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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 1 Disclosures • I am an employee of Genentech, Inc • I will discuss investigational use of: – 18F-fluorothymidine (FLT) 2 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 3 The Drug Development Process: Low success rates at every stage Pre-Clinical Drug Discovery Development Clinical Development Success rate (Ph1 to Approval): Approx 10-20% Kola & Landis Nat Rev Drug Disc 2004 DiMasi & Grabowski J Clin Onc 2007 Drug Basic Target Candidate Research ID Selection IND Phase 1 Phase 2 Phase 3 Approval studies 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 5 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 6 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)? 7 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) 8 Copyright ® American Society of Clinical Oncology Perik, P. J. et al. J Clin Oncol; 24:2276-2282 2006 Imatinib in GIST: Early changes in FDGPET predict subsequent tumor shrinkage FDG-PET Pretreatment Day 8 CT scans Pretreatment Week 4 Week 24 Stroobants et al Eur J Cancer 2003 GIST=Gastrointestinal stromal tumor 9 FDG-PET: Sunitinib effect in imatinibresistant 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, placebocontrolled Phase 3 (n=312): Dileo et al GI ASCO 2005 Van den Abeele et al. ASCO 2005 Demetri et al ASCO 2005 Sunitinib package insert – 50mg daily 4 wks on, 2 wks off – Sunitinib arm: RR (RECIST) 6.8 % – HR for TTP = 0.33 p<0.0001 (vs placebo) 10 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 11 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: Data for 1991-2000 for 10 largest pharmaceutical companies • Increases cost of Phase 2 drug development Kola & Landis, Nature Reviews Drug Discovery 2004 12 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 13 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 14 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 15 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 16 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 17 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 18 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 19 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 20 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) 21 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 22 Study design Diagnostic CT FDG-PET FLT-PET Day Day -14 to -1 (screening) 0 Diagnostic CT FDG-PET FLT-PET 14 Diagnostic CT FDG-PET FLT-PET 56 Every 56 day Erlotinib Rx until progressive disease, intolerable toxicity, or up to 1 year Determine progression free survival Continued follow-up until death, or up to 1 year following enrollment of last patient Overall Survival 23 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 24 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 25 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 26 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 27 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 28 Thank you 29