ACRIN EISC VIRGINIA COMMONWEALTH UNIVERSITY AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK ACRIN 6688...
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Transcript of ACRIN EISC VIRGINIA COMMONWEALTH UNIVERSITY AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK ACRIN 6688...
ACRIN EISC
VIRGINIA COMMONWEALTH UNIVERSITYAMERICAN 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: 750184IND Number: 71,260
ACRIN EISC
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,MPHDept Radiology Dept of Surgery Dept of Pathology
Richmond, VA Richmond, VA Richmond, VA [email protected] [email protected] [email protected]
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 [email protected] [email protected]
VCU Study Statistician ACRIN Study Statistician Donna K McClish, PhD Fenghai Duan, PhDDepartment of Biostatistics Ctr for Statistical SciencesRichmond, VA 23298 Brown [email protected] [email protected]
ACRIN EISC
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
Buck AK, Methods 2009: 48:205
[F-18] FLT Background
ACRIN EISC
Buck AK, Methods 2009: 48:205
Preliminary Studies
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aggressive
lymphoma
Low grade
lymphoma
Ki-67 labeling index: >90%
Ki-67 labeling index: <
5%
Buck AK, Methods 2009: 48:205
Non-Invasive detection and grading of malignant lymphomausing FLT PET as surrogate marker of tumor proliferation
ACRIN EISC
BloodThe 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
ACRIN EISC 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
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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
ACRIN EISC
Obtain pre-treatment Proliferative Indices
Establish Eligibility
Baseline Imaging
Mid-therapy Imaging
Chemotherapy
Surgical Resection
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-3)
•18FLT PET/CT(FLT-2)
Obtain post-treatment Proliferative Indices
• Pathologic response, • Ki-67 and mitotic index, surgical specimens
Early therapy Imaging
Chemotherapy
[F-18] FLT Study Outline
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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 ProtocolTiming of FLT PET Studies
ACRIN EISC
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
ACRIN EISC
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
ACRIN EISC
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
ACRIN EISC
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
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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
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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
AnalysesSUV30 ∆SUV60-120
SUV60 Patlak slope SUV120 FluxFLT
∆SUV30-60 k3
Imaging ProtocolImaging Sessions
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[18F] FLT Parameters Compared To Pre-Rx (FLT-1) parameters Ki-67/mit index, biopsy
Clinical ResponseCT ResponsePathological 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
ResponseCT Response
Pathological Response (pCR and
RCB)
Imaging ProtocolImaging Sessions
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Participant Accrual
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
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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
ACRIN EISC
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