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Study Protocol and Statistical Analysis Plan Official Title: A Phase III, Multicenter, Randomized Study of Atezolizumab (Anti-PD- L1 Antibody) in Combination With Enzalutamide Versus Enzalutamide Alone in Patients With Metastatic Castration-Resistant Prostate Cancer After Failure of an Androgen Synthesis Inhibitor and Failure of, Ineligibility for, or Refusal of a Taxane Regimen NCT Number: NCT03016312 Document Date: Protocol Version 8: 14 February 2020 PROTOCOL TITLE: A PHASE III, MULTICENTER, RANDOMIZED STUDY OF ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) IN COMBINATION WITH ENZALUTAMIDE VERSUS ENZALUTAMIDE ALONE IN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER AFTER FAILURE OF AN ANDROGEN SYNTHESIS INHIBITOR AND FAILURE OF, INELIGIBILITY FOR, OR REFUSAL OF A TAXANE REGIMEN PROTOCOL NUMBER: CO39385 VERSION NUMBER: 8 EUDRACT NUMBER: 2016-003092-22 IND NUMBER: 131196 TEST PRODUCTS: Atezolizumab (RO5541267) and enzalutamide MEDICAL MONITOR: , M.D., Ph.D. SPONSOR: F. Hoffmann-La Roche Ltd DATE FINAL: Version 1: 29 September 2016 DATES AMENDED: Version 2: 7 March 2017 Version 3: 4 April 2017 Version 4: 29 June 2017 Version 5: 2 March 2018 Version 6: 23 August 2018 Version 7: 5 August 2019 Version 8: See electronic date stamp below. PROTOCOL AMENDMENT APPROVAL Date and Time (UTC) Title Approver's Name 14-Feb-2020 17:27:37 Company Signatory CONFIDENTIAL This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, including Genentech, Inc. in the United States. The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional Review Board. It is understood that this information will not be disclosed to others without written authorization from Roche except to the extent necessary to obtain informed consent from persons to whom the drug may be administered. Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd Protocol CO39385, Version 8 TABLE OF CONTENTS PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10 PROTOCOL SYNOPSIS .................................................................................... 11 1. BACKGROUND .......................................................................................... 27 1.1 Background on Prostate Cancer............................................ 27 1.1.1 Current Therapies for Metastatic Prostate Cancer ................ 27 1.1.2 Treatment Patterns for Metastatic Prostate Cancer................................................................................... 30 1.2 Background on Atezolizumab................................................ 31 1.3 Study Rationale and Benefit-Risk Assessment...................... 32 1.3.1 Rationale for Treatment with Atezolizumab ........................... 32 1.3.2 Rationale for Combination Treatment with Atezolizumab and Enzalutamide ........................................... 33 1.3.2.1 Androgen Deprivation Therapy.............................................. 33 1.3.2.2 Enzalutamide......................................................................... 33 1.3.2.3 Atezolizumab Tolerability Profile during Combination Treatment ......................................................... 34 1.3.3 Benefit-Risk Assessment....................................................... 34 2. OBJECTIVES AND ENDPOINTS ............................................................... 34 3. STUDY DESIGN ......................................................................................... 38 3.1 Description of the Study......................................................... 38 3.2 Independent Data Monitoring Committee .............................. 42 3.3 End of Study and Length of Study ......................................... 44 3.4 Rationale for Study Design .................................................... 44 3.4.1 Rationale for Atezolizumab Dose and Schedule.................... 44 3.4.2 Rationale for Patient Population ............................................ 45 3.4.3 Rationale for Choice of Enzalutamide ................................... 46 3.4.4 Rationale for Open-Label Design .......................................... 47 3.4.5 Rationale for Stratification Factors......................................... 47 3.4.6 Rationale for Safety Run-In ................................................... 48 3.4.7 Rationale for the Use of Response Criteria ........................... 49 3.4.7.1 PCWG3 Criteria..................................................................... 49 Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd 3/Protocol CO39385, Version 8 3.4.8 Rationale for Treatment Beyond Radiographic Progression ........................................................................... 49 3.4.9 Rationale for Biomarker Assessments................................... 49 3.4.9.1 Rationale for Collection of Tumor Specimens (Fresh and/or Archival) .......................................................... 49 3.4.9.2 Rationale for Collection of Tumor Specimens at Progression ........................................................................... 50 3.4.9.3 Rationale for Blood and Urine Sampling for Biomarkers ............................................................................ 50 3.4.9.4 Rationale for Sampling for Genomics Analysis...................... 50 3.4.10 Rationale for Patient-Reported Outcome Assessments ......................................................................... 51 4. MATERIALS AND METHODS .................................................................... 51 4.1 Patients.................................................................................. 51 4.1.1 Inclusion Criteria.................................................................... 52 4.1.2 Exclusion Criteria................................................................... 54 4.2 Method of Treatment Assignment and Blinding ..................... 58 4.3 Study Treatment .................................................................... 59 4.3.1 Formulation, Packaging, and Handling.................................. 59 4.3.1.1 Atezolizumab ......................................................................... 59 4.3.1.2 Enzalutamide......................................................................... 59 4.3.2 Dosage, Administration, and Compliance.............................. 59 4.3.2.1 Atezolizumab ......................................................................... 59 4.3.2.2 Enzalutamide......................................................................... 60 4.3.3 Investigational Medicinal Product Accountability ................... 61 4.3.4 Post-Study Access to Atezolizumab ...................................... 61 4.4 Concomitant Therapy ............................................................ 62 4.4.1 Permitted Therapy ................................................................. 62 4.4.2 Cautionary Therapy for Atezolizumab ................................... 63 4.4.3 Cautionary Therapy for Enzalutamide ................................... 64 4.4.4 Prohibited Therapy ................................................................ 64 4.5 Study Assessments ............................................................... 65 4.5.1 Informed Consent Forms and Screening Log........................ 65 Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd 4/Protocol CO39385, Version 8 4.5.2 Medical History, Concomitant Medication, and Demographic Data................................................................. 65 4.5.3 Physical Examinations........................................................... 66 4.5.4 Vital Signs.............................................................................. 66 4.5.5 Tumor and Response Evaluations......................................... 66 4.5.6 Laboratory, Biomarker, and Other Biological Samples................................................................................. 67 4.5.7 Electrocardiograms................................................................ 71 4.5.8 Patient-Reported Outcomes .................................................. 72 4.5.8.1 EORTC QLQ-C30.................................................................. 73 4.5.8.2 EORTC Quality-of-Life: Urinary Scale (QLQ-PR25) .......................................................................... 73 4.5.8.3 Pain Assessments: Selected Questions from BPI and BPI-SF............................................................................ 73 4.5.8.4 Analgesic Log........................................................................ 74 4.5.8.5 PRO-CTCAE ......................................................................... 74 4.5.8.6 EQ-5D-5L .............................................................................. 74 4.5.9 Optional Samples for Research Biosample Repository ............................................................................. 75 4.5.9.1 Overview of the Research Biosample Repository.................. 75 4.5.9.2 Approval by the Institutional Review Board or Ethics Committee .................................................................. 75 4.5.9.3 Sample Collection.................................................................. 75 4.5.9.4 Confidentiality .......................................................................
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