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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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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


Virginia commonwealth university american college of radiology imaging network acrin 6688

Protocol Investigators

VCU Study ChairVCU Study Co-ChairVCU Study Co-Chair

Paul R Jolles, MDHarry D Bear, MD, PhDMichael O Idowu,MD,MPH

Dept Radiology Dept of Surgery Dept of Pathology

Richmond, VA Richmond, VA Richmond, VA

[email protected]@[email protected]

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

[email protected]@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

[email protected]@stat.brown.edu


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


Virginia commonwealth university american college of radiology imaging network acrin 6688

Preliminary Studies

Buck AK, Methods 2009: 48:205


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


Virginia commonwealth university american college of radiology imaging network acrin 6688

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).


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


Virginia commonwealth university american college of radiology imaging network acrin 6688

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

SUV60Patlak slope

SUV120FluxFLT

∆SUV30-60k3

Imaging Protocol

Imaging Sessions


Virginia commonwealth university american college of radiology imaging network acrin 6688

[18F]FLT Parameters Compared To

Pre-Rx (FLT-1) parametersKi-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) parametersKi-67/mit index, surgical

(absolute values and % change from FLT-1) Clinical Response

CT Response

Pathological Response (pCR and RCB)

Imaging Protocol

Imaging Sessions


Virginia commonwealth university american college of radiology imaging network acrin 6688

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


  • Virginia commonwealth university american college of radiology imaging network acrin 6688

    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


    Virginia commonwealth university american college of radiology imaging network acrin 6688

    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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