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A Phase Ib/II Study Evaluating the Safety and Efficacy Of Official Title: A Phase Ib/II Study Evaluating the Safety and Efficacy of Obinutuzumab in Combination With Atezolizumab Plus Polatuzumab Vedotin in Patients With Relapsed or Refractory Follicular Lymphoma and Rituximab in Combination With Atezolizumab Plus Polatuzumab Vedotin in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma NCT Number: NCT02729896 Document Date: Protocol Version 8: 07-November-2018 PROTOCOL TITLE: A PHASE Ib/II STUDY EVALUATING THE SAFETY AND EFFICACY OF OBINUTUZUMAB IN COMBINATION WITH ATEZOLIZUMAB PLUS POLATUZUMAB VEDOTIN IN PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA AND RITUXIMAB IN COMBINATION WITH ATEZOLIZUMAB PLUS POLATUZUMAB VEDOTIN IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA PROTOCOL NUMBER: BO29561 VERSION NUMBER: 8 EUDRACT NUMBER: 2015-004845-25 IND NUMBER: 128036 TEST PRODUCT: Obinutuzumab (RO5072759) Rituximab (RO0452294) Atezolizumab (RO5541267) Polatuzumab vedotin (RO5541077) MEDICAL MONITOR: , Ph.D. SPONSOR: F. Hoffmann-La Roche Ltd DATE FINAL: Version 1: 12 November 2015 DATES AMENDED: Version 2: 14 January 2016 Version 3: 28 June 2016 Version 4: 17 November 2016 Version 5: 4 May 2017 Version 6: 21 December 2017 Version 7: 1 May 2018 Version 8: See electronic date stamp below. PROTOCOL AMENDMENT APPROVAL Approver's Name Title Date and Time (UTC) Company Signatory 07-Nov-2018 02:00:10 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 The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential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. Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd Protocol BO29561, Version 8 PROTOCOL AMENDMENT, VERSION 8 RATIONALE Protocol BO29561 has been amended to include new safety information. Changes to the protocol, along with a rationale for each change, are summarized below: Lists of risks for atezolizumab and guidelines for managing patients who experience atezolizumab-associated adverse events have been revised to include nephritis (Sections 5.1.3 and 5.1.7.2 [Table 14]). Considering no new safety signals have been identified since protocol amendment Version 7, regular Internal Monitoring Committee assessments will no longer take place and ad hoc meetings maybe called at the discretion of the Medical Monitor in case of newly identified safety signals (Section 3.1.4). Post-trial access language was changed allowing patients still under study treatment to enter an extension study in case of earlier closure of Study BO29561 (Section 4.3.4). The Medical Monitor information has been updated (Section 5.4.1). The survival follow-up period has been added back to Appendices 1 and 2 for the assessment of new anti-lymphoma treatment and survival follow-up. Survival follow-up was removed in error during the previous amendment. Appendix 3 has been updated to remove pharmacokinetic sampling one year after the last dose of polatuzumab vedotin. As most of the patients have discontinued study treatment and have not provided this sample, collecting these data from the remaining patients (n 3) will be of limited value. Substantive new information appears in italics. Additional minor changes have been made to improve clarity and consistency. This amendment represents cumulative changes to the original protocol. Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 2/Protocol BO29561, Version 8 TABLE OF CONTENTS PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13 PROTOCOL SYNOPSIS .................................................................................... 14 1. BACKGROUND .......................................................................................... 25 1.1 Background on Non-Hodgkin's Lymphoma ........................... 25 1.1.1 Follicular Lymphoma ............................................................. 25 1.1.2 Diffuse Large B-Cell Lymphoma............................................ 25 1.2 Background on Obinutuzumab .............................................. 26 1.2.1 Nonclinical Studies with Obinutuzumab................................. 27 1.2.2 Clinical Studies with Obinutuzumab ...................................... 27 1.2.2.1 Clinical Safety of Obinutuzumab............................................ 27 1.2.2.2 Clinical Pharmacokinetics of Obinutuzumab.......................... 28 1.2.2.3 Clinical Efficacy of Obinutuzumab in Patients with Non-Hodgkin’s Lymphoma .................................................... 28 1.3 Background on Atezolizumab................................................ 29 1.3.1 Nonclinical Studies with Atezolizumab .................................. 30 1.3.2 Clinical Studies with Atezolizumab ........................................ 30 1.3.2.1 Summary of Clinical Safety of Atezolizumab ......................... 30 1.3.2.2 Clinical Pharmacokinetics of Atezolizumab ........................... 32 1.3.2.3 Summary of Clinical Activity of Atezolizumab........................ 32 1.4 Background on Polatuzumab vedotin .................................... 33 1.4.1 Nonclinical Studies with Polatuzumab Vedotin ...................... 33 1.4.2 Clinical Studies with Polatuzumab Vedotin............................ 34 1.4.2.1 Clinical Safety of Polatuzumab Vedotin................................. 34 1.4.2.2 Clinical Pharmacokinetics of Polatuzumab Vedotin .................................................................................. 35 1.4.2.3 Clinical Activity of Polatuzumab Vedotin................................ 36 1.5 Study Rationale and Benefit-Risk Assessment...................... 37 1.5.1 Rationale for Protocol BO29561, Version 7........................... 37 1.5.2 PD-L1/PD-1 Pathway in Lymphoma ...................................... 38 1.5.3 Clinical Experience with PD-L1/PD-1 Pathway Inhibitors in Lymphoma.......................................................... 38 1.5.4 Rationale for Treatment Combination.................................... 39 Obinutuzumab, Rituximab, Atezolizumab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 3/Protocol BO29561, Version 8 1.5.4.1 Mechanistic Rationale............................................................ 39 1.5.4.2 Nonclinical Data..................................................................... 40 1.5.4.3 Clinical Data .......................................................................... 41 1.5.5 Benefit-Risk Assessment....................................................... 44 2. OBJECTIVES AND ENDPOINTS ............................................................... 44 2.1 Safety Objective .................................................................... 45 2.2 Efficacy Objectives ................................................................ 45 2.2.1 Primary Efficacy Objective..................................................... 45 2.2.2 Secondary Efficacy Objectives .............................................. 45 2.2.3 Exploratory Efficacy Objectives ............................................. 46 2.3 Pharmacokinetic Objective .................................................... 46 2.4 Immunogenicity Objectives.................................................... 46 2.5 Biomarker Objective .............................................................. 46 3. STUDY DESIGN ......................................................................................... 47 3.1 Description of the Study......................................................... 47 3.1.1 Overview of Study ................................................................. 47 3.1.2 G Atezo Pola Treatment Group (Patients with Follicular Lymphoma) ............................................................ 48 3.1.2.1 Dose-Escalation Phase ......................................................... 48 3.1.2.2 Expansion Phase................................................................... 51 3.1.3 R Atezo Pola Treatment Group (Patients with Diffuse Large B-Cell Lymphoma)........................................... 51 3.1.3.1 Treatment Regimens and Safety Run-In Rules ..................... 51 3.1.4 Internal Monitoring Committee............................................... 52 3.1.5 Safety Follow-Up ................................................................... 53 3.2 End of Study and Length of Study ......................................... 53 3.3 Rationale for Study Design .................................................... 53 3.3.1 Rationale for Patient Population ............................................ 53 3.3.2 Rationale for Dose and Schedule .......................................... 54 3.3.2.1 Rationale for Obinutuzumab and Rituximab Dose and Schedule......................................................................... 54 3.3.2.2 Rationale for Atezolizumab Dose and Schedule.................... 54 3.3.2.3 Rationale for Polatuzumab Vedotin Dose and Schedule...............................................................................
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