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Alpelisib Plus Fulvestrant in PIK3CA-Altered

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Alpelisib Plus Fulvestrant in PIK3CA-Altered Clinical Development BYL719 Clinical Trial Protocol CBYL719X2101 A phase IA, multicenter, open-label dose escalation study of oral BYL719, in adult patients with advanced solid malignancies, whose tumors have an alteration of the PIK3CA gene Authors Document type Amended Protocol Version EUDRACT number 2010-018782-32 Version number 09 (Clean) Development phase Ia Document status Final Release date 03-Dec-2015 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis Downloaded From: https://jamanetwork.com/ on 09/27/2021 Novartis Confidential Page 2 Amended Protocol Version 09 (Clean) Protocol No. CBYL719X2101 Table of contents Table of contents ................................................................................................................. 2 List of figures ...................................................................................................................... 5 List of tables ........................................................................................................................ 5 List of Post-text supplements (PTS) .................................................................................... 6 List of abbreviations ............................................................................................................ 7 Amendment 9 .................................................................................................................... 11 Oncology clinical study protocol synopsis ........................................................................ 24 1 Background........................................................................................................................ 36 1.1 PI3K Alpha signaling in malignant cells ............................................................... 36 1.2 Overview of chosen cancer indications ................................................................. 37 1.3 Overview of BYL719 ............................................................................................ 38 1.3.1 Non-clinical pharmacokinetics and metabolism ................................... 39 1.3.2 Safety pharmacology and toxicology.................................................... 39 1.3.3 Genotoxicity study ................................................................................ 42 1.3.4 Biomarker development ........................................................................ 42 1.3.5 Clinical experience ................................................................................ 44 1.4 Overview of fulvestrant ......................................................................................... 44 1.4.1 Clinical experience with fulvestrant...................................................... 44 1.4.2 Combination of fulvestrant and PI3K inhibitors ................................... 44 1.4.3 Anticipated risks and safety considerations of the study drug combination ........................................................................................... 45 2 Study rationale/purpose ..................................................................................................... 45 3 Objectives .......................................................................................................................... 46 3.1 Primary objective ................................................................................................... 46 3.1.1 End-point for primary objective ............................................................ 46 3.2 Secondary objectives ............................................................................................. 46 3.2.1 End-points for secondary objectives ..................................................... 47 3.3 Exploratory objectives ........................................................................................... 47 3.3.1 End-points for exploratory objectives ................................................... 47 4 Study design ...................................................................................................................... 48 5 Population .......................................................................................................................... 50 5.1 Inclusion criteria .................................................................................................... 51 5.2 Exclusion criteria ................................................................................................... 52 6 Treatment........................................................................................................................... 54 6.1 Investigational and control drugs........................................................................... 54 Downloaded From: https://jamanetwork.com/ on 09/27/2021 Novartis Confidential Page 3 Amended Protocol Version 09 (Clean) Protocol No. CBYL719X2101 6.1.1 Study drug ............................................................................................. 54 6.1.2 How supplied ........................................................................................ 55 6.1.3 Preparation and storage ......................................................................... 55 6.2 Treatment arms ...................................................................................................... 55 6.3 Patient numbering .................................................................................................. 56 6.4 Treatment assignment ............................................................................................ 56 6.5 Treatment blinding................................................................................................. 56 6.6 Treating the patient ................................................................................................ 56 6.6.1 Study drug/study treatment administration ........................................... 56 6.6.2 Permitted study drug adjustments ......................................................... 66 6.6.3 Management of pneumonitis................................................................. 67 6.6.4 Other concomitant medications............................................................. 74 6.6.5 Study drug discontinuation ................................................................... 76 6.6.6 Premature patient withdrawal ............................................................... 77 6.6.7 Study evaluation completion ................................................................. 78 6.6.8 Emergency unblinding of treatment assignment ................................... 78 7 Visit schedule and assessments ......................................................................................... 78 7.1 Information to be collected on screening failures.................................................. 87 7.2 Patient demographics/other baseline characteristics ............................................. 87 7.3 Treatments ............................................................................................................. 87 7.4 Efficacy.................................................................................................................. 87 7.4.1 Efficacy assessment .............................................................................. 87 7.4.2 Tumor response ..................................................................................... 88 7.4.3 Tumor markers ...................................................................................... 88 7.5 Safety ..................................................................................................................... 89 7.5.1 Adverse events ...................................................................................... 89 7.5.2 Physical examination, neurological examination, weight, height ......... 91 7.5.3 Vital signs.............................................................................................. 91 7.5.4 Performance status ................................................................................ 92 7.5.5 Laboratory evaluations .......................................................................... 92 7.5.6 Radiological examinations .................................................................... 95 7.5.7 Cardiac assessments .............................................................................. 96 7.6 Tolerability ............................................................................................................ 97 7.7 Resource utilization ............................................................................................... 97 7.8 Patient-reported outcomes ..................................................................................... 97 7.9 Pharmacokinetics ................................................................................................... 97 Downloaded From: https://jamanetwork.com/ on 09/27/2021 Novartis Confidential Page 4 Amended Protocol Version 09 (Clean) Protocol No. CBYL719X2101 7.9.1 Pharmacokinetic blood sample collection and handling ....................... 98 7.9.2 Analytical method ............................................................................... 101 7.10 Biomarkers........................................................................................................... 101 7.10.1 Biomarker assessments in tumor samples ........................................... 102 7.10.2 Biomarker assessments in blood ........................................................
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