1. Genentech Research Early Development (gRED)
Molecular Imaging in Clinical Drug Development: Challenges of multi-site clinical trials
Andrea Pirzkall, MD
Genentech Research Early Development (gRED)
CTN workshop 2/1/10

2. Disclosures I am an employee of Genentech, Inc
I will discuss investigational use of:
18F-fluorothymidine (FLT)

3. Outline Value of novel imaging agents in clinical drug development
Importance of multi-center trials
Challenges for drug developers doing multi-center trials with investigational imaging agents
A specific example—FLT-PET
How we did it
What we would like to see in the future

4. The Drug Development Process: Low success rates at every stage
Pre-Clinical
Development
Drug Discovery
Clinical Development
Success rate (Ph1 to Approval): Approx 10-20%
Kola & Landis Nat Rev Drug Disc 2004
DiMasi & Grabowski J Clin Onc 2007
Drug
Candidate
Selection
Basic
Research
Target ID
IND
studies
Phase 1
Phase 2
Phase 3
Approval
IND=Investigation New Drug
Application 4

5. Oncology drug development: Low success rates at every stage of clinical development
Data for for 10 largest pharmaceutical companies
Kola & Landis, Nature Reviews Drug Discovery 2004

6. New tools for clinical drug development needed
High failure rate for drug candidates at every stage of clinical development
New approaches to clinical drug development are needed
FDA’s Critical Path Initiative
Imaging approaches particularly promising
Potential new tools to improve clinical drug development

7. Potential uses of imaging in clinical development of (oncology) drugs
Imaging presence of target on tumor
Identification of appropriate patient population for treatment
Imaging biodistribution of drug
How much drug reaches tumor compared to other tissues/organs?
Imaging pharmacodynamic changes
Imaging biological effect of drug on tumor (or other tissues/organs)
Is the drug binding to target?
Is the drug inhibiting the target?
Is the drug inducing the expected downstream biochemical changes?
Imaging surrogate efficacy endpoints
Are changes occurring in tumor that are associated with improved outcome (e.g. progression free or overall survival)?

8. Imaging presence of target on tumor: 111In-labeled trastuzumab and her2+ tumors
Single-photon emission computed tomography (SPECT) to image labeled anti-her2 antibody
Fused CT and 111In-DTPA-trastuzumab SPECT image (96 hours after tracer injection)
Copyright ® American Society of Clinical Oncology
Perik, P. J. et al. J Clin Oncol; 24:

9. Imatinib in GIST: Early changes in FDG-PET predict subsequent tumor shrinkage
Pretreatment Day 8
CT scans
Pretreatment
Week 4
Week 24
Stroobants et al Eur J Cancer 2003
GIST=Gastrointestinal stromal tumor

10. FDG-PET: Sunitinib effect in imatinib-resistant GIST
Single arm phase 1/2 study:
50 mg daily on different schedules
RR (RECIST) 9.1% (5/55)
Qualitative PET response rate at 7 days 62% (33/53)
Randomized, placebo-controlled Phase 3 (n=312):
50mg daily 4 wks on, 2 wks off
Sunitinib arm: RR (RECIST) 6.8 %
HR for TTP = p< (vs placebo)
Dileo et al GI ASCO 2005
Van den Abeele et al. ASCO 2005
Demetri et al ASCO 2005
Sunitinib package insert

11. How to prioritize efforts to use imaging for clinical drug development?
High failure rate of molecules at every stage of clinical development
Imaging could potentially improve development at every phase
Late failure (e.g. failure in pivotal Phase 3 studies) is much more costly than early failures
High priority goal: shift failures to earlier in process
Biggest impact on drug development: Reduce Pivotal (Phase 3) failures
Improve Go/No Go to Phase 3 decisions

12. Current basis for Go/No Go decision to Phase 3 in Oncology
Small, single arm Phase 2 studies:
Tumor shrinkage (RECIST) used to decide Go/No Go to Phase 3
Inadequate for many new oncology molecules
Large, randomized phase 2 studies
Typically with time to progression endpoints
Long duration, large numbers of patients
Not sustainable:
Increases cost of Phase 2 drug development
Data for for 10 largest pharmaceutical companies
Kola & Landis, Nature Reviews Drug Discovery 2004

13. Using new technologies (imaging) to improve Go/No Go decision to Phase 3
Required characteristics of new technology:
Yield useful information in relatively small Phase 2 studies:
Single arm, short duration
Assess drug activity in absence of tumor shrinkage
Improve upon current RECIST criteria

14. General performance requirements for (imaging) test
To guide individual patient decisions:
Need excellent positive and negative predictive value
If test has high error rates won’t be used
To guide development of a novel drug:
Relatively low bar to improve upon current decision making
Relatively high error rates would still be an improvement

15. Are available imaging technologies sufficient?
Available imaging technologies may be well suited to the task:
FDG-PET: Measure changes in tumor metabolic rate
FLT-PET: Measure changes in tumor proliferative rate
DCE-MRI: measure blood flow/vascular permeability
These measure biological changes likely associated with effective anti-cancer drugs
could improve clinical drug development in the near future
Other newer technologies may ultimately prove superior
But, establishing their place in drug development will take longer

16. FDG-PET imaging is promising for clinical oncology drug development
Wide clinical availability
Numerous publications on clinical use
Commonly used in management of many patients with cancer
In cancer drug development:
Some dramatic examples
However, more work needed to inform Go/No Go to Phase 3 decisions

17. Need to do multi-center trials
Many imaging agents have entered the clinic
Few have been evaluated in multi-center trials
significantly limiting impact
Even FDG-PET: relatively few multi-center results reported
E.g., only now, are multi-center studies underway to confirm the association between FDG-PET response and clinical outcome from standard therapy in common cancers:
Non-small cell lung cancer: ACRIN 6678
Non-Hodgkin Lymphoma: CALGB
Coordinated by the Foundation for NIH

18. Need for multi-center studies
Increase confidence if similar results obtained at different clinical sites
Facilitates broader availability
Adequate numbers of patients in an acceptable time frame
Fast way to impact clinical practice and use in drug development

19. Challenges for therapeutics developers doing multi-center trials with investigational imaging agents
Regulatory
Quality/reliability of imaging agent
Quality/consistency of image acquisition
Quality/consistency of image interpretation

20. A Specific Example
A study of FDG- and FLT-PET in patients with non-small cell lung cancer receiving erlotinib
Purpose of study:
Determine FDG- and FLT-PET response rates and association with clinical outcome
Determine feasibility of multi-center study with FDG- and FLT-PET

21. Example: Erlotinib
Small molecule, orally bioavailable inhibitor of epidermal growth factor receptor (EGFR)
Approved for treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen
Randomized clinical study (BR.21) of erlotinib vs placebo in NSCLC showed
RECIST response rate of 8.9% with erlotinib (0.9% with placebo)
Median overall survival with erlotinib 6.7 months (4.7 months with placebo)

22. Evaluating FDG- and FLT-PET with an established targeted therapy
Purpose of study:
Determine FDG- and FLT-PET response rates and association with clinical outcome
Determine feasibility of multi-center study with FDG- and FLT-PET
Use an established targeted therapy (erlotinib in non-small cell lung cancer)
Study is not intended to evaluate erlotinib

23. Determine progression free survival
Study design
Diagnostic CT
Diagnostic CT
Diagnostic CT
FDG-PET
FLT-PET
Day 14 56
Every 56 day
Day -14 to -1
(screening)
Erlotinib Rx
Continued follow-up until death, or up to 1 year following enrollment of last patient
until progressive disease,
intolerable toxicity, or up to 1 year
Determine progression free survival
Overall
Survival

24. FLT in a multi-center setting: Regulatory path
FLT is not approved by FDA
Filed an IND for FLT
Benefited from NCI’s Cancer Imaging Program having already filed an IND for FLT
Needed to ensure quality of FLT manufacturing process and product
Challenging to monitor multiple sites using different processes

25. FLT in a multi-center setting: Quality/reliability of imaging agent
In the U.S., decided to work with a commercial producer/distributor
Ensured adequate control of manufacturing process and product quality
Significantly limited geographic area of possible clinical sites

26. Ensuring Image acquisition consistency/quality at clinical sites
Identified an expert imaging group to develop:
An Imaging Charter describing image acquisition procedure
Pre-specified image analysis approach
At each clinical site, an imaging physician (radiology/nuclear medicine) formally identified as a sub-investigator on the study
Representatives of central imaging group visited each imaging site to train and evaluate site personnel
Used case report forms to collect critical parameters for image quality (e.g. radiotracer uptake time)
Provided feedback to imaging sites

27. Summary
Molecular imaging has tremendous potential value for clinical drug development
Impact on drug development has been limited, in part, due to challenges of multi-center clinical studies
Example of FDG/FLT-PET study of erlotinib in NSCLC
Illustrates challenges drug developers face
Initial results to be reported at the 13th World Conference on Lung Cancer in July

28. What we would like to see in the future
For imaging agents requiring an IND, a mechanism that provides:
Broader choice of clinical sites
Shorter time to initiate clinical studies
Confidence in quality/consistency of imaging agent at multiple clinical sites
Confidence in quality/consistency of image acquisition procedures at multiple clinical sites
SNM Clinical Trials Network may address these needs

29. Thank you