Lung Cancer Workshop VII

Application of High Resolution

CT Imaging Data to
Lung Cancer Drug Development:
Measuring Progress
 Evolution of Response Workshop

• Workshop I- Washington DC
• Workshop II- Annapolis, MD
• Workshop III- Bethesda, MD
• Workshop IV- Oak Brook, IL
• Workshop V- Oak Brook, IL
• Workshop VI- Bethesda, MD
• WorkshopVII- Bethesda, MD

Prevention Cancer Foundation vision in 2004 to accelerate

drug development for early lung cancer

www.preventcancer.org
©2006 RUSH University Medical Center
 SPECIAL THANKS TO

B E N E F A C T O R S:

Amgen
Genentech
Novartis
 SPECIAL THANKS TO

S P O N S O R:
Rush University Medical Center

TECHNICAL
C O - S P O N S O R:
Optical Society of America
(OSA)
 AND A SPECIAL THANKS ALSO GOES TO THE

WORKSHOP SPONSOR
Carolyn R. “Bo” Aldigé
Prevent Cancer Foundation

STEERING COMMITTEE
Chair:
• James L. “Jim” Mulshine
Rush University Medical School

Members:
• Ricardo S. “Rick” Avila • Raul San Jose Estepar
Kitware, Inc. Brigham and Women’s Hospital

• Thomas M. “Tom” Baer • David F. Yankelevitz

Stanford Photonics Research Center Mount Sinai Medical Center
 Special Note

This pre-competitive Research Workshop

is supported by unrestricted grants to
Prevent Cancer Foundation: No products
are being endorsed in this forum

©2006 RUSH University Medical Center

Measuring Progress 6 Workshops since 2004
1 Interim COPD Meeting
Interim
Meetings
Annual PCF/Cornell Database
QIBA Workshop NCIA
FDA Give-A-Scan
NIST

Standards & Large Open Image

FDA Approval Databases
Accelerate
Development of
Therapy
Assessment
Methods
Algorithms &
Reproducibility
Reference
& Comparison
Methods

Early Clinical Trials Open Source

NIST BioChange Publications Lesion Sizing Toolkit
Volcano
Oncology Workshop Reports
Quantitative CT Monograph
ISP Oncology Special Issue
  Workshop Accomplishments
• Neoadjuvant window of
opportunity trial performed
in resectable NSCLC
patients
• Drug given daily for~3 wks
• High Resolution CT done
before & after drug
exposure prior to lung CA
resection
• Endpoint frequency of
tumor shrinkage by
volumetric CT
• Image results compared to
molecular/pathological
outcomes
N Altorki et al, ASCO, 2008
©2006 RUSH University Medical Center
 Publications from Workshops

• Mulshine JL et al. Oncology, 20:1608-10, 2006

• Baer TM, Mulshine JL, Jacobs JJ, Skeletal Radiol, 36:799-801, 2007
• Mulshine JL and Baer T. (Editors) Quantitative Imaging Tools for
Lung Cancer Drug Assessment. Wiley Press, NY, 2008
• Mulshine JL et al. Oncology, 23, 2009

• Nikolinakos et al. Plasma cytokine and angiogenic factor

profiling identifies markers associated with tumor shrinkage in
early-stage non-small cell lung cancer patients treated with
pazopanib. Cancer Res. 2010 Mar 15;70(6):2171-9. Epub 2010
Mar 9.

• Workshop VI-Optic Express Special Interactive Scientific

Publishing Supplement Planned

©2006 RUSH University Medical Center

 Optic Express Special Issue

• Medical Optics and

Biotechnology
• RECIST versus volume measurement in medical CT using
ellipsoids of known size
• Abstract
•  | Full Text: PDF (162 KB)
• | Browse Datasets: MIDAS
•
• Optics Express, Vol. 18, Issue 8, pp. 8151-8159
• Zachary H. Levine, Bruce R. Borchardt, Nolan J.
Brandenburg, Charles W. Clark, Bala Muralikrishnan, Craig
M. Shakarji, Joseph J. Chen, and Eliot L. Siegel
• Full-Text PDF contains links to datasets. See ISP homepage
for software requirements and other information.

http://www.opticsinfobase.org/oe/virtual_issue.cfm?vid=105

©2006 RUSH University Medical Center

Kitware Open-source Lesion Sizing Toolkit

Rick Avila
Luis Ibanez
Karthik Krishnan
Wesley Turner

http://public.kitware.com/LesionSizingKit/
 Impact of Tobacco-CDC Analysis

• Tobacco use causes more deaths

each year than alcohol use, car
crashes, suicide, acquired
immunodeficiency syndrome (AIDS),
homicide, and illegal drug use
combined
• In addition, smoking accounts for
$167 billion annually in health care
expenditures and productivity losses
CDC. Annual smoking-attributable mortality, years of potential life
lost, and productivity losses---US, 1997--2001. MMWR 2005;54:625--8.

©2006 RUSH University Medical Center

Lung Cancer & Tobacco Mortality

©2006 RUSH University Medical Center

 New Research Directions

The chronic deposition

of tobacco particulates
includes a number of
carcinogens & toxins;
their presence in the
distal airway drives
pathogenesis of lung
CA and COPD

©2006 RUSH University Medical Center

 Volumetric CT:
A Potential Biomarker of Response

1 December 2008

Andrew Buckler
Director, Cross-Modality Imaging Systems, Philips
Healthcare
Chair, Volumetric CT Team, Quantitative Imaging Biomarker
3 October 2008 15
Alliance
 Optimal Integration of Quantitative Imaging

Tools for quantitative imaging vary in

precision from RECIST to volumetrics
(or perhaps even a more sensitive
signature in the future). Need to
understand the trial design when a ruler
(RECIST) is sufficient or when the
additional measurement precision is
enabling. This is likely to involve the
evolution to new trial designs.

©2006 RUSH University Medical Center

 Preop Treatment with Pazopanib

• New trial design

evaluating drug effect
in early lung CA
• Pazopanib, a GSK,
dual kinase, VEGF
inhibitor with activity
in lung CA
• Pazopanib will now
be evaluated in
RCT of adjuvant
RX
N Altorki, Proc ASCO, 2008 Waterfall plot showing tumor volume growth
quantitated from CT scans for all study patients

©2006 RUSH University Medical Center

 New Model for Lung CA Development

• Evaluate relevant target with good

safety profile in Phase I trial
• Move to Neoadjuvant Window Trial
• Move to Adjuvant Trial
• Move to Chemoprevention Trial

Time to Market??—Under 7years

©2006 RUSH University Medical Center

Rationale for Aerosol Delivery to Manage
Early, Airway-Confined Lung CA

Carcinogen Medicine
 Where do the therapeutic
aerosol deposit in the lung?
 Focus from Six to Seventh Workshop

Make drug development clinical trials

• Faster (Window trials—quantitative
endpoint);Cheaper (Adaptive Bayesian Design, two
to three weeks of drug exposure);Better (Phantom
calibration, standardize method, open source
reference tools, defined molecular targets, tailored
delivery systems)
• Tighter (variance), lighter (dose),
standardized (protocol/profile)

©2006 RUSH University Medical Center

 Clinical Issues: Quantitative Imaging
Chairs: D Yankelevitz, N Altorki

• 1) How do we build on the precedent of the Pazopanib neoadjuvant window trial and
the Abigail trials to advance the integration of quantitative imaging in lung cancer drug
development efforts?
• 2) What did we learn about the rigorous efforts of Merck to incorporate quantitation in
advance stage lung cancer trials? What is the next step in this regard?
• 3) How does the clinical community support the evolution of the use of imaging as a
response biomarker to allow the evolution of more efficient drug evaluation?
• 4) Is it time to require an imaging section of each clinical trial protocol to define the
process for imaging acquisition, quality control and study interpretation in an analogous
fashion to how a statistical section of a protocol would be developed?
• 5) How do we effect a change in clinical trial reporting to mandate the supplemental
submission of primary imaging data as would be expected with primary molecular
diagnostic data?
• 6) How do we communicate to the clinical community information about quantitative
imaging validation and ensure that knowledge about the correct application of this
emerging tool moves from drug trials to clinical care in a robust fashion?
• 7) How do we encourage the development of a national image management resource
to manage the number of clinical images and associated meta data that will be produced
by lung cancer clinical trials. In a related view, how do we create an imaging infrastructure
to routinely capture lung images with associated meta data from any source that could be
used to enable the development of more effective lung cancer-directed quantitative
imaging tools?

©2006 RUSH University Medical Center

 Breakout A: Image Software & Infrastructure

Chairs: R Avila, T Baer, G Zahlmann, A Buckler

• Open Image Archives There remains an unmet need for high quality and open lung cancer
image dataset collections with associated metadata...
• Question 1: Pharmaceutical companies regularly collect very high quality imaging datasets
under strictly controlled study conditions. As a community, we have long recognized that
making some of this data publicly available could result in a dramatic increase in the size
and quality of publicly available datasets. What specific steps can we make to encourage
and facilitate pharmaceutical companies to contribute subsets of clinical trial datasets to
open image archives?
• Question 2: A large number of researchers are performing clinical as well as phantom
studies. What can we do to encourage these groups to contribute this data to open image
archives?
• Question 3: The Give-A-Scan pilot project demonstrated the potential for patients to donate
lung cancer imaging datasets. What steps should be taken to improve upon this pilot study?
• Image Analysis Software Resources
• Question 4: What needs to be done to improve upon the lesion sizing toolkit and support
more research groups and activities?
• Question 5: How do we establish increased collaboration and software sharing between
lung cancer and COPD research communities?
• Imaging Infrastructure
• Benchmarks and Evaluation
• Question 6: How can we improve upon these benchmark activities to obtain more valuable
information on the performance of different algorithms and systems?

©2006 RUSH University Medical Center

 Outcomes?

• Plan to integrate phantoms into studies

• Extend open publication of imaging files for
quantitative imaging studies such as with ISP
• Support Advocate initiative to assemble give a scan
• Refine imaging profiles based on available lessons
learned from early trials
• Vision for national image management architecture?
• Strategies to extend participation in quantitative
imaging to other stakeholders

©2006 RUSH University Medical Center

 Kudos To Our Supporters

• Bo Aldige as leader of the Prevent Cancer

Foundation has supported this forum for seven years
through a large number of unrestricted corporate
grants including the cost of an imaging database at
Cornell
• The Optical Society of America with T Baer and L
Rogan has supported the development of a
monograph, the lesion sizing tool kit, ISP
infrastructure and the Optics Express Special Issue
• RSNA has supported the robust QIBA effort
• NCI, NHLBI NLM, FDA, NIST have all made
significant investments in this space

©2006 RUSH University Medical Center