ACRIN Breast Committee

Fall Meeting 20106688 PHASE II STUDY OF FLUORINE-18 3'-DEOXY-3'-FLUOROTHYMIDINE (F-18-FLT) IN

INVASIVE BREAST CANCERLale Kostakoglu, MD, MPH David Mankoff, MD, PhD

Fenghai Duan , PhD

ACRIN Breast Committee

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 on tm cell proliferation, especially using targeted drugs

Buck AK, Methods 2009: 48:205

[F-18] FLT Background

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

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

Obtain pre-treatment Obtain pre-treatment proliferative Indicesproliferative Indices

Establish EligibilityEstablish Eligibility

Baseline Imaging Baseline Imaging

Post-therapy Imaging Post-therapy Imaging

Surgical ResectionSurgical Resection

Chemotherapy cycle 1Chemotherapy cycle 1

• Baseline organ functionBaseline organ function• Pathologically confirmed diseasePathologically confirmed disease• Determine primary systemic Rx Determine primary systemic Rx

Ki-67, mitotic index on bx sample or Ki-67, mitotic index on bx sample or re-biopsy (if available)re-biopsy (if available)

1818FLT PET/CTFLT PET/CT(FLT-1)(FLT-1)

1818FLT PET/CTFLT PET/CT(FLT-3)(FLT-3)

1818FLT PET/CTFLT PET/CT(FLT-2)(FLT-2)

Obtain post-treatment Obtain post-treatment proliferative Indicesproliferative Indices

• Pathologic response, Pathologic response, • Ki-67, mitotic index, surg. specimensKi-67, mitotic index, surg. specimens

Early therapy Imaging Early therapy Imaging

Chemotherapy last cycle Chemotherapy last cycle

[F-18] FLT Study Outline

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

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

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 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

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

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

AnalysesSUV30 Patlak slope SUV30-60FluxFLT

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 and % change from FLT1)(absolute 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 specimenKi-67/mit index, surg specimen

(absolute and % change from FLT1) (absolute 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 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

Pathologic Complete Response

http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3

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

Accrual Goals

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 1

Virginia Commonwealth Univ. 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

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

THANK YOU!