Slides from the 2012 conferences

1. Oncology translational imaging for early phase
anticancer drug development
Sabin Carme
SMi – Biomarkers Summit 2012
London

2. OUTLINE
• Current needs for drug development and introduction to
translational approach
•Preclinical validation of the best imaging marker (example with
PET and MRI)
•Flexible Clinical imaging study design (example with PET and
MRI)
•Quantitative imaging data interpretation (example with PET
and MRI)
• Back translation

6. Parallel progression of primary tumours and metastases
Klein, Nature Reviews Cancer 9, 302-312, April 2009
normal
tissue
sub-clinical
cancer
localised
cancer
(detectable)
locally
advanced
cancer
metastatic
cancer with increasing malignancy
CANCER PROGRESSION

7. Hanahan and Weinberg,
Cell. 2000;100:57-70

8. METHODS TO TREAT CANCER
•Prevention
•Surgery
•Radiotherapy
•Supportive Care
•Chemotherapy
•Hormonal therapy
•Biological therapy
•Radioactive material
• Cytotoxics
• Targeted
• Therapeutic vaccines
• Immunotherapy
• Monoclonal antibodies
http://cancerhelp.cancerresearchuk.org/about-cancer/treatment/
DRUGS
Combined With

9. Radiochemistry and QC
Physics
Data modelling and IT
Clinical
Trial Design Application
Expertise
Supports
Preclinical
Efficacy
Phase II
FITH to POC
Microdosing
Phase 0
OBD
Phase Ib
POC to CommitPre-Clinical
MTD
Phase Ia
IMAGING STUDY
Development Need
•Safety >> Biodistribution
Radiolabeled drug
•Efficacy >> PD
PET FDG
PET FLT
PET new tracers
>>PK
Radiolabeled drug

10. ASSESSING RESPONSE AND PROGRESSION
FOR CANCER CLINICAL TRIALS
Complete
Response
TARGETLESIONS:
SUMOFLESIONDIAMETER/S
TIME (weeks)
0 8 16 24 32
Partial
Response
Stable
Disease
Progressive
Disease(PD)
-30%
+20%
-Crude method
to assess whether a
drug is working
-Radiologists around
The world do things
Differently
-Often need to bring
Data centrally for 1-3
Radiologists to review

11. •18F-FDG is a glucose analog
•18F-FDG is taken up by cells phosphorylated by
hexokinase and retained by tissues with high
metabolic activity.
•FDG is missing this 2' hydroxyl and thus cannot be
further metabolized in cells.
•FDG-PET can be used for
•Diagnosis, staging
•Monitoring treatment of cancers
FDG PET Imaging

12. Imatinib/gleevec
•Sequential positron emission
tomography (PET) scans
obtained in a patient with GIST
•(A) at baseline
•(B) 1 month after imatinib
•The tumour in the lower bowel
•Visual/size assessment:
Diminished noticeably after
treatment
•Semi-Quantitative assessment:
The SUV at the two time points
• 4.5 (A)
• 1.24 (B)
Sci. STKE, 20 February 2007
Vol. 2007, Issue 374, p. pe8
FDG

13. Dose
D1-D15
SUVmax reduction
at D15
0.5 mg QD 44%
Baseline D15
Baseline Follow-up
Jeffrey R. Infante ASCO 2010
FDG
MEK GSK1120212
•B-Raf-Mutant Melanoma
•Visual:
Number of hot spots decreases
•Semi-Quantitative
SUV decreases

14. FLT-PET (A,B)
FDG-PET (C,D)
Patient with aggressive lymphoma
•Intense focal FLT uptake in
•Axilla
•the neck
•the mediastinum
•the right groin.
•Arrows, lesions detected additionally to
conventional FDG staging procedures.
Cancer Res November 15, 2006 66; 11055
FLT
FLT-PET a proliferation marker
FLT PET Imaging

15. http://benchmarks.cancer.gov/2010/07/imaging-agent-development-and-early-phase-clinical-trials/
Imaging Agent
Development and Early
Phase Clinical Trials
July 9, 2010
By Linda Perrett

16. Gambhir SS.
Principles of Molecular Imaging

19. Readily available
“metabolic tracer”
Cell assay
screening
for
suitable
tracer
Animal
qualification
PK/PD
modeling
Selection
Utilization in dose
selection
Early efficacy read-out
Novel existing
tracer
Development of
new tracer
Animal
qualifications
for drug
Utilization for dosing
regime
Guide biopsy time point
Explore stratification
Chemistry and
screening
6-8 cpds
Animal
qualification
Tox
Human
micro-
dosing
Utilization for dose
selection
Dosing regime
Explore stratification
Ensure
availability
Selection
Integrated PK, PD, trial design, Modeling & Simulation
-- Timeline --
Combining tracer qualification with early clinical processes
NEW TRACER QUALIFICATION

20. Preclinical
Input
Dose - Time
FDG or
FLT
Uptake
Dose - Time
PD
Biomarker
PD Biomarker
FDG or
FLT
Uptake
In vitro
cells
+ FDG/FLT SUV
vs. PD markers
In vivo
xenograft
Preclinical
Tracer Selection
Correlation Dose - Time

21. Clinical
Study Rational
PET PD markers
Clinical
Study Progress
PreClinical in vivo
Study Progress
PreClinical in vitro
Tracer selection
Study report
and Conclusion
• Dose response
• Timing optimal uptake
• PD markers correlation
• TAC
• PD marker of drug Specificity
• Metabolism
• Dose efficacy
• Cold compound competition
Adaptive design based on
Data Analysis and
interpretation
Part 1
Part 2
BACK TRANSLATION DESIGN

22. Translational
Biodistribution in
a relevant animal
model
PD PK
Dose response in
a relevant animal
model
Imaging
GO-NoGO
Clinical study Clinical study
NoGo
No parameters
changes in organ of
interest
NoGo
No uptake in organ
of interest
Go
Propose
clinical
protocol
Kill the drug
PET tracer
MRI measurement
Radiolabelled
Drug
Go
Risk
Try Other PET tracers /
MRI sequence

23. SubmitIND INDApproval
FTIHStudySet-up
FTIHStudy(FSFV toSAC)
ImagingStudy Set-up
ImagingStudy (FSFVto SAC)
Proof of Concept
FormulationOptimization ManufacturingClinical Supply
Phase IISet-up
Phase II (FSFV toSAC)
Committo phase III
New Drug : Early Phase Development
Critical Path
Imaging study can impact the timelines from
IND to Commit to Medicine

24. FS FV
Protocol
publishing
IRAS
ARSAC Approval
IMPD Clinical
Summary
Tracer feasibility
Product Master file : CMC
chapter + SMPC MHRA Q/A
Approval
Ethics Approval
NHS Clinic Site
CRO
selection
Costing
Contract
NHS trust R&D
Approval
Site Specific
Information
ARSAC Form
Dosimetry
Human simulation
Rats
Peer review
meeting
Draft protocol
Study initiation timelines
MRI feasibility
Sequence / post processing
development
4-8 months (estimate)

25. FS FV
Collection of
clinical data /
samples
image analysis /
modelling
Patient visits
planning and slots
booking
Patient dosing
planning
Demographic,
PK/PD analysis
Reporting
Warning+Action
Study team
meetings
Collection / QC of
imaging Data
Study completion timelines
6-24 months (estimate)
Regulatory
approvals
Regulatory
amendments
Statistical
analysis
Study
Report
Scientific
communications
publications
LS LV
Database
freezing
Study
Closure

26. Success for the Imaging Study
Robust Biomarker Imaging Toolkit
- Setting-up and validation of methods : Methodology studies
- Preclinical validation / information
- Strong Radiochemistry
- Strong Physic
- Strong Analysis / IT
Good liaison with Project Team (Sponsor):
- Understand Scientific concept, study objectives
- Propose pragmatic means to achieve it
- Reporting, portfolio management, warnings and corrective actions
Realistic recruitment prevision (Investigators):
-CIC Recruitment office operational
-Good Investigational clinical sites
-CRO
Experienced Clinical Team :
- Clinical professionals – doctors, nurses, study coordinators, technologists
-Training in GCP/ICH
Excellent “study team” spirit
-Team involved during the progress of the study