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Study Protocol, GCP, and Legal Aspects Protocol CDX011-05 A Phase II Study of Glembatumumab Vedotin, an Anti-gpNMB Antibody- Drug Conjugate, as Monotherapy or in Combination with Immunotherapies in Patients with Advanced Melanoma Sponsored by: Celldex Therapeutics, Inc. IND # 74907 Protocol Version: Amendment 4: September 28, 2017 Amendment 3: November 17, 2016 Amendment 2: May 11, 2016 Amendment 1: June 10, 2015 Original Protocol: August 4, 2014 This study is to be conducted in accordance with the ethical principles that originate from the Declaration of Helsinki and that are consistent with ICH guidelines on Good Clinical Practice and regulatory requirements, as applicable. Confidential The information contained in this protocol is confidential and is intended for the use by clinical Investigators. It is the property of Celldex Therapeutics, Inc. or its subsidiaries and should not be discussed with, copied by or distributed to persons not involved in the clinical investigation unless such persons are bound by a confidentiality agreement. Protocol CDX011-05 Celldex Therapeutics, Inc. Amendment 4 CONFIDENTIAL INFORMATION TABLE OF CONTENTS 1. STUDY PERSONNEL AND STUDY ADMINISTRATION ....................................................6 2. GLOSSARY OF ABBREVIATIONS .........................................................................................7 3. PROTOCOL SYNOPSIS ..........................................................................................................10 4. SCHEDULE OF ASSESSMENTS ............................................................................................23 5. BACKGROUND/RATIONALE ...............................................................................................32 5.1. Advanced Melanoma ...........................................................................................................32 5.2. Glembatumumab Vedotin ....................................................................................................37 5.2.1. gpNMB ..........................................................................................................................37 5.2.2. Glembatumumab Vedotin: Nonclinical Summary .........................................................39 5.2.3. Glembatumumab Vedotin: Clinical Summary ...............................................................39 5.2.4. Clinical Study CR011-CLN-11: Glembatumumab Vedotin in Patients with Advanced Melanoma ......................................................................................................................44 5.2.5. Clinical Study CDX011-05: Glembatumumab Vedotin in Patients with Advanced Melanoma ......................................................................................................................47 5.3. Varlilumab ...........................................................................................................................47 5.3.1. CD27 ..............................................................................................................................47 5.3.2. Varlilumab: Nonclinical Summary ................................................................................48 5.3.3. Varlilumab: Clinical Summary ......................................................................................50 5.4. PD-1 Targeted Checkpoint Inhibitor ...................................................................................52 5.4.1. Programmed Death–1 (PD-1) ........................................................................................52 5.5. CDX-301 ..............................................................................................................................52 5.5.1. CDX-301: Nonclinical Summary ..................................................................................53 5.5.2. CDX-301: Clinical Summary ........................................................................................54 5.6. Study Rationale ....................................................................................................................57 5.6.1. Rationale for Combining Glembatumumab Vedotin and Immunotherapy ....................57 5.6.2. Rationale for Varlilumab Dose ......................................................................................60 5.6.3. Rationale for CDX-301 Dose.........................................................................................61 5.6.4. Rationale for Permitting Continued Treatment in Cases of Apparent Progressive Disease...........................................................................................................................61 6. STUDY OBJECTIVES ..............................................................................................................61 7. INVESTIGATIONAL PLAN ....................................................................................................62 7.1. Overall Design and Plan of the Study ..................................................................................62 7.2. Selection of Study Population .............................................................................................65 7.2.1. Number of Patients ........................................................................................................65 7.2.2. Subject Eligibility ..........................................................................................................65 7.2.3. Measures to Minimize Bias ...........................................................................................69 7.2.4. Withdrawals and Replacement of Patients ....................................................................69 7.2.5. Completion of Study ......................................................................................................71 8. STUDY TREATMENT .............................................................................................................72 8.1. Glembatumumab Vedotin ....................................................................................................72 8.1.1. Description, Packaging, and Labeling ...........................................................................72 8.1.2. Storage ...........................................................................................................................72 8.1.3. Preparation and Administration .....................................................................................72 8.2. Varlilumab ...........................................................................................................................74 8.2.1. Description, Packaging, and Labeling ...........................................................................74 September 28, 2017 Page 2 of 130 Protocol CDX011-05 Celldex Therapeutics, Inc. Amendment 4 CONFIDENTIAL INFORMATION 8.2.2. Storage ...........................................................................................................................74 8.2.3. Preparation and Administration .....................................................................................74 8.3. Nivolumab ...........................................................................................................................75 8.3.1. Description, Packaging, and Labeling ...........................................................................75 8.3.2. Storage and Handling .....................................................................................................76 8.3.3. Preparation and Administration .....................................................................................76 8.4. Pembrolizumab ....................................................................................................................77 8.4.1. Description, Packaging, and Labeling ...........................................................................77 8.4.2. Storage and Handling .....................................................................................................77 8.4.3. Preparation and Administration .....................................................................................77 8.5. CDX-301 ..............................................................................................................................78 8.5.1. Description, Packaging, and Labeling ...........................................................................78 8.5.2. Storage ...........................................................................................................................78 8.5.3. Preparation and Administration .....................................................................................79 8.6. Dose Modifications ..............................................................................................................79 8.6.1. Glembatumumab vedotin ...............................................................................................79 8.6.2. Varlilumab .....................................................................................................................80 8.6.3. PD-1 Targeted Checkpoint Inhibitor .............................................................................81 8.6.4. CDX-301 ........................................................................................................................81 8.7. Treatment-Limiting Toxicity (TLT) ....................................................................................81 8.8. Potential Toxicity and Management of Toxicity .................................................................82 8.9. Accountability ......................................................................................................................85
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