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A Biomarker-Integrated Study in Patients with Advanced Non-Small Cell Lung Cancer Treated in the Front-Line (FL) Setting

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A Biomarker-Integrated Study in Patients with Advanced Non-Small Cell Lung Cancer Treated in the Front-Line (FL) Setting MDACC Protocol 2010-0097 BATTLE-FL Protocol March 7, 2013 BATTLE-FL: A Biomarker-Integrated Study in Patients with Advanced Non-Small Cell Lung Cancer Treated in the Front-Line (FL) Setting Principal Investigator: John Heymach, MD, PhD Co-Principal Investigator: William N. William, Jr., MD George Simon, MD Biostatistician: J. Jack Lee, PhD Pathology: Ignacio Wistuba, MD Dept. of Thoracic/Head and Neck Medical Oncology University of Texas M. D. Anderson Cancer Center 1 MDACC Protocol 2010-0097 BATTLE-FL Protocol March 7, 2013 Study Schema Consented, registered, and enrolled Biopsy performed Biomarker profile sent Biomarker results not needed prior to initiating treatment Treatment assignment Proceed with randomization (Arm 1) (Arm 2) (Arm 3) Carboplatin + Carboplatin + Carboplatin + Pemetrexed x 4 Pemetrexed + Pemetrexed + Interim Analysis for cycles followed Bevacizumab Cixutumumab followed by Futility (at the time by maintenance followed by maintenance maintenance of half the expected Pemetrexed Pemetrexed + Pemetrexed + failures) Bevacizumab Cixutumumab Pemetrexed Primary Endpoint is PFS; Sample size 225 patients. Restaging after 2 cycles of therapy Optional biopsy of tumor for biomarkers after 2 cycles Continue on study if stable or response. Up to 4 cycles of Pemetrexed/Carboplatin +/- biologic, then biologic treatment with Pemetrexed If progression, then off-study The trials with their respective drugs will be compared to one another. They will be analyzed individually based on their biomarker profiles and the likelihood of enhancing PFS based on the biomarkers. 2 MDACC Protocol 2010-0097 BATTLE-FL Protocol March 7, 2013 Table of Contents 1 OBJECTIVES ............................................................................................................................. 7 1.1 Primary Objectives ............................................................................................................... 7 1.2 Secondary Objectives ........................................................................................................... 7 1.3 Study Design ........................................................................................................................ 7 2 BACKGROUND AND RATIONALE ....................................................................................... 8 2.1 Non-Small Cell Lung Cancer ............................................................................................... 8 2.2 Molecularly Targeted Therapy in NCSLC ........................................................................... 9 2.3 Biomarker Driven Targeted Therapy Clinical Trials Program (BATTLE-1) .................... 10 2.4 RATIONALE ..................................................................................................................... 11 3 STUDY AGENTS .................................................................................................................... 13 3.1 Pemetrexed Background .................................................................................................... 13 3.2 Pemetrexed in Second-Line NSCLC Therapy ................................................................... 13 3.3 Pemetrexed in First-Line NSCLC Therapy ........................................................................ 14 3.4 Pemetrexed with Carboplatin in First-Line NSCLC Therapy ............................................ 15 3.5 Pemetrexed Maintenance Therapy in NSCLC ................................................................... 16 3.6 Bevacizumab Background .................................................................................................. 17 3.7 Bevacizumab in NSCLC .................................................................................................... 17 3.8 Cixutumumab (IMC-A12) Background ............................................................................. 18 3.8.1 Nonclinical Studies with Cixutumumab ...................................................................... 20 3.8.2 Cixutumumab Preclinical Toxicology and Pharmacokinetics ..................................... 20 3.8.3 Cixutumumab Clinical Studies .................................................................................... 24 3.8.4 Phase I ......................................................................................................................... 24 4 EXPERIMENTAL PLAN ........................................................................................................ 27 4.1 Overview of Study Design ................................................................................................. 27 4.2 Patient Assignment in the Biomarker-Integrated Clinical Trials ....................................... 28 4.3 Patient Eligibility ................................................................................................................ 29 4.3.1 Inclusion Criteria ......................................................................................................... 29 4.3.2 Exclusion Criteria ........................................................................................................ 30 4.4 Study Withdrawal ............................................................................................................... 31 3 MDACC Protocol 2010-0097 BATTLE-FL Protocol March 7, 2013 4.5 Treatment Plan ................................................................................................................... 32 5 CARBOPLATIN...................................................................................................................... 32 6 PEMETREXED ....................................................................................................................... 32 6.1 Investigational Product Description ................................................................................... 32 6.2 Drug Accountability ........................................................................................................... 33 6.3 Packaging and Storage ........................................................................................................ 33 6.4 Preparation and Administration ......................................................................................... 33 6.5 Pretreatment Medications ................................................................................................... 34 6.6 Treatment Schema .............................................................................................................. 34 6.7 Treatment Duration ............................................................................................................ 35 6.8 Concomitant Medications and Therapy ............................................................................. 35 6.9 Treatment of Pemetrexed Toxicity and Dose Modification: .............................................. 36 6.10 Hematologic Toxicity ....................................................................................................... 36 6.11 Creatinine Clearance ........................................................................................................ 36 6.12 Non-hematologic Toxicity ............................................................................................... 37 6.13 Dose Reductions ............................................................................................................... 37 7 BEVACIZUMAB .................................................................................................................... 39 7.1 Investigational Product Description ................................................................................... 39 7.2 Product Descriptions .......................................................................................................... 39 7.3 Pretreatment Medications and Testing ............................................................................... 39 7.4 Warnings and Precautions .................................................................................................. 39 7.5 Treatment of Infusion Reactions due to Bevacizumab ...................................................... 40 7.6 Treatment Schema .............................................................................................................. 40 7.7 Treatment Duration ............................................................................................................ 40 7.8 Treatment of Toxicity and Dose Modification ................................................................... 43 7.9 Other Toxicities .................................................................................................................. 45 8 CITUXUMUMAB ................................................................................................................... 45 8 Cixutumumab ......................................................................................................................... 45 8.1 Investigational Product Description ................................................................................... 45 8.2 Drug Accountability ........................................................................................................... 46 8.3 Package and Storage ........................................................................................................... 46 4 MDACC Protocol 2010-0097 BATTLE-FL Protocol March 7, 2013 8.4 Cixutumumab Dosage and Administration .......................................................................
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