Integrating Imaging and Clinical Data in Oncology Trials - ICON hosted Webinar 2013
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Integrating Imaging and Clinical Data in Oncology Trials 10 September 2013
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Transcript of Integrating Imaging and Clinical Data in Oncology Trials - ICON hosted Webinar 2013
Integrating Imaging and Clinical Data in
Oncology Trials
10 September 2013
• ICON plc is a global provider of outsourced development
services to the pharmaceutical, biotechnology and medical
device industries.
• The company specializes in the strategic development,
management and analysis of programs that support clinical
development - from compound selection to Phase I-IV
clinical studies.
• ICON currently operates from 79 locations in 37 countries
and has approximately 10,045 employees.
• Further information is available at www.iconplc.com
About ICON
• ICON Signature Series is our thought leadership
program that offers expert insights into value-driven
strategies for clinical development.
• The program features ICON and external experts in all
aspects of clinical development and post-approval
product value strategies.
• For a list of featured topics and upcoming events go
to: http://www.iconplc.com/icon-views/
• ICON Signature Series is our thought leadership
program that offers expert insights into value-driven
strategies for clinical development.
• The program features ICON and external experts in all
aspects of clinical development and post-approval
product value strategies.
• For a list of featured topics and upcoming events go
to: http://www.iconplc.com/icon-views/
ICON Signature Series
Introductions
Gregory Goldmacher, MD, PhD
Senior Director, Medical & Scientific Affairs, Director
Oncology
ICON Clinical Research
Email: [email protected]
Dr. Goldmacher is a radiologist and provides medical,
scientific and regulatory leadership for trials in every phase of
clinical development, as well as training physicians and study
staff worldwide in clinical trial imaging methods.
Dr. Goldmacher is also Co-Chair of the Volumetric CT
Committee of QIBA, and a member of the QIBA Steering
Committee.
Introductions
Barbara Wachtendorf, BS, CNMT, RDMS, RVT
Director, Clinical Operations
ICON Clinical Research
Email: [email protected]
Clinical Research Experience • 10 years at ICON Clinical Research
• Manage global clinical trials
• Phase I through Phase IV
Therapeutic Area Experience • Breast and endometrial cancers • Hematologic malignancies • Pancreatic • Prostate • Sarcoma • Head / neck • Diagnostic imaging agents
Other Experience • Over 23 years of clinical experience as a Certified Nuclear
Medicine Technologist as well as a Registered Diagnostic Medical
Sonographer and Registered Vascular Technologist.
Topics
• Clinical Data in Response Assessment
– Response criteria background
– Range of clinical data roles
– Workflow considerations
• Clinical Considerations
• Data Collection
• Radiology and Clinical Mapping
• More Considerations
Goals in Efficacy Endpoints
• Disease severity over time
• Compare groups
• Avoid bias and variability
– Bias false positives
– Variability false negatives
Severity
Time
Treatment
Control
Severity
Time
Treatment
Control
High variability Low variability
Response Criteria
… Baseline Treat Visit 1 Visit 2
Endpoints • Date of progression PFS
• Best overall response ORR
• etc…
Lesion responses
Visit 1 response Visit 2 response
Lesion responses Lesions
Quantitative Qualitative
Treat
Criteria are rules about
• What and how to quantify
• Categories and thresholds (e.g. PR = 30% ↓ )
• Lesions Visits Endpoints
• How to add clinical factors
Response Categories
Category Meaning
CR Complete Response /
Remission All disease gone
PR Partial Response /
Remission Substantially decreased
Threshold varies
SD Stable Disease No definite change
PD Progressive Disease Treatment has failed Threshold varies
Some Criteria In Common Use
Indication Criteria
Solid tumors WHO RECIST
HCC, mesothelioma Modified RECIST
Prostate cancer PCWG2
GIST Choi
Glioblastoma Macdonald RANO
Lymphoma RCML (“Cheson”)
Multiple myeloma MM IWG
CLL Hallek
Solid Tumors
• Response Criteria In Solid Tumors (RECIST)
• Small role for clinical data
• Clinical data
– Pre-trial radiation therapy
– Tumor marker levels
– Histology (rarely)
RECIST
Baseline Treat Visit 1 Visit 2
Lesions
Target Non-target
Treat
Target
Non-target
New
Visit
CR, PR, SD, PD
CR, SD, PD
Yes, No
Target
Non-target
New
Visit PR
RTx Tumor
Markers
CR
CR
CR
No
…
Glioblastoma
• Response Assessment in Neuro-Oncology (RANO)
• Clinical data
– Steroid dosing
– Neuro status
• ECOG score
• Karnofsky performance status
– Lansky play scale
• Neurological exam findings
Baseline Treat Visit 1 Visit 2
Lesions
Target Non-target
Treat
Target
Non-target
New
Visit MRI
CR, PR, SD, PD
CR, SD, PD
Yes, No
Target
Non-target
New
Visit MRI CR, PR, SD, PD
Steroids
Neuro
Off, decreased, stable, increased
Stable/impr, worsened
Final
RANO
Combining MRI and clinical info
Response Definition
CR CR by MRI
No steroids above physiological levels
Clinical status stable or improved compared to baseline
PR PR by MRI
Steroid dose not increased compared to baseline
Clinical status stable or improved compared to baseline
SD SD by MRI
Steroid dose not increased compared to baseline
Clinical status stable or improved compared to baseline
PD PD by MRI
Clinical status worsened compared to baseline or best MRI visit
Steroid dose stable or higher compared to best response visit
General rule: worst category by neuro, imaging, steroids (except steroid increase alone ≠ PD )
OR
Not this alone
Steroids
• CR by MRI but still on steroids PR
• PR by MRI with steroids up SD
• SD by MRI, clinically stable, steroids up SD… for now
– If next visit shows either neuro or MRI worsening,
call PD when the steroids were increased
Lymphoma
• Response Criteria in Malignant Lymphoma
– “Cheson”
– 1999, 2007
• Clinical data
– Bone marrow
– B-symptoms (fever, weight loss, sweats)
– Physical exam (nodes, liver, spleen)
Lymphoma Response
• Two methods
• Method 1: Match a checklist of conditions
– For CR, you need (A), (B), (C), …
– For PR, you need (A), (B), (C), …
– For SD…
• Method 2: Step-by-step
Complete Remission (CR)
• All nodal and non-nodal lesions disappeared
• PET (if used) negative
• No palpable hepatosplenomegaly; nodules disappeared
• Complete disappearance of clinical evidence of disease and
disease-related symptoms
• Any pre-existing malignancy cleared on repeat bone marrow biopsy
– Detailed rules around this (immunohistochemistry, specific lymphoma
types)
Partial Remission (PR)
• ≥ 50% decrease in SPD of the quantified lesions
• No increase in the size of the other nodes, liver, or spleen
• Splenic/hepatic nodules regressed by ≥ 50% in SPD
• No measurable disease present in other organs
• No new sites of disease (e.g., nodes > 15 mm in any axis)
• PET positive in at least one previously involved lesion
• Marrow irrelevant for PR if positive prior to treatment
– If positive, cell type should be specified (e.g. large-cell lymphoma or small
neoplastic B cells).
– CR by above criteria, but with persistent bone marrow involvement is PR
Relapsed or Progressive Disease (RD/PD)
• ≥ 50% increase from nadir in the SPD of any previously involved nodes,
or in a single involved node, or the size of other lesions (e.g., splenic or
hepatic nodules)
– A lymph node with SA <10 mm must increase by ≥ 50% and to a size of 15 ×
15 mm or more than 15 mm in the long axis.
• At least a 50% increase in the longest diameter of any single previously
identified node >10 mm in short axis
• Appearance of new abnormal nodes or any new lesion > 15 mm in any
axis – New FDG-positive site is only PD if confirmed with other modalities
Stable Disease (SD)
• Failing to attain the criteria needed for a CR or PR, but not fulfilling
those for progressive disease.
Lymphoma Response
• Match a checklist of conditions for response levels
– For CR, you need (A), (B), (C), …
– For PR, you need (A), (B), (C), …
– For SD…
• Step by step
– Target lesions
– Non-target lesions
– New lesions } CT response + PET
Imaging response Marrow biopsy
Physical exam
b-symptoms } Final response
RCML
Baseline Treat EOT Visit Visit
Lesions
Treat
CT
PET
Imaging CR, PR, SD, PD
Marrow
H & P
Cleared, not cleared
Normal, abnormal
Final PR
Chronic Lymphocytic Leukemia
• IWCLL 2008
– “Hallek”
• Clinical data
– Hematology (lymphocytes, PMNs, plt, Hgb)
– Marrow
– Treatment (G-CSF, erythropoietin)
– Histology
CLL Response
Baseline Treat Visit Visit
Lesions
Treat
Imaging
Marrow
H & P
Final
Blood
Imaging
Marrow
H & P
Final
Blood
CLL Response
CR PR SD PD
Group A
Nodes None >1.5 cm Decrease ≥50% -49+ to + 49% Increase ≥50%
Liver/spleen Normal size Decrease ≥50% -49+ to + 49% Increase ≥50%
Symptoms None Any Any Any
PMNs >1500/μL >1500/μL
or 50% increase Any Any
Clonal B cells None Decrease ≥50% -49+ to + 49% Increase ≥50%
Group B
Platelets >100,000/μL >100,000/μL
or 50% increase -49+ to + 49% Decrease ≥50%
Hemoglobin >11 g/dL >11 g/dL
or 50% increase
≤11g/dL, ↑<50%
to ↓<2g/dL
Decrease
>2g/dL
Marrow
Normocellular
<30% lymph
no nodules
≥30% lymph
Nodules
Not done
No change
Increase lymph
to >30% from
normal
AND
≥ 1
≥ 1
Imaging
Clinical
Role of Clinical Data
• Range from small to dominant
• Usually can only worsen response
Clinical Data At Sites
• More clinical data more PD called locally
• Endpoint based on central PD danger: underpowered
– Consider confirmation of progression reads
Workflow
• Publications provide definitions and logic… NOT a uniform process
• Example 1: Lymphoma
– Category definitions vs “step by step”
• Example 2: Glioblastoma
RANO Process
RANO Process
Lesion
responses
MRI
response
Clinical
data +
Final
response
Neuroradiologist expertise
Neuro-oncologist
expertise
Workflow
Rad 1 Rad 2 Adjudication
Radiology
Result Clinical
Final Result
Clinical Considerations
• Data collection
• Radiology vs. Clinical data mapping
• Data management
• Complete vs. Iterative Reviews
Data Collection
• Independent review charter
– *Most important document*
• EDC System considerations
– Criteria requirements
• RECIST 1.1: Prior/ On Study radiotherapy
• RANO: Steroid dosing, Radiotherapy, Neuro exam
• IWG Criteria: Physical exam, Bone Marrow, Labs, etc.
– Disease considerations
– Medical Input
– Central Collection
– Labs
– Consistent data
Radiology and Clinical Mapping
• Radiology based
– RECIST 1.1, RANO, Cheson 2007
– Visit windows
• Clinical cycles based
– Cheson 2007, Hallek, MM IWG
– Visit grouping: Disease dependent
More Considerations
• Data management (Independent review side)
– Transfers from the EDC system
• Specific Data delivery specifications – EDC fields= clinical data shown
– Complete Dates for mapping
• Include in budget
• Complete vs. Iterative Reviews
– Completed patients- Simplest
– Comparing previously read clinical data with incoming transfer
– Interim clinical data cleaning
• Monitoring
Thank You
