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

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

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

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

Oncology drug development: Low success rates at every stage of clinical development Data for 1991-2000 for 10 largest pharmaceutical companies Kola & Landis, Nature Reviews Drug Discovery 2004

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

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)?

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; 24:2276-2282 2006

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

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 2005 Van den Abeele et al. ASCO 2005 Demetri et al ASCO 2005 Sunitinib package insert

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

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 1991-2000 for 10 largest pharmaceutical companies Kola & Landis, Nature Reviews Drug Discovery 2004

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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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