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A Phase II, Open-Label Study of Ponatinib, a Multi-Targeted Oral A Phase II, open-label study of ponatinib, a multi-targeted oral tyrosine kinase inhibitor, in advanced non- small cell lung cancer harboring RET translocations Version 8/22/2018 A Phase II, open-label study of ponatinib, a multi-targeted oral tyrosine kinase inhibitor, in advanced non-small-cell lung cancer harboring RET translocations NCT01813734 Protocol ID: 13-103 Version Date: August 22, 2018 1 Confidential A Phase II, open-label study of ponatinib, a multi-targeted oral tyrosine kinase inhibitor, in advanced non- small cell lung cancer harboring RET translocations Version 8/22/2018 Schema Genotyping of tumor for RET translocation (Pre-study evaluation) Register Ponatinib Progressive disease, Stable disease, partial or Unacceptable toxicity complete response Off study Continue Treatment 3 Confidential A Phase II, open-label study of ponatinib, a multi-targeted oral tyrosine kinase inhibitor, in advanced non- small cell lung cancer harboring RET translocations Version 8/22/2018 Schema ................................................................................................................................3 Table of Contents ................................................................. Error! Bookmark not defined. 1 Objectives ...................................................................................................................8 1.1 Study Design ..............................................................................................................8 1.2 Primary Objective .....................................................................................................8 1.3 Secondary Objectives ................................................................................................8 1.4 Primary Endpoint ......................................................................................................8 1.5 Secondary Endpoints .................................................................................................8 2 Background ................................................................................................................9 2.1 Study Agent ................................................................................................................9 2.2 Study Disease ............................................................................................................15 2.3 Study Rationale ........................................................................................................16 3 Participant Selection ................................................................................................17 3.1 Eligibility Criteria ....................................................................................................17 3.2 Exclusion Criteria ....................................................................................................19 4 Registration Procedures ..........................................................................................21 4.1 General Guidelines for DF/HCC and DF/PCC Institutions ................................21 4.2 Registration Process for DF/HCC and DF/PCC Institutions ..............................21 4.3 General Guidelines for Other Participating Institutions .................................21 4.4 Registration Process for Other Participating Institutions ...................................22 5 Study Procedures .....................................................................................................22 5.1 Study Procedures Descriptions .............................................................................22 5.2 Screening Period ......................................................................................................24 5.3 Screen Failures .........................................................................................................24 5.4 Active Study Period .................................................................................................24 5.5 End of Treatment .....................................................................................................25 5.6 30 Days After End of Treatment ............................................................................25 5.7 Follow-up Period ......................................................................................................25 5.8 Duration of Therapy / Subject Discontinuation ....................................................25 6 Treatment Plan ........................................................................................................26 6.1 Study Drug ...............................................................................................................26 6.2 Selection of Starting Dose .......................................................................................27 6.3 Treatment Administration ......................................................................................27 6.4 Formulation, Packaging, and Labeling .................................................................27 6.5 Handling ...................................................................................................................27 6.6 Availability ...............................................................................................................28 4 Confidential A Phase II, open-label study of ponatinib, a multi-targeted oral tyrosine kinase inhibitor, in advanced non- small cell lung cancer harboring RET translocations Version 8/22/2018 6.7 Storage ......................................................................................................................28 6.8 Ordering ...................................................................................................................28 6.9 Accountability ..........................................................................................................28 6.10 Destruction and Return ...........................................................................................28 6.11 Required Concomitant Therapy ............................................................................29 6.12 Permitted Treatment ...............................................................................................29 6.13 Prohibited Treatment ..............................................................................................30 6.14 Treatments to be Used with Caution .....................................................................30 6.15 Potential Drug-Drug Interactions ..........................................................................30 7 Expected Toxicities and Dose Modifications .........................................................30 7.1 Management of Adverse Drug Reactions ..............................................................31 7.2 Dose Delays and Reductions ...................................................................................31 7.3 Dose Delay and/or Reduction for Adverse Events (AEs) Attributable to the Study Drug 31 7.4 Management of Selected Adverse Events ...........................................................34 8 Study Calendar ........................................................................................................37 9 Measurement of Effect ............................................................................................40 9.1 Antitumor Effect– Solid Tumors ..........................................................................40 9.1.1 Definitions .................................................................................................................40 9.1.2 Disease Parameters ..................................................................................................40 Methods for Evaluation of Measurable Disease ............................................................41 9.1.3 Response Criteria.....................................................................................................42 9.1.4 Duration of Response ..............................................................................................45 9.1.5 Progression-Free Survival.......................................................................................45 Progression-Free Survival (PFS) is defined as the duration of time from study entry to time of objective disease progression. .....................................................................................45 9.1.6 Response Review ......................................................................................................45 10 Adverse Event Reporting Requirements ...............................................................45 10.1 Definitions ................................................................................................................45 10.1.1 Adverse Event (AE) .............................................................................................45 10.1.2 Serious adverse event (SAE) ...............................................................................46 10.1.3 Expectedness .........................................................................................................46 10.1.4 Attribution ............................................................................................................47 10.2 Procedures for AE and SAE Recording and Reporting ......................................47 10.3 Reporting Requirements .........................................................................................48 10.4 Reporting to the Study Sponsor ...........................................................................48
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