routine by the treating physician based upon the % change in anatomic tm size between the pre, early-, and post-treatment time points  The assessment of size will be made per routine of the treating physician and will typically be performed by one of the following: PE, mammography, US, or breast MRI  The same method should be used consistently for each patient throughout this study. The categorization of clinical response is categorized as described in Table Response Category Criteria Complete Response (CR): Disappearance of the primary tumor Partial Response (PR): At least a 30% decrease in the LD of primary tm, from baseline LD Progressive Disease (PD): At least a 20% increase in the LD of primary tm, taking as reference the smallest LD since treatment started Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor ncrease to qualify for PD Clinical Response

26 The ACRIN BDMC will monitor participant accrual Total target accrual is 54 participants in 18 mos During the 1 st year, accrual will be reviewed monthly with the intention of resolving any recruitment barriers Starting ~ 1 mo after a site is approved to begin enrollment, If a site’s actual accrual falls below 60% of what is reported in the PSA, the Protocol Support Enrollment Committee (PSEC), will determine a fu action plan to identify accrual barriers and develop strategies to support the site in meeting accrual goals The ACRIN Steering Committee regularly reviews the overall trial accrual and may request information about a trial’s accrual performance Accrual Goals

27 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 Accrual Goals

28  The accrual period for this protocol is 18 months  The number of subjects will be chosen to insure 80% power to test whether an FLT parameter (such as change from baseline to early treatment) is predictive of complete pathological response  More specifically, the sample size is based on testing whether the area under the ROC curve is different from 0.50  Assuming 25% success rate (75% failure rate), power of 80%, we would need n=80 if true area is 0.7, n=49 if true area is 0.75, n=33 if true area is 0.8 and n=23 if true area is 0.85.  As the true area under the ROC curve for FLT is expected to be at least 0.75, we believe that a sample of 49 participants would be sufficient for the primary analysis  Please note that with this number, the half length of 95% CI for the correlation estimation between FLT uptake parameters and Ki-67 score can be as small as 0.107 if the sample correlation is 0.80, and can be as small as 0.030 if the sample correlation is 0.95  After an additional 10% inflation to account for potentially incomplete data, we propose to enroll 54 participants into the study. Statistical Considerations

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

30 Opened Accrual Participating Institutions and Accrual Status University of Pennsylvania School of Medicine3/4/20101 Washington University Medical School7/28/20100 Thomas Jefferson University Hospital5/4/20102 University of Washington8/18/20100 Virginia Commonwealth University Health System9/14/20097 Scottsdale Medical Imaging, LTD7/28/20100 Milton S. Hershey Medical Center9/21/20100 Excel Diagnostics Imaging Clinics7/28/20101 Mount Sinai Medical Center4/27/20101 Fox Chase Cancer Center8/23/20100 University of Arkansas9/24/20100 Wake Forest University9/24/20100

31 THANK YOU!

32 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). Research Radiopharmaceutical

33  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=jsconvert3http://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

34 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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