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Study Protocol Official Title: A Randomized Study Comparing Maintenance Therapy With Subcutaneous Rituximab Continued Until Progression With Observation Only In Patients With Relapsed or Refractory, Indolent Nonhodgkin’s Lymphoma Who Completed and Responded To Rituximab-Based Immunochemotherapy Induction and Initial 2-Year Rituximab Maintenance Therapy Administered Subcutaneously NCT Number: NCT 01461928 Document Date: Protocol Amendment Summary, Version 4.0, dated 06-Jul-2017 Protocol, Version 4.0, 11-Jul-2017 SPONSOR: F. HOFFMANN-LA ROCHE LTD Grenzacherstrasse 124 CH-4070 Basel, Switzerland CLINICAL STUDY PROTOCOL TITLE: A RANDOMIZED STUDY COMPARING MAINTENANCE THERAPY WITH SUBCUTANEOUS RITUXIMAB CONTINUED UNTIL PROGRESSION WITH OBSERVATION ONLY IN PATIENTS WITH RELAPSED OR REFRACTORY, INDOLENT NON- HODGKIN’S LYMPHOMA WHO COMPLETED AND RESPONDED TO RITUXIMAB-BASED IMMUNOCHEMOTHERAPY INDUCTION AND INITIAL 2-YEAR RITUXIMAB MAINTENANCE THERAPY ADMINISTERED SUBCUTANEOUSLY PROTOCOL NUMBER: MO25455 VERSION NUMBER: 4.0 EUDRACT NUMBER: 2010-023407-95 IND NUMBER: Not applicable TEST PRODUCT: Rituximab (RO 045-2294) MEDICAL MONITOR: Dr. SPONSOR: F. Hoffmann-La Roche Ltd DATE FINAL: Version 1: 19 April 2011 DATES AMENDED: Version 2: 26 July 2012 Version 3: 23 September 2012 Version 4: 06 July 2017 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 The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential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 Rituximab - F. Hoffmann-La Roche Ltd Protocol MO25455 Version 4.0 Page 1 of 5 35272&2/$0(1'0(179(56,21 5$7,21$/( 7KHLQWHQWLRQRIWKHSURWRFROKDVEHHQWRFROOHFWDGYHUVHHYHQW $( DQGVHULRXVDGYHUVH HYHQW 6$( LQIRUPDWLRQIURPSDWLHQWVGXULQJPDLQWHQDQFH,,RQDUPV$DQG%LQRUGHUWR SHUIRUPDVDIHW\FRPSDULVRQDVSDUWRIWKHVHFRQGDU\REMHFWLYH+RZHYHU7DEOHLQ SURWRFROYHUVLRQSHUPLWVWKHFHVVDWLRQRI$(DQG6$(GDWDFROOHFWLRQIURPSDWLHQWV RQDUP%GD\VSRVWWUHDWPHQW3URWRFROYHUVLRQZDVZULWWHQWREDODQFHWKH$( DQG6$(UHSRUWLQJUHTXLUHPHQWV • 7DEOHKDVEHHQUHYLVHGWRFODULI\WKH$(DQG6$(UHSRUWLQJGXUDWLRQ $GGLWLRQDOPLQRUFKDQJHVKDYHEHHQPDGHWRLPSURYHFODULW\DQGFRQVLVWHQF\ • 7KH HQG RI VWXG\ VHFWLRQ LQ WKH V\QRSVLV RI SURWRFRO ZDV UHYLVHG WR FODULI\ WKDW PDLQWHQDQFH ,, DUP % SDWLHQWV DUH H[SHFWHG WR IROORZ WKH VDPH VFKHGXOH RI DVVHVVPHQWDVSDWLHQWVRQDUP$ • 3URWRFROFRYHUSDJHSURWRFRODPHQGPHQWDFFHSWDQFHIRUPDQGDSSHQGL[XQGHU WKHVHFWLRQRIPHGLFDOPRQLWRUFRQWDFWLQIRUPDWLRQIRUDOOVLWHVKDYHEHHQUHYLVHGWR UHIOHFWWKHQHZ5RFKHPHGLFDOFRQWDFW • 3URWRFROFRYHUSDJHKDVEHHQUHYLVHGWRUHIOHFWWKHQHZ5RFKHVWDWLVWLFLDQ • 7KH QXPEHU RI SDWLHQWV VHFWLRQ LQ WKH V\QRSVLV RI SURWRFRO DQG 6HFWLRQ ZHUH XSGDWHGWRUHIOHFWWKHILQDOQXPEHURISDWLHQWVUDQGRPL]HGWRPDLQWHQDQFH,,WKHUDS\ DQGWKHHQUROPHQWWLPHOLQH • 6HFWLRQ7DEOHIRRWQRWHV L DQG W VHFWLRQVHFWLRQVHFWLRQ VHFWLRQZHUHUHYLVHGWRUHPRYHWKHUHIHUHQFHWRVWDEOHGLVHDVHDWWKHHQGRI PDLQWHQDQFH, • 6HFWLRQ KDV EHHQUHYLVHG WR FODULI\ WKDWWKH WULDO FDQ EH VWRSSHG LI WKH WK 3)6HYHQWKDVEHHQUHSRUWHG • ,Q 7DEOH IRU WKH ULWX[LPDE WUHDWPHQW DGPLQLVWUDWLRQ URZ WKH IRRWQRWH OLQN LQ WKH 0DLQWHQDQFH,,FROXPQZDVFRUUHFWHG • ,QWKHQRWHVVHFWLRQIRU7DEOHDQGVHFWLRQFODULILFDWLRQZDVDGGHGUHJDUGLQJ WKHPRYHPHQWRISDWLHQWVLQWRRIIWUHDWPHQWIROORZXSIROORZLQJWKHHQGRIWUHDWPHQW RUWKHLUSDUWLFLSDWLRQLQPDLQWHQDQFH,,DUP% • 6HFWLRQ KDV EHHQ UHYLVHG UHPRYLQJ WKH JXLGDQFH WR UHFRUG DQG DVVHVV WKH LQGLYLGXDO V\PSWRPV RI LQIXVLRQ UHODWHG UHDFWLRQV DQG DGPLQLVWUDWLRQ UHODWHG UHDFWLRQV • 6SHOOLQJHUURUVZHUHFRUUHFWHGWKURXJKRXWWKHSURWRFRO 7KLVDPHQGPHQWUHSUHVHQWVFXPXODWLYHFKDQJHVWRWKHRULJLQDOSURWRFRO 5LWX[LPDE)+RIIPDQQ/D5RFKH/WG 3URWRFRO029HUVLRQ 3DJHRI PROTOCOL AMENDMENT, VERSION 4.0: SUMMARY OF CHANGES GLOBAL CHANGES International Scientific Director has replaced International Medical Director as protocol approver and Medical Monitor Contact Information for All Sites. Statistician has replaced Statistician. PROTOCOL SYNOPSIS The protocol synopsis has been updated to reflect the changes to the protocol, where applicable. SECTION 3.1: OVERVIEW OF STUDY DESIGN Old Text: Response assessment will be conducted by the Investigator every 6 months during Maintenance I according to the Cheson response criteria for indolent lymphoma1 (see Appendix 1) or by the recommendations for Waldenström’s macroglobulinemia2 (see Appendix 2). Patients with PD at any time during the study will come off study treatment and will start Off-Treatment Follow-Up, being followed for survival until the end of the study. Patients with SD at the end of Maintenance I will come off study treatment and will enter Off-Treatment Follow-Up, being followed for PD and survival until the end of the study. SECTION 3.2: NUMBER OF PATIENTS / ASSIGNMENT TO TREATMENT GROUPS Old text: Approximately 700 enrolled patients are expected to yield a minimum of 330 randomized patients (Maintenance II). The estimated recruitment period is approximately 24 months. New text: Approximately 700 enrolled patients were expected to yield a minimum of 330 randomized patients (maintenance II). At the conclusion of enrolment and all randomizations 694 patients were enrolled and 276 patients were randomized to maintenance II. The recruitment period was expected to be approximately 24 months. Enrolment of the 694 patients required 31 months TABLE 5: SCHEDULE OF ASSESSMENTS In Table 5 for the rituximab treatment administration row the footnote in the Maintenance II column was incorrectly associated to footnote (t). The association was corrected to footnote (u). Rituximab - F. Hoffmann-La Roche Ltd Protocol MO25455 Version 4.0 Page 3 of 5 Footnote (i): Old text: Patients with SD at the end of either Induction or Maintenance I will come off study treatment and will enter Off-Treatment Follow-Up, being followed every 6 months for PD and survival until the end of the study. Note: New text: After the end-of-treatment or the end of participation in observation arm B all patients will enter Off-Treatment Follow-up and be followed for resolution of AEs related to SC rituximab induction/maintenance therapy as per Table 14, survival, disease status (which might include bone marrow and tumour assessment if PD not already documented) and whether a new anti-lymphoma treatment has been started. SECTION 5.1.3: Assessments during the Treatment Period Old text: Patients with SD at the end of either Induction or Maintenance I will come off study treatment and will enter Off-Treatment Follow-Up, being followed every 6 months for PD and survival until the end of the study. SECTION 5.1.3.2: Maintenance I Old text: Patients with PD at any time during the study will come off study treatment and will start Off-Treatment Follow-Up, being followed for survival until the end of the study. Patients with SD at the end of Maintenance I will come off study treatment and will enter Off-Treatment Follow-Up, being followed for PD and survival until the end of the study. SECTION 5.1.5: End of Treatment Assessments Old text: Patients with SD at the end of either Induction or Maintenance I will come off study treatment and will enter Off-Treatment Follow-Up, being followed every 6 months for PD and survival until the end of the study. SECTION 5.1.6: Off-Treatment Follow-up Old text: After discontinuation of study treatment patients will enter Off-Treatment Follow-up and will be followed every 6 months until the end of the whole study for resolution of all SAEs, survival, disease status (which might include bone marrow and tumour assessment if PD not already documented) and whether a new anti-lymphoma treatment has been started. New text: After discontinuation of study treatment or participation in observation Arm B patients will enter Off-Treatment Follow-up and will be followed every 6 months until the end of the whole study for resolution of all SAEs, survival, disease status (which Rituximab - F. Hoffmann-La Roche Ltd Protocol MO25455 Version 4.0 Page 4 of 5 might include bone marrow and tumour assessment if PD not already documented) and whether a new anti-lymphoma treatment has been started. SECTION 5.2.1: Tumour Response Criteria Old text: At the end of Maintenance I, patients with PD or SD will come off study treatment. Patients with PD will start Off-Treatment Follow-Up, being followed for survival until the end of the study. Patients with SD will enter Off-Treatment Follow-Up, being followed for PD and survival until the end of the study. Patients having a CR or PR will be randomized and will continue into Maintenance II. SECTION 5.2.1: Tumour Response Criteria Old text: At the end of Maintenance I, patients with PD or SD will come off study treatment. Patients with PD will start Off-Treatment Follow-Up, being followed for survival until the end of the study. Patients with SD will enter Off-Treatment Follow-Up, being followed for PD and survival until the end of the study. Patients having a CR or PR will be randomized and will continue into Maintenance II. Table 14: Duration of Reporting and Follow-up of Adverse Events Table 14 has been revised to clarify
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