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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

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Disclosures

• I am an employee of Genentech, Inc

• I will discuss investigational use of:– 18F-fluorothymidine (FLT)

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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

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The Drug Development Process:Low success rates at every stage

Basic Research

TargetID

Drug Candidate Selection

INDstudies

Phase 1 Phase 2 Phase 3 Approval

Drug Discovery Pre-Clinical

Development Clinical Development

Success rate (Ph1 to Approval): Approx 10-20% Kola & Landis Nat Rev Drug Disc 2004 DiMasi & Grabowski J Clin Onc 2007

IND=Investigation New DrugApplication

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Oncology drug development: Low success rates at every stage of clinical development

Data for 1991-2000 for 10 largest pharmaceutical companiesKola & Landis, Nature Reviews Drug Discovery 2004

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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

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Potential uses of imaging in clinical development of (oncology) drugs

1. Imaging presence of target on tumor• Identification of appropriate patient population for treatment

2. Imaging biodistribution of drug– How much drug reaches tumor compared to other

tissues/organs?

3. 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?

4. Imaging surrogate efficacy endpoints– Are changes occurring in tumor that are associated with

improved outcome (e.g. progression free or overall survival)?

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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)

Perik, P. J. et al. J Clin Oncol; 24:2276-2282 2006Copyright ® American Society of Clinical Oncology

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Imatinib in GIST: Early changes in FDG-PET predict subsequent tumor shrinkage

Stroobants et al Eur J Cancer 2003

FDG-PETPretreatment Day 8

CT scans

Pretreatment

Week 4

Week 24

GIST=Gastrointestinal stromal tumor

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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 = 0.33 p<0.0001 (vs

placebo)Dileo et al GI ASCO 2005Van den Abeele et al. ASCO 2005Demetri et al ASCO 2005Sunitinib package insert

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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

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Current basis for Go/No Go decision to Phase 3 in Oncology

1. Small, single arm Phase 2 studies:– Tumor shrinkage (RECIST) used

to decide Go/No Go to Phase 3– Inadequate for many new

oncology molecules

2. 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 1991-2000 for 10 largest pharmaceutical companies

Kola & Landis, Nature Reviews Drug Discovery 2004

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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

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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

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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

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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

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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 580603 – Coordinated by the Foundation for NIH

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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

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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

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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

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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)

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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

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Study designDiagnostic CT

Erlotinib Rx

0

Diagnostic CT

Every 56 day

Diagnostic CT

until progressive disease, intolerable toxicity, or up to 1 year

Continued follow-up until death, or up to 1 year following enrollment of last patient

Determine progression free

survival

OverallSurvival

14 56

Day -14 to -1(screening)

FDG-PETFLT-PET

FDG-PETFLT-PET

FDG-PETFLT-PET

Day

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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

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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

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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

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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

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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

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Thank you