Transcript ECOG-ACRIN Studies with Novel PET/CT Imaging

COG-ACRIN Studies with Novel PET/CT Imaging
David Mankoff
Division of Nuclear Medicine
Department of Radiology
University of Pennsylvania
Molecular Imaging to Guide Therapy:
Outline
• Guiding themes for novel PET/CT trials
• Highlight of completed, active, and develpng
trials
• Tools for trials with novel PET/CT imaging
Anatomic versus Functional Imaging
• Anatomic Imaging
• Relies on tumor size, shape, density
• e.g., mammography, CT
• Measures response by changes in size
• Functional/molecular imaging
• Relies on in vivo tumor biology: perfusion,
metabolism, molecular features
• e.g., MRI, PET
• Measures response by changes in
functional/molecular processes
Imaging Modalities Used for Cancer
Anatomic
Functional
and
Molecular
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Computed Tomography (CT)
Ultrasound
Magnetic Resonance Imaging (MRI)
Optical Imaging
Magnetic Resonance Spectroscopy (MRS)
Radionuclide imaging
• Positron Emission Tomography (PET)
• Single-Photon Emission Computed
Tomography (SPECT)
PET/CT
Combines Molecular and Anatomical Imaging
(Alessio, Rad Clin N Amer, 2005)
Imaging and Cancer Therapy
Novel Approaches to Biomarker Imaging
• Choosing the right patients
• Is the therapeutic target present?
• Choosing the right drug
• Does the drug reach the target?
• Getting the right result
• Is there a pharmacodynamic response?
• Predicting the outcome
• Will response lead to better patient survival?
ACRIN Experimental Imaging
Sciences Committee (EISC)
ECOG-ACRIN EISC Trials
active or completed:
 ACRIN 6682 - 64Cu-ATSM PET and cervical hypoxia
 ACRIN 6684 - 18F-FMISO PET and brain tumor hypoxia
 ACRIN 6687 - 18F- PET and prostate bone metastasis response
 ACRIN 6688 - 18F-FLT and breast cancer response
 ACRIN 6691 – Optical imaging of breast cancer response
 ACRIN 6701 - DCE-MRI test/re-test in prostate cancer
opening:
 EAI141 – FLT PET/CT to measure AML response
 EAI142 – FES PET/CT to predict breast cancer response
Hypoxia as An Imaging Biomarker for
Cancer: ACRIN 6682 and 6684
• Why hypoxia?
• Promotes an aggressive phenotype –with accelerated
angiogenesis and glucose metabolism, and enhanced
survival
• An established resistance factor for radiotherapy
• An emerging target for systemic therapy
• Two tracers tested
• 18F-fluoromisonidazole – best tested and vlaidated
• 60Cu-ATSM – alternative approach; does not require
cyclotron
Imaging to Direct Hypoxia-Specific Treatment
Rischin J Clin Oncol 24:298, 2006
• Advanced H & N Ca
• Randomized to
• XRT + Cisplatin/5-FU
• XRT + Cisplatin/Tirapazamine (TPZ)
• FMISO PET (observational only)
FDG PET
FMISO PET
Time-toLocoregional Failure
FMISO+/TPZ
FMISO+/5FU
ACRIN 6682
Phase II Trial of 64Cu-ATSM PET/CT in
Cervical Cancer
Principal Investigator: Farrokh Dehdashti, MD
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22 Sep 2011
Background
• Tumor hypoxia is an important prognostic
factor in cervical cancer and predicts for
decreased overall and disease-free survival
• Hypoxic-measuring tools are needed:
– To predict patient outcome
– To select hypoxia-specific interventions on an
individual basis
– To evaluate response to hypoxia-specific
interventions
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22 Sep 2011
ACRIN EISC
Measurement of Hypoxia with 60Cuand 64Cu-ATSM-PET
CT
60Cu-ATSM-PET
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22 Sep 2011
FDG-PET
64Cu-ATSM-PET
ACRIN 6682 Schema
Pre-therapy clinical whole-body FDG-PET/CT
Stages IB2 –IVA invasive squamous cell carcinoma, scheduled to undergo
radiation therapy and concurrent cisplatin chemotherapy
Pre-therapy pelvic 64Cu-ATSM-PET/CT and analysis of tumor biopsy
for hypoxic markers
Concurrent chemoradiotherapy
Clinical FDG-PET/CT three (3) months after completion of therapy
Clinical follow-up for detection of recurrence and/or death
N=100, enrollment period=18 months
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22 Sep 2011
University of Washington
KA Krohn
FMISO PET Predicts outcome for GBM Patients
Spence, Clin Cancer Res 14:2623, 2008
MRI
FMISO PET
Hypoxic
(FMISO not hot)
Not
Hypoxic
(FMISO hot)
University of Washington
Multi-Center Trial of FMISO PET and MRI in
Glioblastoma – ACRIN 6684
Single-Center
Results
(Spence, Clin Cancer Res
14:2623, 2008)
Multi-Center Results
FMISO PET
MRI
ECOG-ACRIN EISC Trials
active or completed:
 ACRIN 6682 - 64Cu-ATSM PET and cervical hypoxia
 ACRIN 6684 - 18F-FMISO PET and brain tumor hypoxia
 ACRIN 6687 - 18F- PET and prostate bone metastasis response
 ACRIN 6688 - 18F-FLT and breast cancer response
 ACRIN 6691 – Optical imaging of breast cancer response
 ACRIN 6701 - DCE-MRI test/re-test in prostate cancer
opening:
 EAI141 – FLT PET/CT to measure AML response
 EAI142 – FES PET/CT to predict breast cancer response
2013 ASCO Annual Meeting – Oral Abstract Session:
Genitourinary (Prostate) Cancer – Abstract 5003
18F-fluoride
PET response to dasatinib in castrationresistant prostate cancer bone metastases correlates with
progression-free survival: Preliminary results from ACRIN
6687
Evan Y. Yu, Fenghai Duan, Mark Muzi, Jeremy Gorelick, Bennett B. Chin,
Joshi J. Alumkal, Mary-Ellen Taplin, Ben Herman, Celestia S. Higano,
Robert K. Doot, Donna Hartfeil, Philip G. Febbo, David A. Mankoff
Fluoride PET/CT & Bone Metastasis
Emission Image
Emission, CT, and Fused
Genomic guided therapy with 18F-Fluoride PET imaging
as a pharmacodynamic biomarker
18F-Fluoride
18F-Fluoride
PET
PET
ACRIN 6687 and DOD PCCTC collaboration
• Metastatic,
Castration
Resistant Prostate
Cancer
• Evidence of
disease
progression
• Disease
Amenable to
Biopsy
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Nilutamide
150 mg PO QD
Dasatinib
100 mg PO QD
18F-Fluoride
PET
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18F-Fluoride
Add
Dasatinib
100 mg PO QD
Add Nilutamide
150 mg PO QD
PET
P
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Univariate analysis with PCWG2 PFS
Predictor
Baseline or Δ
response to
dasatinib
HR/OR (95% CI)
P-Value
Gleason*
Baseline
1.121 (0.667-1.885)
0.6655
PSA
Baseline
Δ
UNTX
Baseline
Δ
1.002 (1.000-1.005)
1.001 (0.999-1.002)
1.007 (1.001-1.013)
0.999 (0.980-1.019)
0.0330
0.5242
0.0278
0.9369
BAP
Baseline
Δ
1.004 (0.999-1.008)
1.011 (0.994-1.028)
0.0918
0.2184
SUVmax
Baseline
Δ
1.006 (0.969-1.045)
0.905 (0.816-1.002)
0.7442
0.0558
Flux (Ki)
Baseline
Δ
46.790 (0.120-18,245.43)
<0.001 (<0.001-0.761)
0.2064
0.0472
Transport (K1)
Baseline
Δ
1.396 (0.091-21.416)
0.068 (<0.001-2,192.577)
0.8107
0.6116
*Focus
of this abstract is PFS, but Gleason had statistically significant correlation with time to SRE and OS
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ECOG-ACRIN EISC Trials
active or completed:
 ACRIN 6682 - 64Cu-ATSM PET and cervical hypoxia
 ACRIN 6684 - 18F-FMISO PET and brain tumor hypoxia
 ACRIN 6687 - 18F- PET and prostate bone metastasis response
 ACRIN 6688 - 18F-FLT and breast cancer response
 ACRIN 6691 – Optical imaging of breast cancer response
 ACRIN 6701 - DCE-MRI test/re-test in prostate cancer
opening:
 EAI141 – FLT PET/CT to measure AML response
 EAI142 – FES PET/CT to predict breast cancer response
Biologic Events in Response to
Successful Cancer Therapy
Rationale for Measuring Early Response by Cell
Proliferation Imaging
Rx
Cellular Proliferation
DNA Synthesis
or
Cell Death
Viable Cell Number
Tumor size
ACRIN 6688: Phase II Study of FLT-PET in Invasive
Breast Cancer
PI: Lale Kostakoglu, MD
May, 2014
ECOG-ACRIN Group Meeting, Chicago, IL
ACRIN 6688 Study Outline
Establish Eligibility
Obtain pre-treatment
proliferative Indices
*
Baseline Imaging
• Baseline organ function
• Pathologically confirmed disease
• Determine primary systemic Rx
Ki-67, mitotic index on bx sample or re-biopsy (if
available)
18FLT
PET/CT
(FLT-1)
Chemotherapy cycle 1
*
Early therapy Imaging
18FLT
PET/CT
(FLT-2)
18FLT
PET/CT
(FLT-3)
Chemotherapy last cycle
Post-therapy Imaging
Surgical Resection
Obtain post-treatment proliferative
Indices
• Pathologic response,
• Ki-67, mitotic index, surg. specimens
ACRIN 6688: FLT PET to Measure Early Breast Cancer
Response (PI: Lale Kostakoglu)
PreTherapy
7 d Post-
Best ΔSUVmax cut-off for predicting pCR = -51% (sensitivity
56%;specificity 79%).
(Kostakoglu, J Nucl Med, 2015)
ECOG-ACRIN EISC Trials
active or completed:
 ACRIN 6682 - 64Cu-ATSM PET and cervical hypoxia
 ACRIN 6684 - 18F-FMISO PET and brain tumor hypoxia
 ACRIN 6687 - 18F- PET and prostate bone metastasis response
 ACRIN 6688 - 18F-FLT and breast cancer response
 ACRIN 6691 – Optical imaging of breast cancer response
 ACRIN 6701 - DCE-MRI test/re-test in prostate cancer
opening:
 EAI141 – FLT PET/CT to measure AML response
 EAI142 – FES PET/CT to predict breast cancer response
EAI141: EARLY ASSESSMENT OF TREATMENT
RESPONSE IN AML USING [18F]FLT PET/CT
IMAGING
Robert Jeraj, Ryan Mattison,
Lale Kostakoglu, Elisabeth Paietta,
David Mankoff (EISC), Mark Litzov (Leukemia),
Fenghai Duan (Statistics)
[email protected]
FLT PET as a response biomarker
Post-therapy
(2 wks)
Pre-therapy
Chemo
CLINICAL
OUTCOME
(6 mo)
Complete
remission
FLT PET
SUV
10
Chemo
5
0
Resistant
disease
Vanderhoek et al 2011, Leuk Res 35: 310
SUV
10
5
Day 2
Day 4
Resistant Disease
Complete Remission
High NPV of FLT PET for predicting CR
Day 5
Day 6
Post
0
SUVmean
SUVmax
Coefficient
of Variation
Complete
Remission
0.81 ± 0.03
3.6 ± 0.4
0.33 ± 0.02
Resistant
Disease
1.6 ± 0.1
11.4 ± 0.8
0.71 ± 0.04
t-test: p<0.001 for SUVmean, SUVmax, CV
Day 2
Post
Vanderhoek et al 2011, Leuk Res 35: 310
EAI141 clinical trial
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2.
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4.
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Baseline Imaging
(optional)1
[F-18] FLT PET/CT
C
H
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Nadir
Bone Marrow3
&
Post-Treatment Imaging2
[F-18] FLT PET/CT
Remission Bone
Marrow4
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Optional Imaging must be done 1 week prior to initiation of therapy.
Post-Treatment Imaging must be completed 10-17 days after initiation of first induction cycle and prior to reinduction.
Nadir Bone Marrow should be completed 7-10 days after completion of induction therapy.
Remission Bone Marrow should be completed 28-35 days after initiation of first induction therapy. Will be used to
determine pathologic response.
ECOG-ACRIN EISC Trials
active or completed:
 ACRIN 6682 - 64Cu-ATSM PET and cervical hypoxia
 ACRIN 6684 - 18F-FMISO PET and brain tumor hypoxia
 ACRIN 6687 - 18F- PET and prostate bone metastasis response
 ACRIN 6688 - 18F-FLT and breast cancer response
 ACRIN 6691 – Optical imaging of breast cancer response
 ACRIN 6701 - DCE-MRI test/re-test in prostate cancer
opening:
 EAI141 – FLT PET/CT to measure AML response
 EAI142 – FES PET/CT to predict breast cancer response
Targeted Breast Cancer Therapy:
The Estrogen Receptor (ER) and Endocrine Treatment
Endocrine Therapy
Response Rate:
ER -
< 5%
ER +
50% - 75%
(Johnson and Dowsett, Nar Rev
Cancer 3:821, 2002)
[F-18]-Fluoroestradiol (FES):
PET Estrogen Receptor (ER) Imaging
FES
Estradiol
OH
OH
*
F
HO
HO
Relative Binding
(FES vs Estradiol)
ER
SHBG
0.9
0.2 - 0.8
(Kieswetter, J Nucl Med, 1984)
Validation: ER+ vs ER- Tumors
FDG
coronal
FES
axial
ERLiver
ER+
Glucose Metabolism
ER Expression
FES Uptake Predicts Breast Cancer
Response to Hormonal Therapy
Example 1
Pre-Rx
Post-Rx
• Recurrent
sternal lesion
• ER+ primary
Excellent
response
• Recurrent Dz
strongly FES+
after 6 wks
Letrozole
Example 2
FES
• Newly Dx’d
met breast CA
• ER+ primary
• FES-negative
bone mets
University of Washington
FDG
FDG
No response
to several
different
hormonal Rx’s
(Linden, J Clin Onc, 2006)
ECOG-ACRIN Biomarker Trial of FES PET: EAI142
Dehdashti & Linden
FES PET
MBC from ER+
Primary
Primary Aim
FDG PET
Endocrine Therapy
Validation Aim
Biopsy
Response
PFS
3, 6 month
assessment
• First line therapy
• Stand-alone imaging trial:
– Clinical indication for endocrine therapy
– Standard Rx allowed (AI, FUL, TAM)
– Allow measurable and non-measurable disease
Group Meeting • Nov 14-16, 2013
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Clinical Trials and Novel Imaging:
How are Novel PET Probes Supplied and Tested?
• Compound Development and Regulatory Authority
• NCI Cancer Imaging Program, public domain
• INDs for Fluoride, FLT, FMISO, FES
• Industry compounds – hold IP and IND
• Academic centers – Physician held INDs
• Probe supply
• Commercial regional cyclotron suppliers
• Academic Centers
• Support for multi-center clinical trials
• NCI – Phase I/II program
• NCI Clinical Trials
• Networks – e.g., SNM Clinical Trials Network
NCI Quantitative Imaging Network (QIN)
 Develop quantitative imaging (QI) methods that are automated,
platform independent and reproducible to use in therapy trials
 Share, test, refine, validate, and finally evaluate these methods in
therapy trials using four working groups organized across all sites
1
Image Data
Collection &
Variance
Studies
2:
Data
Analysis &
Software
Tool
Validation
3.
Informatic
s&
Data
Sharing
TCIA
Link to a
Clinical Trial
4.
Clinical
Trial Design
&
Developmen
t
Annotated image databases
with metadata & outcomes
Developmen
t
Tool Validation
QIN
(courtesy of Larry Clarke)
Goal: Consensus on data collection /analysis &
Technical resource for clinical trials
Thank you!