Operations Office – Boston March 2, 2016 Martha Kruhm, MS RAC Head, Protocol and Information Office Quality Assurance Section CTEP, DCT, NCI 6130 Executive Blvd, EPN Room 7000 Bethesda, MD 20892 Dear Ms. Kruhm: Enclosed is Addendum #5 to E3611, A Randomized Phase II Study of Ipilimumab at 3 mg/kg or 10 mg/kg Alone or in Combination with High Dose Interferon-α in Advanced Melanoma. This amendment is in response to Drs. Howard Streicher, James Zwiebel, and Meg Mooney’s Request for Rapid Amendment on March 1, 2016. The following revisions to E3611 protocol have been made in this addendum: Section Change 1. Cover page Updated version date 2. Section 5.3 Replaced ipilimumab CAEPR with updated Version 2.7, June 28, 2015 The following revisions to E3611 Informed Consent Document have been made in this addendum: Section Change 1. Cover page Updated version date 2. “Non immune-based Removed instructional text titled “Please note the following in reviewing Risks Associated these risks” and replaced condensed risk list with updated Version 2.7, with Ipilimumab” June 28, 2015 If you have any questions regarding this addendum, please contact [email protected] or 617-632-3610. We request review and approval of this addendum to E3611 so ECOG-ACRIN may activate it promptly. Thank you. i 900 Commonwealth Avenue, Boston, MA 02215 p: 617.632.3610 f: 617.632.2990 ecog-acrin.org Sincerely, Pamela Cogliano Protocol Development Manager Enclosure CC: Ahmad Tarhini, MD, PhD Carol Chami, R.N. Sandra Lee, ScD Melinda Flood Uma Rao, MD Bruce Giantonio, M.D. Robert L. Comis, M.D John Kirkwood, MD Kerry Higgins Ross Goldberg Mary Steele Sarah Archambault Jean MacDonald Donna Marinucci James Corkery Lauren Lambert Amy Li Lam Le ii E3611 A Randomized Phase II Study of Ipilimumab at 3 mg/kg or 10 mg/kg Alone or in Combination with High Dose Interferon-α in Advanced Melanoma STUDY CHAIR: Ahmad A. Tarhini MD, PhD STUDY CO-CHAIR: John M Kirkwood, MD STUDY STATISTICIAN: Sandra Lee, ScD PATHOLOGY CO-CHAIR: Uma Rao, MD MELANOMA COMMITTEE CHAIR: John M Kirkwood, MD Version Date: March 2, 2016 STUDY PARTICIPANTS ACTIVATION DATE US Sites Only December 27, 2012 Addendum #1 – Incorporated prior to activation Addendum #2 – 5/14 Addendum #3 - 10/14 Addendum #4 - 4/15 Addendum #5 – 3/16 Agents IND# NSC# Supply Ipilimumab 10200 732442 NCI Supplied Interferon 377523 Commercial 1 ECOG-ACRIN E3611 Cancer Research Group Version Date: March 2, 2016 Table of Contents Schema ...................................................................................................................... 6 1. Introduction ........................................................................................................ 7 1.1 Management of Metastatic Melanoma and the Role of CTLA4 Blockade 7 1.2 IFN-2b and the Role of High-Dose IFN-α2b (HDI) as Adjuvant Therapy for High-risk Resected Melanoma ............................................................. 8 1.3 CTLA-4 and T Cell Activation ..................................................................... 9 1.4 Summary of Results of Investigational Program of Ipilimumab ............. 10 1.5 Overall Risk/Benefit Assessment of Ipilimumab Studies ........................ 27 1.6 A phase II study of tremelimumab combined with HDI for metastatic melanoma ............................................................................................... 28 1.7 Study Rationale ....................................................................................... 34 2. Objectives ......................................................................................................... 37 2.1 Primary Endpoints ................................................................................... 37 2.2 Secondary Endpoints............................................................................... 37 3. Selection of Patients ......................................................................................... 38 3.1 Eligibility Criteria ..................................................................................... 38 4. Registration Procedures.................................................................................... 42 4.1 Protocol Number ..................................................................................... 44 4.2 Investigator Identification ....................................................................... 44 4.3 Patient Identification .............................................................................. 44 4.4 Eligibility Verification .............................................................................. 44 4.5 Stratification Factors ............................................................................... 44 4.6 Additional Requirements ........................................................................ 44 4.7 Instructions for Patients who Do Not Start Assigned Protocol Treatment45 5. Treatment Plan ................................................................................................. 46 5.1 Administration Schedule ......................................................................... 46 5.2 Adverse Event Reporting Requirements ................................................. 48 5.3 Comprehensive Adverse Events and Potential Risks List ........................ 56 5.4 Dose Modifications ................................................................................. 60 5.5 Supportive Care and Prohibited Therapies ............................................. 80 5.6 Duration of Therapy ................................................................................ 81 5.7 Duration of Follow-up ............................................................................. 81 6. Measurement of Effect ..................................................................................... 82 6.1 Antitumor Effect – RECIST ....................................................................... 82 6.2 Definition of Tumor Response Using irRC ............................................... 90 7. Study Parameters .............................................................................................. 93 7.1 Therapeutic Parameters.......................................................................... 93 7.2 Arms A and C: Patients Treated with HDI and Ipilimumab at 10 mg/kg (Arm A) or 3 mg/kg (Arm C) .................................................................... 94 7.3 Arms B and D: Patients Treated with Ipilimumab alone at 10 mg/kg (Arm B) or 3 mg/kg (Arm D) ............................................................................. 97 2 ECOG-ACRIN E3611 Cancer Research Group Version Date: March 2, 2016 7.4 Biological Sample Submissions ............................................................. 100 8. Drug Formulation and Procurement ............................................................... 101 8.1 Ipilimumab ............................................................................................ 101 8.2 Alfa Interferon ....................................................................................... 105 9. Statistical Considerations ................................................................................ 110 9.1 Endpoints and Sample Size ................................................................... 110 9.2 Stratification .......................................................................................... 111 9.3 Gender and Ethnicity ............................................................................ 112 10. Pathology Review ............................................................................................ 113 10.1 Pathology Materials Required For This Protocol .................................. 113 10.2 Shipping Procedures ............................................................................. 114 10.3 ECOG-ACRIN Sample Tracking System .................................................. 115 11. Submission of Samples ................................................................................... 116 11.1 Sample Submission Schedule ................................................................ 116 11.2 Sample Preparation Guidelines ............................................................. 116 11.3 Shipping Kits .......................................................................................... 117 11.4 Shipping Procedures ............................................................................. 117 11.5 Use of Specimens in Research .............................................................. 118 11.6 Sample Inventory Submission Guidelines ............................................. 118 12. Electronic Data Capture .................................................................................. 119 12.1 Records Retention ................................................................................. 119 3 ECOG-ACRIN E3611 Cancer Research Group Version Date: March 2, 2016 13. Patient Consent and Peer Judgment .............................................................. 120 14. References ...................................................................................................... 120 Appendix I Pathology Submission Guidelines ...................................................... 125 Appendix II Patient Thank You Letter ................................................................... 131 Appendix III Patient Interferon Diary ................................................................... 132 Appendix IV E3611 Cooperative Research and Development