Investigator Initiated Study IRB-29839 An open-label pilot study to evaluate the efficacy and safety of a combination treatment of Sonidegib and BKM120 for the treatment of advanced basal cell carcinomas Version 05 September 2016 NCT02303041 DATE: 12Dec2018 1 Coordinating Center Stanford Cancer Center 875 Blake Wilbur Drive Stanford, CA 94305 And 450 Broadway, MC 5334 Redwood City, CA 94603 Protocol Director and Principal Investigator Anne Lynn S Chang, MD, Director of Dermatological Clinical Trials 450 Broadway St, MC 5334 Redwood City, CA 94603 [email protected] Co-Investigator Anthony Oro, MD PhD 450 Broadway St, MC 5334 Redwood City, CA 94603 [email protected] Biostatistician Shufeng Li, MS 450 Broadway St, MC 5334 Redwood City, CA 94603 [email protected] Study Coordinator Ann Moffat 450 Broadway St, MC 5334 Redwood City, CA 94603 [email protected] 2 Table of Contents 1 Background ................................................................. 7 1.1 Disease Background ..................................................... 7 1.2 Hedgehog Pathway and mechanism of action ............................... 7 1.3 PI3K Pathway and mechanism of action ................................... 9 1.4 Sonidegib Compound Information ............ 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Bookmark not defined. 1.4.1 Preclinical Studies for Sonidegib ....................................................................11 1.4.2 Muscular system...............................................................................................13 1.4.3 Skeletal system ................................................................................................13 1.4.4 Reproductive system ........................................................................................14 1.4.5 Gastro-intestinal system ...................................................................................14 1.4.6 Renal system ....................................................................................................15 1.4.7 Clinical experience with Sonidegib..................................................................15 1.5 Buparlisib (BKM120)..............................................................................................20 1.5.1 Preclinical studies of Buparlisib.......................................................................20 1.5.2 Clinical experience with Buparlisib .................................................................25 1.6 Study Rationale .......................................................................................................32 2 Study objectives .........................................................................................................33 3 Exploratory Investigational plan ................................................................................34 3.1 Overall study design ...........................................................................................34 3.2 Study population..................................................................................................34 3.2.1 Patient population.........................................................................................34 3.2.2 Inclusion and exclusion criteria....................................................................35 4 Treatments ............................................................................................................... 40 4.1 Dose modification, interruption or discontinuation of treatment .............................40 4.1.1 Monitoring of buparlisib suspected toxicities ..............................................55 4.1.2 Known Undesirable Side Effects of buparlisib ............................................55 4.2 Treatment Administration.........................................................................................65 4.2.1 Buparlisib Administration ............................................................................65 4.2.2 Sonidegib Administration ............................................................................66 4.2.3 Concomitant therapy ....................................................................................67 4.3 Visit schedule and assessments ................................................................................74 4.3.1 Evaluation and Visit Schedule (Table 20).................................................... 74 4.3.2 Efficacy assessments ....................................................................................77 4.3.3 Safety assessments .......................................................................................77 4.3.4 Treatment compliance ..................................................................................78 4.3.5 Novartis instructions for rapid notification of serious adverse events .........80 5 Investigational agent sampling and shipping information .........................................84 5.1 Investigational treatment .....................................................................................84 5.2 How supplied .......................................................................................................85 5.2.1 Buparlisib .....................................................................................................85 5.2.2 Sonidegib...................................................................................................85 3 5.3 Storage and Preparation ...................................................................................85 5.4 Disposal and destruction...................................................................................86 6 Data management ...................................................................................................86 6.1 Data collection .................................................................................................86 6.1.1 Variables....................................................................................................87 6.2 Analysis of the primary and key secondary variable(s) ...................................87 7 Statistical methods...................................................................................................87 7.1 Statistical Methods ...........................................................................................87 7.1.1 Statistical model, hypothesis, and method of analysis...............................87 7.1.2 Handling of missing values/censoring/discontinuations ...........................87 8 References .............................................................................................................88 9 APPENDICES........................................................................................................91 4 List of abbreviations AE Adverse Event AKT See PKB (protein Kinase B) ALT Alanine aminotransferase/glutamic pyruvic transaminase/GPT ANC Absolute Neutrophil Count AST Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT BUN Blood Urea Nitrogen CBC Complete Blood Count CK Creatinine Kinase / Phosphokinase CK-MB Creatinine Kinase – Muscle and Brain isoenzyme CR Complete Response CRD Clinical Research and Development CS Cowden Syndrome CT Computed Tomography CTC Circulating Tumor Cells CTCAE Common Terminology Criteria for Adverse Events DLT Dose Limiting Toxicity DSMB Drug Safety Monitoring Board ECG Electrocardiogram ECHO Echocardiogram EGFR Epidermal Growth Factor Receptor 18F-FDG [18F]-Fluorodeoxyglucose FPG Fasting Plasma Glucose GCP Good Clinical Practice GI Gastrointestinal HIV Human Immunodeficiency Virus ICH International Conference on Harmonization HDL High density lipoprotein IEC Independent Ethics Committee IRB Institutional Review Board LDL Low density lipoprotein LVEF Left Ventricular Ejection fraction MRI Magnetic Resonance Imaging MTD Maximum Tolerated Dose MUGA Multiple Gated Acquisition Scan PD Pharmacodynamic PET Positron Emission Tomography PI3K Phosphatidylinositol 3’- kinase PK Pharmacokinetic PKB Protein Kinase B (or AKT) PT Prothrombin Time 5 PTEN Phosphatase and Tensin homolog PTT Partial Thromboplastin Time (also known as APTT) QTc QT interval (corrected) RBC Red Blood Cells REB Research Ethics Board RECIST Response Evaluation In Solid Tumors S6K Protein Kinase S6 SAE Serious adverse event SOP Standard Operating Procedure SUV Standardized Uptake Value TTP Time to Progression ULN Upper Limit of Normal WBC White Blood Count WCBP Women of Childbearing Potential WHO World Health Organization 6 1 Background 1.1 Disease Background Basal cell carcinoma (BCC) is the most common human malignancy with an estimated 2 million cases diagnosed annually (American Cancer Society 2010). Most of these forms of skin cancer are highly curable if found and treated early. However, a fraction of these are highly aggressive and difficult-to-treat with conventional therapies. These can become life-threatening and even metastasize to distant organs. These BCCs are collectively termed advanced BCCs (aBCCs). Recently, the Smoothened inhibitor (SI) class of drugs has emerged as a highly targeted therapy for BCCs resulting in the ability to shrink BCCs while causing minimal collateral damage. (Sekulic et al., 2012) However, less than 50% of aBCCs respond to (SIs). Of those that respond, approximately 20% become resistant to SIs after 1 year. (Chang and Oro, 2012) Recently, our group has identified one mechanism of SI drug resistance, specifically increase in the PI3 kinase pathway (Chang et al., 2013, in press) Hence, we propose a preliminary proof-of-principle clinical trial to describe the overall