1. A Framework for Device-Based Clinical Research in Image-Guided Therapies Keyvan Farahani, PhD Gary Dorfman, MD Image-Guided Interventions Branch Cancer Imaging Program NCI

2. Interventional Oncology (IO) IGI Defined: Device-based, minimally-, non- invasive cancer therapies* that use real-, or near real-time intra-procedural imaging for localization, targeting, monitoring, control, and endpoint determination. * not just IR – also RT, endoscopy, surgery, etc.

3. Interventional Oncology Potential Clinical Utilities: –Primary Palliation (Bone Mets, Celiac Axis Block) –Secondary Palliation (PCN, PBD, G-, J-tubes) –Adjunctive Therapy (PV Embolization, Access) –Bridge to Definitive Rx (HCC) –Cure (Early / Screen Detected CA, Pre-CA, Indeterminate Lesions) –Intermediate Facilitator for Development of Molecularly Targeted Therapies

4. Molecular Imaging (and Intervention?) Molecular Signature of Cancer Cell Targeted Therapy Imaging Device (IGI Device?) Imaging Probe

5. NCI Support for IO: Current Environment CTWG / TRWG / Multi-PI Initiative Existing PAs –R01 / SBIR / STTR –Platform Development, Clinical Trials –Now Two Quick Trials Mechanisms However, Current Payline is Dismal… NCI Unique in Offering Clinical Trials Support Outside of Investigator Initiated Mechanisms “I2” Imaging Initiatives, Including: –IO Clinical Trials Support –Informatics (caBIG, NCIA, databases, analysis algorithms)

6. NCI IO Initiatives: Current CIP IGI Branch Initiatives –Largely Basic Science Through Investigator Initiated Pathways –Discovery, Development, Delivery –Translational Research (inc. Early Trials) –Clinical Trials Infrastructure Targeted Towards Image-Guided, Device-Based Therapy Similar to the Infrastructure Provided for Pharmaco- therapies Phase 0 – IV (Phase A – D) Goal: Bring Therapies with Disease-specific Indications to Market

7. Interventional Oncology Ideally Supported by Funded Research –Discovery / development – (Preclinical & ~ Phase 0) –Optimization – (Preclinical and Phase 0 – early II) –Validation for specific cancers / stages – (Phase II – IV) –Regulatory approval – (Later Phase II and III) –Supportive payor policies– (Later Phase II – IV) –Widespread physician acceptance – (Later Phase II – IV) –Patient recognition and “informed” demand

8. Clinical Trials Nomenclature: Phase 0 – IV vs. Pilot / Pivotal Pharma Phase 0 – IV –Works for many but not all drug trials –Poor fit for IGI / IO trials based on standard definitions & procedures FDA/CDRH Pilot and Pivotal Designation –Regulatory purpose –No accepted linkage to “Phase 0 – IV” –Not sufficiently granular for scientific endpoints –Approval process different than CDER/CBER

9. Clinical Trials Construct: A Proposed Matrix for IO Trials Phase A – D –A (0 / I, Pilot) – Single site: safety, QA, effect, optimize I & I – lesion, organ, patient –B (I / II, Pilot) – Single / Multi-site: effect, standardize, translate, early data – lesion, organ, early patient level data –C (II, Pilot / Pivotal) – Multi-site: organ/lesion outcome &/or more robust patient level data –D (III / IV, Pivotal) – Multi-site: patient level data, comparative, randomized preferred

10. IO Clinical Trial Endpoints: Definitions of Success and Failure IO Therapies often repeatable Consider adoption of vascular definitions: –Primary Success – result post intent to treat –Primary Assisted Success – add’l Rx, different site –Secondary Success – re-treatment of residual / recurrent disease at previously treated site –Failure – residual, recurrent, new disease Patient Refuses or Is Ineligible for Added Therapy; Death; etc. Worthy of Consideration: –Local control –Systemic control –Intent to treat and treatment plan –Purpose of treatment: cure, long-term control, control as bridge therapy, palliation

11. Interventional Oncology Imaging Issues – RECIST, etc. RECIST Criteria unless modified do not apply –Non-IGI RECIST issues already limiting –Immediate post-IGI lesion larger –Imaging lesion ≠ disease (viable tumor) –Recurrence / residual may not alter lesion dimensions Validation of imaging findings Imaging/sensing equivalent of the surgical tumor- free margin – Future interventional oncology; likely multi-parametric, co-registered data: anatomic, physiologic.

12. NCI IO Initiatives: IO Clinical Trials Infrastructure Targeted Towards Providing an Infrastructure for Image-Guided, Device-Based Therapy Similar to the Infrastructure Provided for Pharmacotherapies Phase 0 – IV (Phase A – D) Goal: Bring Therapies with Disease-specific Indications to Market Phase II and III Currently Implemented Through Existing Cooperative Groups Infrastructure is not All or Nothing –Variations in Collaborative Mechanisms –Use of NCIA to Support non-NCI Trial under Specific Conditions

13. NCI IO Clinical Initiatives: Current Device Rx Strategy Meetings (2-3 / Year) –Exploratory “By Invitation” Meetings (Stage I and II Breast Cancer) –“Open / Private” Device Rx Development Meetings (Renal Cell Cancer) –Disease / Technology Focused –Multi-purpose (Multilateral Education, Prioritization, Potential Solicitations) Support for Later Phase Clinical Trials –Collaboration among NCI, FDA, CMS –Strong Ties with Industry (CTA, CSA, pre-IDE, etc.) –Utilizes Cooperative Group Mechanism –Two Protocols in Process NOW

14. NCI IO Clinical Initiatives: Current 7 th Annual Forum on Biomedical Imaging in Oncology - Feb 1-2, 2007 –Collaboration with NEMA, AdvaMed, MDMA –Will Focus on Opportunities for Collaboration including Clinical Trials –QC and Uncertainty Measurements SPORE and CC Initiatives –Tissue Acquisition in Early Phase Clinical Trials –Standardized Imaging Protocols During IO Trials –Trans-SPORE Activities

15. Phase II / III Infrastructure: Current “Implementation” PI / Industry Collaborator Work Through Cooperative Group to Submit Concept –Considerations - ±IDE, ±CPT, etc. –CSA / CTA between NCI and Industry Concept Approved –Pre-IDE Meeting with ODE/CDRH/FDA (include NCI, PI, etc.) –Contract between Cooperative Group and Industry –Protocol Developed –IDE Application by NCI (if necessary) –CMS Discussions Regarding Funding Clinical Care Protocol (and IDE) Approved by NCI and FDA Protocol Activated (Potential CTSU Listing) –Image Support through NCIA

16. Conclusion: IGI methods offer new challenges and possibilities in cancer care Opportunities for academia, industry, and federal agencies to work closely together to address issues and bring new therapies to the bedside