ACRIN 6688

PHASE II STUDY OF 3'-DEOXY-3'-18F FLUOROTHYMIDINE (FLT) IN INVASIVE BREAST

CANCER

Principal Investigator: Lale Kostakoglu, MD

9/30/10

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

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

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

Preliminary Studiesproliferation 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

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

SUVmax in CR/PR SUVmax 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

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

7 dys post- therapy

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

VIRGINIA COMMONWEALTH UNIVERSITYAMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK

ACRIN 6688 (amendment 6)

PHASE II STUDY OF 3'-DEOXY-3'-18F FLUOROTHYMIDINE (FLT) IN INVASIVE BREAST CANCER

Protocol Investigators

VCU Study Chair VCU Study Co-Chair VCU Study Co-ChairPaul R Jolles, MD Harry D Bear, MD, PhD Michael O Idowu, MD Dept Radiology Dept of Surgery Dept of PathologyRichmond, VA Richmond, VA Richmond, VA prjolles@vcu.edu hdbear@vcu.edu midowu@mcvh-vcu.edu

ACRIN Study Co-Chair ACRIN Study Co-ChairDavid Mankoff, MD, PhD Lale Kostakoglu, MD, MPHProfessor of Radiology Professor of Radiology Seattle Cancer Care Alliance Mount Sinai School of Medicine Seattle, WA New York, NY 10029dam@u.washington.edu lale.kostakoglu@mssm.edu

VCU Study Statistician ACRIN Study Statistician Donna K McClish, PhD Fenghai Duan, PhDDepartment of Biostatistics Ctr for Statistical SciencesRichmond, VA 23298 Brown Universitymcclish@mail2.vcu.edu fduan@stat.brown.edu

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

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

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)

18FLT PET/CT(FLT-1)

18FLT PET/CT(FLT-3)

18FLT 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

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

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

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 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

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

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

Study Calendar

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 1st 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

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 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.

AnalysesSUV30 Patlak slope SUV30-60 FluxFLT

SUV60 k3

Imaging Sessions

FLT Parameters FLT Parameters Compared ToCompared To

Pre-Rx (FLT1) parametersPre-Rx (FLT1) parameters Ki-67/mit index, biopsyKi-67/mit index, biopsy

Clinical ResponseClinical Response

Path. Response (pCR and RCB)Path. Response (pCR and RCB)

After one cycle (FL2) parameters After one cycle (FL2) parameters Clinical ResponseClinical Response

(absolute values and % change from FLT1)(absolute values and % change from FLT1)Response from other imaging Response from other imaging modalities (as available)modalities (as available)

Path Response (pCR and RCB)Path Response (pCR and RCB)

Post-therapy (FLT3) parametersPost-therapy (FLT3) parameters Ki-67/mit index, surg specKi-67/mit index, surg spec

(absolute values and % change from FLT1) (absolute values and % change from FLT1) Clinical ResponseClinical Response

Response from other imaging Response from other imaging modalities (as available)modalities (as available)

Path. Response (pCR and RCB)Path. Response (pCR and RCB)

Data Analysis

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

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 CategoryResponse Category CriteriaCriteria

Complete Response (CR):Complete Response (CR): Disappearance of the primary tumorDisappearance of the primary tumor

Partial Response (PR):Partial Response (PR): At least a 30% decrease in the LD of primary tm, from baseline At least a 30% decrease in the LD of primary tm, from baseline LDLD

Progressive Disease (PD):Progressive Disease (PD): At least a 20% increase in the LD of primary tm, taking as At least a 20% increase in the LD of primary tm, taking as reference the smallest LD since treatment started reference the smallest LD since treatment started

Stable Disease (SD):Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor ncrease to Neither sufficient shrinkage to qualify for PR nor ncrease to qualify for PDqualify for PD

Clinical Response

Accrual Plot and Current Accrual Rate

Last 3 months:Avg 2 pts/month

0

2

4

6

8

10

12

Total Number

Number of Sites Openfor Enrollment

Number of SitesAccruing Patients

Study Accrual duringYear

Number of Sites Open for Enrollment 1 1 1 2 3 4 4 7 9 12 12

Number of Sites Accruing Patients 1 1 1 1 1 1 1 3 5 5 5

Study Accrual during Year 1 1 0 2 0 0 0 3 3 0 10

Nov. 2009

Jan. 2010

Feb. 2010

Mar. 2010

Apr. 2010

May. 2010

Jun. 2010

Jul. 2010

Aug. 2010

Sep. 2010

Total

Last three months:Average 2 pts/month

Opened Accrual

Participating Institutions and Accrual Status

University of Pennsylvania School of Medicine 3/4/2010 1

Washington University Medical School 7/28/2010 0

Thomas Jefferson University Hospital 5/4/2010 2

University of Washington 8/18/2010 0

Virginia Commonwealth University Health System 9/14/2009 7

Scottsdale Medical Imaging, LTD 7/28/2010 0

Milton S. Hershey Medical Center 9/21/2010 0

Excel Diagnostics Imaging Clinics 7/28/2010 1

Mount Sinai Medical Center 4/27/2010 1

Fox Chase Cancer Center 8/23/2010 0

University of Arkansas 9/24/2010 0

Wake Forest University 9/24/2010 0

THANK YOU!