Study Protocol
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2012N149024_05 CONFIDENTIAL The GlaxoSmithKline group of companies EZH117208 TITLE PAGE Division: Worldwide Development Information Type: Protocol Amendment Title: A phase I open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2816126 in subjects with relapsed/refractory diffuse large B cell lymphoma, transformed follicular lymphoma, other Non-Hodgkin’s lymphomas, solid tumors and multiple myeloma Compound Number: GSK2816126 Development Phase: I Effective Date: 20-MAR-2017 Protocol Amendment Number: 5 Author (s): PPD Global Clinical Operations Sciences, USA Drug Metabolism and Pharmacokinetics, USA Cancer Epigenetics, USA Non--Clinical Safety, USA Cancer Research Epigenetics Management, USA Non-Clinical Safety, USA Statistics, Oncology TA Group, USA Global Clinical Operations Sciences, USA Clinical Oncology, USA Clinical Oncology, USA Cancer Epigenetics DPU, USA Clinical Pharmacology Modeling & Simulation, USA Statistics, Oncology TA Group, USA Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 1 2012N149024_05 CONFIDENTIAL The GlaxoSmithKline group of companies EZH117208 Revision Chronology GlaxoSmithKline Date Version Document Number 2012N149024_00 2013-JUL-11 Original 2012N149024_01 2013-OCT-23 Amendment No. 1 applies only to sites in the UK. Following review of the protocol by the MHRA, the following changes were made: 1. Removed wording from the protocol stating that GSK2816126 treatment will continue until commercial availability. 2. The stopping criterion based on QTc will be changed to ≥500 msec. 3. Added a QTc stopping criterion that patients will be withdrawn if they experience an increase in QTc >60msec from baseline following dose reduction and re-challenge. 2012N149024_02 2013-OCT-30 Amendment No.: 02 applies to all study sites. Following review of the protocol by the FDA, the following changes were made: 1. The starting dose of GSK2816126 is reduced from 125 mg/dose to 50 mg/dose 2. Updated Dose Limiting Tox language 3. Revised 100% dose escalation wording 4. Decreased QTc baseline exclusion criterion 5. Added regular ECG monitoring timings 6. Added blood glucose testing to our list of clinical lab tests 7. Removed any wording pertaining to the use of central labs 8. Removed wording from the protocol stating that GSK2816126 treatment will continue until commercial availability 9. Clarify that PET scans are optional 10. Elaborated on CT scan timings 11. The stopping criterion based on QTc will be changed to ≥500 msec 12. Added a QTc stopping criterion that subjects will be withdrawn if they experience 2 2012N149024_05 CONFIDENTIAL The GlaxoSmithKline group of companies EZH117208 an increase in QTc >60 msec from baseline following dose reduction and re-challenge 13. Added explanatory language to T&E Table around coagulation, CT and standalone PET assessments 14. Changed corticosteroid exclusion criteria 2012N149024_03 2015-APR-03 Amendment No. 03 03 applies to all study sites and includes the addition of solid tumor malignancies and other NHLs to Part 1 of the study, transformed follicular lymphoma subjects to Part 2 and multiple myeloma subjects to both Part 1 and 2. The protocol title, study rationale, objectives, endpoints, hypotheses, inclusion/exclusion criteria, background, preclinical pharmacology and safety, risk/benefits, investigational plan, population rationale, T&E table, tumor biomarker analysis have all been updated to reflect these changes. RECIST criteria and multiple myeloma response criteria have also been added. A description of genetic research has been added to the appendix. To accommodate these changes we have also augmented the number of subjects, evaluation of futility, organ function table, data management and statistical analysis. Other additions include dose adjustment for hematologic and non hematologic toxicity, description of the investigational product and time windows for the PK sample collection table. Additions were also made to the Pharmacodynamics and Translational Research sections to cover potential studies in a surrogate tissue. Updated the Prohibited Meds Table 13 and Table 14. Removed PD analysis from Part 2. 2012N149024_04 2016-MAR-17 Amendment No. 4 Amendment 04 applies to all study sites and includes the following updates: 1. Updated primary and secondary medical monitor contact information 2. Extend the period of post treatment contraception for women to 2 weeks (14 days) (previously 1 week). 3. Updated requirement for pregnancy test to within 7 days of first dose (previously within 14 days of first dose) and added requirements for repeat testing every 4 weeks. 4. Added requirement that any female subject who becomes pregnant while on study be withdrawn from the study. 5. Added that subjects be instructed to avoid excess exposure to sunlight and UV and to use protective measures if outdoors. 6. Modified the storage period for diluted investigational product prior to infusion to 12 hours (previously 48 hours). 7. Updated prohibited medications to clarify exclusion of IV ondansetron and palonosetron (oral doses up to 8mg TID are permitted). 3 2012N149024_05 CONFIDENTIAL The GlaxoSmithKline group of companies EZH117208 2012N149024_05 2017-MAR-20 Amendment No. 5 Amendment 5 applies to all global sites. Updates were made throughout the protocol to correct minor inconsistencies, spelling errors and provide further clarification. The following updates have been made to the this amendment to align with updated GSK SOPs and Guidance documents, as well as, to include expansion cohorst in Part 1 of the study to explore further efficacy and safety data: Updates made to the Part 1 and Part 2 Objectives, Endpoints and study hypothesis to align with the added Part 1 expansion cohorts of GCB DLBCL and solid tumors containing EZH2 inhibitor sensitizing mutations or prostate cancer to support MTD/RP2D and initiation of planned part 2 analysis Study design and number of subjects updated to include the added Part 1 expansion cohorts and update Part 2 expansion cohort Inclusion and exclusion criteria updated to define eligibility of GCB DLBCL and solid tumor subjects in Part 1 expansion cohort. Exclusion for Central nervous system metastases, invasive malignancy other than disease under study and prior allogeneic transplant added. Male and female contraception use and pregnancy information updated in inclusion criteria and Section 10 to align with GSK written standards Statistical methods/Section 12 updated to include Part 1 interim analysis of futility and efficacy for GCB DLBCL subjects. Part 2 updated to further clarify that expansion design is planned based on predictive probability methodology. Rather than early stop for either futility or efficacy, Part 2 allows early stop for futility only. Number of subjects to be enrolled into the Part 2 expansion cohorts updated accordingly Risk Assessment updated to include: updated list of medications with risk and possible risk of tpd that are prohibited or to be used with caution; drugs that are to be used with caution will require additional ECG monitoring; clarify instructions for the treatment of infusion reactions; new drug interaction data; additional data and instructions for phototoxicity; and data and mitigation strategy for increased ALT levels seen in higher doses. PK/PD cohort moved from Part 1 to Part 2 Study rationale updated to include supporting rationale for inclusion of GCB- DLBCL and solid tumor subjects (to include prostate cancer) Safety management guidelines updated to clarify QTcF to be used for eligibility 4 2012N149024_05 CONFIDENTIAL The GlaxoSmithKline group of companies EZH117208 and stopping criteria Time and Events tables updated to clarify required assessments. Added clarification that brain scans are required for all subjects at screening and bone scans should be completed as clinically indicated. Collection of Blood for PD biomarkers removed and collection of whole blood for biomarkers added Response criteria added for subjects with prostate cancer in Appendix 7 of the protocol Adverse event and serious adverse event Section 8 updated to align with latest GSK written standards, to include: further definition of events which would meet liver stopping and monitoring criteria, as well as, definition and process for study treatment restart and rechallenge after a liver event and removal of Section 8.4 addressing disease related event Section 9 updated with latest list of prohibited medications and those to be used with caution 5 PPD PPD PPD 2012N149024_05 CONFIDENTIAL EZH117208 SPONSOR/MEDICAL MONITOR INFORMATION PAGE Medical Monitor and Sponsor Contact Information: Role Name Day Time Phone After-hours GSK Address Number Phone/Cell/ Pager Number Primary PPD PPD PPD 1250 South Collegeville Road, Medical PPD MD, Mailstop UP 4410 Monitor PhD Collegeville, PA 19426, USA PPD Secondary PPD Office: PPD PPD 1250 South Collegeville Road, Medical MD Mailstop UP 4410 Monitors Cell: PPD Collegeville, PA 19426, USA PPD PPD Office: PPD PPD 1250 South Collegeville Road, Mailstop UP 4410 Collegeville, PA 19426, USA PPD Sponsor Registered Address: GlaxoSmithKline Iron Bridge Road Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK Telephone: PPD GlaxoSmithKline Five Moore Drive P.O. 13398 Research Triangle Park, NC 27709-3398, USA Telephone: PPD GlaxoSmithKline 1250 South Collegeville Road Collegeville, PA 19426, USA Telephone Number: PPD In some countries,