Protocol 2011-0579 Page 1 Title: An Open-Label Phase II Study of the Combination of GSK2118436 (Dabrafenib) and GSK1120212 (Trametinib) in Patients with Metastatic Melanoma which is Refractory or Resistant to BRAF Inhibitor. Coordinating Center: The University of Texas M. D. Anderson Cancer Center *Principal Investigator: Michael A. Davies, M.D.,Ph.D. University of Texas M. D. Anderson Cancer Center 1515 Holcombe Blvd, Unit 430 Tel. 713-792-2921 Fax 713-745-1046 Email: [email protected] Statistician: Study Coordinator: Roland Bassett Lauren Simpson 1515 Holcombe Blvd. Unit 350 1515 Holcombe Blvd. Unit 430 Houston, TX 77030 Houston, TX 77030 Telephone 713-792-6330 Telephone 713-792-7346 Fax 713-563-4243 Fax 713-745-1046 [email protected] [email protected] Effective Date: April 09, 2014 Protocol Amendment Number: 05 Downloaded From: https://jamanetwork.com/ on 09/26/2021 Protocol 2011-0579 Page 2 TABLE OF CONTENTS ABBREVIATIONS ........................................................................................................................ 5 1. INTRODUCTION .................................................................................................... 9 1.1. Background ................................................................................................................ 9 1.1.1. MEK1/2 Inhibitor GSK1120212 ............................................................................ 9 1.1.1.1. Preliminary Safety Data for GSK1120212 from First-in-Human Study ......... 9 1.1.2. BRAF Inhibitor GSK211843 .................................................................................10 1.1.2.1. Preliminary Clinical Data for GSK2118436 ……………………....................... 10 1.1.3. Drug-Drug Interaction Potential Between GSK1120212 and GSK2118436 . 11 1.2. Rationale .................................................................................................................. 12 2. OBJECTIVES AND ENDPOINTS ......................................................................16 2.1. Primary Objective ....................................................................................................16 2.2. Secondary Objective ...............................................................................................16 3. INVESTIGATIONAL PLAN ................................................................................17 3.1. Discussion of Design ...............................................................................................17 3.1.1. Dose Limiting Toxicity Definitions ......................................................................18 3.2. Investigational Product Dosage/Administration ..................................................18 3.3. Dose Adjustment/Stopping Criteria ......................................................................19 3.3.1. Continuation on Study ............................................................................................19 3.3.2. Dose Adjustment ......................................................................................................19 3.3.3. Stopping Criteria ......................................................................................................20 3.3.3.1. Liver Chemistry Stopping Criteria ........................................................................20 3.3.3.2. QTc Withdrawal Criteria ........................................................................................20 3.3.3.3. Left Ventricular Ejection Fraction (LVEF) Stopping Criteria ..........................20 3.3.3.4. Visual Changes Stopping Criteria .........................................................................21 3.3.3.5. Hypertension Stopping Criteria .............................................................................22 3.3.3.6. Pyrexia Stopping Criteria .......................................................................................24 3.3.4. Supportive Care .......................................................................................................26 3.3.4.1 Supportive Measures for Rash ..............................................................................26 Downloaded From: https://jamanetwork.com/ on 09/26/2021 Protocol 2011-0579 Page 3 3.3.4.2 Supportive Measures for Diarrhea .......................................................................27 3.4. Time and Events Table ...........................................................................................28 4. STUDY POPULATION .........................................................................................30 4.1. Number of Subjects .................................................................................................30 4.2. Eligibility Criteria ....................................................................................................30 4.2.1. Inclusion Criteria .....................................................................................................30 4.2.2. Exclusion Criteria ....................................................................................................32 5. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ...................33 5.1. Study Design Considerations .................................................................................33 5.1.1. Analysis Populations ...............................................................................................36 5.1.2. Assessment Windows ..............................................................................................36 5.2. Efficacy Analyses ....................................................................................................36 5.3. Biomarker and Pharmacodynamic Analyses .......................................................37 5.4. Resistance Mechanisms Analysis ..........................................................................37 6. STUDY ASSESSMENTS AND PROCEDURES ..............................................37 6.1. Demographic/Medical History Assessments .......................................................37 6.2. Safety .........................................................................................................................37 6.3. Disease Assessments ...............................................................................................39 6.4. Biomarkers, Pharmacodynamics and Resistance Mechanisms Analysis .......40 7. LIFESTYLE AND/OR DIETARY RESTRICTIONS .......................................41 7.1. Contraception Requirements ..................................................................................41 7.1.1. Female Subjects .......................................................................................................41 7.1.2. Male Subjects ...........................................................................................................42 7.2. Meals and Dietary Restrictions ..............................................................................42 8. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........42 8.1. Permitted Medications ............................................................................................42 8.2. Prohibited Medications ...........................................................................................43 8.3. Cautionary Medications ..........................................................................................43 9. COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS .....................46 9.1. Subject Completion .................................................................................................46 9.2. Subject Withdrawal Criteria ...................................................................................46 9.3. Subject Withdrawal Procedures .............................................................................47 10. INVESTIGATIONAL PRODUCT(S) ..................................................................47 Downloaded From: https://jamanetwork.com/ on 09/26/2021 Protocol 2011-0579 Page 4 10.1. Blinding .....................................................................................................................47 10.2. Packaging and Labeling ..........................................................................................48 10.3. Preparation/Handling/Storage …………………....................................................48 11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ...48 11.1. Definition of Adverse Events .................................................................................49 11.2. Definition of Serious Adverse Events ...................................................................50 11.2.1. Disease-Related Events or Outcomes Not Qualifying as SAEs ........................51 11.2.2. Lack of Anti-cancer Activity .................................................................................51 11.2.3. Clinical Laboratory and Other Abnormal Assessments as AEs and SAE …...51 11.3. Method of Detecting AEs and SAEs .....................................................................51 11.4. Recording of AEs and SAEs ..................................................................................52 11.5. Evaluating AEs and SAEs ......................................................................................52 11.5.1. Assessment of Intensity ..........................................................................................52 11.5.2. Assessment of Causality .........................................................................................52 11.6. Follow-up