Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS)

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1 A service of the U.S. National Institutes of Health Comment Period Extended to 3/23/2015 for Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials Trial record 1 of 2 for: CMEK162B2301 Previous Study Return to List Next Study Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant (COLUMBUS) This study is currently recruiting participants. (see Contacts and Locations) Verified January 2015 by Novartis Sponsor: Novartis Pharmaceuticals Information prov ided by (Responsible Party): Novartis ( Novartis Pharmaceuticals ) ClinicalTrials.gov Identifier: NCT First received: July 24, 2013 Last updated: January 29, 2015 Last verified: January 2015 History of Changes Full Text View Tabular View No Study Results Posted Disclaimer How to Read a Study Record Purpose This is 2-part, randomized, open label, multi-center, parallel group, phase III study comparing the efficacy and safety of LGX818 plus MEK162 to vemurafenib and LGX818 monotherapy in patients w ith locally advanced unresectable or metastatic melanoma w ith BRAF V600 mutation. A total of approximately 900 patients w ill be randomized. Part 1: Patients w ill be randomized in a 1:1:1 ratio to one of 3 treatment arms: Part 2: 1. LGX mg QD plus MEK162 45mg BID (denoted as Combo 450 arm) 2. LGX mg QD monotherapy (denoted as LGX818 arm) or 3. vemurafenib 960mg BID (denoted as vemurafenib arm) Patients w ill be randomized in a 3:1 ratio to one of the 2 treatment arms: 1. LGX mg QD plus MEK162 45mg BID (denoted as Combo 300 arm) or 2. LGX mg QD monotherapy (denoted as LGX818 arm). Condition Interv ention Phase Drug: vemurafenib Phase 3 Study Type: Study Design: Official Title: Interventional Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment A 2-part Phase III Randomized, Open Label, Multicenter Study of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in Patients With Unresectable or Metastatic BRAF V600 Mutant Resource links prov ided by NLM:

2 MedlinePlus related topics: Drug Information available for: Vemurafenib Genetic and Rare Diseases Information Center resources: APUDoma Carcinoid Tumor, Familial Neuroepithelioma U.S. FDA Resources Further study details as prov ided by Nov artis: Primary Outcome Measures: Progression free survival (PFS) [ Time Frame: Approximately 2 years after first patient randomized ] PFS is defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause, w hichever occurs first. PFS w ill be determined based on tumor assessment (RECIST version 1.1 criteria) as per Blinded Independent Review Committee (BIRC) and survival information. The local Investigator's assessments w ill be used as supportive analyses. Secondary Outcome Measures: Overall Survival (OS) [ Time Frame: Up to approximately 5 years after first patient randomized ] OS is calculated as the time from date of randomization to date of death due to any cause. Progression Free Survival (PFS) [ Time Frame: Approximately 2 years w ith update around 3 years after first patient randomized ] PFS is defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause, w hichever occurs first. PFS w ill be determined based on tumor assessment (RECIST version 1.1 criteria) as per Blinded Independent Review Committee (BIRC) and survival information. The local Investigator's assessments w ill be used as supportive analyses. Objective Response Rate (ORR) [ Time Frame: Approximately 2 years after first patient randomized ] ORR calculated as the proportion of patient w ith a best overall response of complete response (CR) or partial response (PR). ORR w ill be calculated for confirmed and unconfirmed responses separately. Time To Response (TTR) [ Time Frame: Approximately 2 years after first patient randomized ] TTR calculated as the time from date of randomization until first documented complete response (CR) or partial response(pr). Disease Control Rate (DCR) [ Time Frame: Approximately 2 years after first patient randomized ] DCR calculated as the proportion of patient w ith a best overall response of CR, PR or stable disease (SD) Duration of objective response (DOR) [ Time Frame: Approximately 2 years after first patient randomized ] DOR calculated as the time from the date of first documented CR or PR to the first documented progression or death due to underlying cancer Safety and tolerability of combination and LGX818 [ Time Frame: Up to approximately 4 years after first patient randomized ] [ Designated as safety issue: Yes ] Number of patients w ith adverse events and serious adverse events, changes in laboratory values, vital signs, electrocardiograms (ECGs), MUGA(Multi Gated Acquisition Scan)/echocardiogram and assessment of physical,dermatological and ocular examinations graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 ECOG Performance status (PS) [ Time Frame: Approximatley 2 years after first patient randomized ] Change from baseline in the ECOG PS Time to definitive 1 point deterioration in ECOG performance status [ Time Frame: Approximatley 2 years after first patient randomized ] Time to definitive 1 point deterioration in the ECOG PS is defined as the time form date of randomization to definitive deterioration, w here deteriorationis considered as definitive if no improvement in the ECOG PS status is observed at a subsequent time of measurement during the treatment period follow ing the time point w here the deterioration is observed. Pharmacokinetics of LGX818 and MEK162 [ Time Frame: Approximatley 2 years after first pateint randomized ]

3 Plasma concentration-profiles of LGX818 and MEK162 and model based PK parameters Time to definitive 10% deteriortaion in global health status (EORTC QLQC30) [ Time Frame: Approximately 2 years after first patient randomized ] Time to definitive 10% deterioration in the global health status score of theeortc QLQ-C30 is the time from the date of randomization to the date of at least 10% relative to baseline w orsening w ith no later improvement above this threshold observed during the course of the study or death due to any cause Global health status (EORTC QLQC30) [ Time Frame: Approximately 2 years after first patient randomized ] Change from baseline in the global health status score of the EORTC QLQ-C30 Time to definitive 10% deterioration in the FACT-M melanoma subscale [ Time Frame: Approximately 2 years after first patient randomized ] Time to definitive 10% deterioration in the FACT-M melanoma (subscale) is the time from the date of randomization to the date of at least 10% relative to baseline w orsening w ith no later improvement above this threshold observed during the course of the study or death due to any cause Global health status (EQ-5D) [ Time Frame: Approximately 2 years after first patient randomized ] Change from baseline in the EQ-5D Estimated Enrollment: 900 Study Start Date: September 2013 Estimated Study Completion Date: March 2018 Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure) Arms Experimental: LGX mg+MEK162 LGX mg QD + MEK162 45mg BID Active Comparator: vemurafenib Vemurafenib 960mg BID Assigned Interv entions MEK162- Orally 15 mg tablets Drug: vemurafenib Tablets in bottles or blisters 240mg Other Names: Zelboraf PLX4032 RO Experimental: LGX mg+MEK162 LGX mg QD + MEK162 45mg BID Experimental: LGX818 LGX mg QD MEK162- Orally 15 mg tablets Eligibility Ages Eligible for Study: Genders Eligible for Study: Accepts Healthy Volunteers: 18 Years and older Both No Criteria Inclusion Criteria:

4 Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknow n primary melanoma (AJCC Stage IIIB, IIIC, or IV) Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization Naïve untreated patients or patients w ho have progressed on or after prior first line immunotherapy for resectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other immunotherapy, radiotherapy or chemotherapy), except the administration of BRAF or MEK inhibitors Evidence of at least one measurable lesion as detected by radiological or photographic methods ECOG performance status of 0 or 1 Adequate bone marrow, organ function, cardiac and laboratory parameters Normal functioning of daily living activities Exclusion Criteria: Any untreated central nervous system (CNS) lesion Uveal and mucosal melanoma History of leptomeningeal metastases History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease. Any previous systemic chemotherapy treatment, extensive radiotherapy or investigational agent other than immunotherapy, or patients w ho have received more than one line of immunotherapy for locally advanced unresectable or metastatic melanoma; Ipilimumab (adjuvant) or other immunotherapy treatment must have ended at least 6 w eeks prior to randomization History of Gilbert's syndrome Prior therapy w ith a BRAF inhibitor and/or a MEK- inhibitor Impaired cardiovascular function or clinically significant cardiovascular diseases Uncontrolled arterial hypertension despite medical treatment HIV positive or active Hepatitis B, and/or active Hepatitis C Impairment of gastrointestinal function Patients w ith neuromuscular disorders that are associated w ith elevated CK. Pregnant or nursing (lactating) w omen Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply w ith the study protocol or complete the study Other protocol-defined inclusion/exclusion criteria may apply Contacts and Locations Choosing to participate in a study is an important personal decision. Talk w ith your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies. Please refer to this study by its ClinicalTrials.gov identifier: NCT Contacts Contact: Novartis Pharmaceuticals Contact: Novartis Pharmaceuticals Show 293 Study Locations Sponsors and Collaborators Novartis Pharmaceuticals Inv estigators Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals More Information No publications provided Responsible Party: Novartis ( Novartis Pharmaceuticals ) ClinicalTrials.gov Identifier: NCT History of Changes

5 Other Study ID Numbers: CMEK162B2301 Study First Received: July 24, 2013 Last Updated: January 29, 2015 Health Authority: Argentina: Ministry of Health Australia: National Health and Medical Research Council Brazil: Ministry of Health Canada: Health Canada Colombia: Institutional Review Board Czech Republic: State Institute for Drug Control France: Ministry of Health Germany: Federal Institute for Drugs and Medical Devices Hungary: Institutional Ethics Committee Israel: Ministry of Health Italy: The Italian Medicines Agency Japan: Pharmaceuticals and Medical Devices Agency Korea: Food and Drug Administration Mexico: Ministry of Health Netherlands: Medicines Evaluation Board (MEB) Norw ay: Norw egian Medicines Agency Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Portugal: National Pharmacy and Medicines Institute Russia: Ministry of Health of the Russian Federation Singapore: Ministry of Health Slovakia: State Institute for Drug Control South Africa: Medicines Control Council Spain: Spanish Agency of Medicines Sw eden: Medical Products Agency Sw itzerland: Sw issmedic Turkey: Ministry of Health United Kingdom: Medicines and Healthcare Products Regulatory Agency United States: Food and Drug Administration Keyw ords provided by Novartis: MEK162 Cutaneous melanoma Skin disease Skin cancer Skin Neoplasms Neoplasm Metastasis BRAF mutant BRAF V600E BRAF V600K Cancer Additional relevant MeSH terms: Neoplasms Neoplasms by Histologic Type Neoplasms, Germ Cell and Embryonal LGX818 vemurafenib combination BRAF inhibitor resistance The combination of a selective BRAF- and a MEK1/2-inhibitor Prior immunotherapy MEK inhibitor Phase III Combo 300, Combo 450 Neoplasms, Nerve Tissue Neuroectodermal Tumors Neuroendocrine Tumors Nevi and s ClinicalTrials.gov processed this record on March 12, 2015

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