Clinical trial NCT02302339
Conditions: Melanoma
Keywords: Advanced melanoma Unresectable melanoma Metastatic melanoma Targeted Treatment for melanoma GPNMB CDX-011 Glembatumumab vedotin Antibody-drug-conjugate Skin neoplasm Varlilumab CDX-1127
Sponsor: Celldex Therapeutics
Start date: 2014-11-01; Completion date: 2018-10-03
Enrollment: 132 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study will examine the effectiveness and safety of glembatumumab vedotin as monotherapy or in combination with immunotherapies in patients with advanced melanoma.

Detailed description:
Glembatumumab vedotin consists of an antibody attached to a drug, monomethyl auristatin E (MMAE), that can kill cancer cells. The fully human antibody is designed to deliver the drug to cancer cells by attaching to a protein called glycoprotein NMB (gpNMB) that is expressed on the cancer cell. The MMAE is then released inside of the cell, where it interferes with cell growth and can lead to cell death of the targeted cell, as well as neighboring cells. Varlilumab is a fully human antibody that binds to CD27. This antibody allows the body's immune system to work against cancer cells. Nivolumab is a fully human antibody and pembrolizumab is a humanized antibody. Both bind to PD-1. CDX-301 is a fully human protein that helps boost production of certain white blood cells. This protein allows the body's immune system to work against tumor cells.

Eligible patients who enroll in the study will receive treatment with one of the following: glembatumumab vedotin, glembatumumab vedotin and varlilumab, glembatumumab vedotin and CDX-301 or glembatumumab vedotin and either nivolumab OR pembrolizumab.

All patients enrolled in the study will be closely monitored to determine if their cancer is responding to treatment and for any side effects that may occur.

Arms: arm 1: glembatumumab vedotin administered as an intravenous infusion on Day 1 of each 21 day cycle. arm 2: glembatumumab vedotin administered as an intravenous infusion on Day 1 of each 21 day cycle. Varlilumab administered as an intravenous infusion on Day 1 of cycles 1, 2, 4, 6, 8 and 10. arm 3: glembatumumab vedotin administered as an intravenous infusion on Day 1 of each 21 day cycle. Nivolumab OR pembrolizumab administered according to institutional standard of care. arm 4: glembatumumab vedotin administered as an intravenous infusion on Day 1 of each 21 day cycle. CDX-301 is injected once a day for five days before cycles 1 and 2.
Interventions: intervention 1: glembatumumab vedotin intervention 2: glembatumumab vedotin and varlilumab intervention 3: glembatumumab vedotin and PD-1 targeted checkpoint inhibitor (nivolumab OR pembrolizumab) intervention 4: glembatumumab vedotin and CDX-301
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_000.pdf: 
 
 
 
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. 
 


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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 


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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 
8.10. Compliance ........................................................................................................................85 
9. CONCOMITANT THERAPY...................................................................................................85 
9.1. Glembatumumab vedotin .....................................................................................................86 
9.2. Varlilumab ...........................................................................................................................86 
9.3. PD-1 Targeted Checkpoint Inhibitor ...................................................................................87 
9.4. CDX-301 ..............................................................................................................................87 
10. STUDY PROCEDURES .........................................................................................................87 
10.1. Schedule of Investigations and Data Collection ................................................................87 
10.1.1. Screening Period ..........................................................................................................87 
10.1.2. Study Enrollment .........................................................................................................88 
10.1.3. Treatment Phase ...........................................................................................................88 
10.1.4. Disease Assessment Visits ...........................................................................................88 
10.1.5. Survival Follow-up ......................................................................................................88 
10.2. Methods of Assessment .....................................................................................................88 
10.2.1. Activity ........................................................................................................................88 
10.2.2. Safety Variables ...........................................................................................................89 
11. STATISTICAL CONSIDERATIONS ....................................................................................94 
11.1. Analysis Endpoints ............................................................................................................94 
11.2. Sample Size and Power Calculation ..................................................................................95 
11.3. Interim Analysis .................................................................................................................95 
11.4. Analysis Populations..........................................................................................................95 
11.4.1. Efficacy Analysis .........................................................................................................95 
11.4.2. Safety Analysis ............................................................................................................96 
11.5. Statistical Methods .............................................................................................................96 


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11.5.1. Efficacy Analysis .........................................................................................................96 
11.5.2. Protocol Therapy and Concomitant Medications ........................................................98 
11.5.3. Safety Analysis ............................................................................................................99 
12. DATA HANDLING AND RECORD KEEPING ...................................................................99 
12.1. Data Quality Assurance .....................................................................................................99 
12.2. Archiving of Study Documentation .................................................................................100 
13. ETHICAL CONSIDERATIONS ...........................................................................................100 
13.1. Independent Ethics Committee or Institutional Review Board .......................................100 
13.2. Ethical Conduct of the Study ...........................................................................................101 
13.3. Patient Information and Informed Consent .....................................................................101 
13.4. Protocol Amendments......................................................................................................102 
13.5. Confidentiality .................................................................................................................102 
14. PUBLICATION POLICY .....................................................................................................102 
15. REFERENCES ......................................................................................................................104 
 
LIST OF APPENDICES 
Appendix 1: Approval Signature .................................................................................................110 
Appendix 2: Investigator Signature .............................................................................................111 
Appendix 3: RECIST 1.1 Criteria ................................................................................................112 
Appendix 4: ECOG Performance Status......................................................................................122 
Appendix 5: Cockroft and Gault Equation ..................................................................................123 
Appendix 6: Approved and/or Investigational Immune-Directed and Molecularly Targeted 
Drugs used with Advanced Melanoma .........................................................................124 
Appendix 7: Summary of Changes ..............................................................................................125 
LIST OF TABLES 
Table 1:  Schedule of Assessments (Cohorts 1-3) .........................................................................23 
Table 2. Schedule of Assessments (Cohorts 4 and 5) ....................................................................28 
Table 3:  Outcomes for Metastatic or Locally Advanced Melanoma Patients Treated with 
Approved Targeted Therapies ........................................................................................35 
Table 4:  Study CR011-CLN-20: Activity Data in Patients with Advanced Breast Cancer..........41 
Table 5:  Study CDX011-03 (“EMERGE”): Response Data for Patients with Advanced 
gpNMB-expressing Breast Cancer* ...............................................................................42 
Table 6:  Study CR011-CLN-11:  Activity Parameters by Dosing Schedule ................................45 
Table 7:  Varlilumab in Combination with Other Therapies .........................................................52 
 
LIST OF FIGURES 
Figure 1:  Study CDX011-03 (“EMERGE”): Progression-free and Overall Survival for Patient 
Subgroups of Interest ......................................................................................................43 
Figure 2:  Study CR011-CLN-11:  Outcomes by gpPNMB Expression Level .............................46 
Figure 3:  Study CR011-CLN-11:  Skin Rash Correlates with Improved Outcome .....................46 
Figure 4:  Enhanced Anti-Tumor Activity with Varlilumab Plus Cyclophosphamide ..................49 
Figure 5:  Favorable T Cell Profile in Tumors of Mice Treated with Varlilumab and 
Cyclophosphamide Chemotherapy .................................................................................50 


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Figure 6. CDX-301 Increases Myeloid Dendritic Cells in Peripheral Blood -  CDX301-02 ........55 
Figure 7. Antigen-specific (anti-NY-ESO-1) T cell responses ......................................................56 
Figure 8:  Varlilumab Induced Immune Responses are Maintained or Increased in 
Combination Treatment with ADC.................................................................................59 
 
 
 


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1.  STUDY PERSONNEL AND STUDY ADMINISTRATION 
Prior to the initiation of the study, Celldex (or its designee) will provide a study roster with contact 
information for applicable study personnel.  
Note: As used throughout this document, “Celldex” refers to Celldex or any designee to whom 
study-related responsibilities have been appropriately delegated. 
 
 
 


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2. GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Definition 
ADC  
Antibody-Drug Conjugate 
AE 
Adverse Event 
ALT (SGPT) 
Alanine Transaminase (Serum Glutamic Pyruvate Transaminase)  
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
Aspartate Transaminase (Serum Glutamic Oxaloacetic Transaminase)  
AT 
Aminotransferase 
BLC1 
B-Cell Leukemia Line 
CI 
Confidence Interval 
CITN 
Cancer Immunotherapy Trials Network  
CPI 
Checkpoint Inhibitor 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTLA 
Cytotoxic T-Lymphocyte Antigen 4 
CYP450 
Cytochrome P450 
DC 
Dendritic Cell 
DCTD 
Division of Cancer Treatment and Diagnosis 
DHHS 
Department of Health and Human Services 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-Linked Immunosorbent Assay 
ERK 
Extracellular-Signal-Regulated Kinases 
FFPE 
Formalin fixed and Paraffin-Embedded 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices 
gpNMB  
Glycoprotein NMB 
GM-CSF 
Granulocyte Macrophage Colony-Stimulating Factor 
HIPAA 
Health Insurance Portability and Accountability Act 
HLA 
Human Leukocyte Antigen 
IC 
Investigator’s Choice 
ICH 
International Conference on Harmonization 
IgG2 
Immunoglobulin G, Subclass 2 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
irAE 
Immune-related Adverse Event 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IRC 
Independent Review Committee 


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Abbreviation 
Definition 
irRECIST 
Immune-related Response Evaluation Criteria for Solid Tumors 
ITT 
Intention to Treat 
i.v. 
Intravenous 
Kg 
Kilogram 
LCMS/MS 
Liquid chromatography-tandem mass spectrometry 
LDH 
Lactate Dehydrogenase 
mAb 
Monoclonal Antibody 
M-CSF 
Macrophage Colony Stimulating Factor 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg  
Milligrams 
mL 
Milliliters 
MMAE  
Monomethyl auristatin E 
MRI 
Magnetic Resonance Imaging 
MS 
Mass Spectrometry 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute (of the United States) 
NCIC 
National Cancer Institute of Canada 
NE 
Not evaluable 
NIH 
National Institutes of Health 
NK 
Natural Killer 
NR 
Not Reported 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PD-1 
Programmed cell death 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
poly-ICLC 
Polyinosinic-polycytidylic acid double-stranded RNA, poly-L-lysine, and 
carboxymethylcellulose (a TLR3 agonist) 
PP 
Per-protocol 
PR 
Partial Response 
qw 
Every week 
q2/3w 
Two of three weeks 
q3w 
Every three weeks 
RBC 
Erythrocyte Count 
RECIST 
Response Evaluation Criteria for Solid Tumors 
ROC 
Receiver Operating Characteristic Curve  
RT-PCR 
Reverse Transcriptase Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SCF 
Stem Cell Factor 
SD 
Stable Disease  
SOPs 
Standard Operating Procedures 


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Abbreviation 
Definition 
TA 
Total Antibody 
TBL 
Total Bilirubin 
TLT 
Treatment-Limiting Toxicity 
ULN 
Upper Limit of Normal 
vc 
Valine-Citrulline 
WBC 
White blood count 
 
 
 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 0  of 1 3 0  
3.  P R O T O C O L S Y N O P SI S  
Pr ot oc ol 
n u m ber: 
C D X 0 1 1- 0 5  
Title:  
A P hase II  st u d y of gle m bat u m u ma b ve d oti n, a n a nti- g p N M B a nti b o d y- dr u g c o nj u gate, 
as m o n ot hera p y or i n c o m bi nati o n wit h i m m u n ot hera p y i n p atie nts wit h ad va nce d 
mela n o ma  
I n vesti gati o nal 
Treat me nt:  
Gle m bat u m u ma b ve d oti n ( C D X - 0 1 1; C R 0 1 1-vc M M A E) : a f ull y-h u ma n I g G 2 
m o n ocl o nal a nti b o d y ( C R 0 1 1) a gai nst gl yc o pr otei n N M B ( g p N M B ) c o u ple d t o 
m o n o met h yl a uristati n E (M M A E ) via a pr otease -se nsiti ve vali ne-citr ulli ne pe pti de 
li n ker 
Varlil u ma b ( C D X- 1 1 2 7): a f ull y h u ma n I g G 1 a g o nist a nti-C D 2 7 m o n ocl o nal a nti b o d y 
( m A b) 
A d diti o nal 
T hera pies:   
Ni v ol u ma b ( O p di v o ®): A f ull y h u ma n I g G 4 m A b a gai nst pr o gra m me d cell deat h 1 
( P D- 1) 
Pe m br oliz u ma b ( Ke ytr u da ®): A h u ma nize d I g G 4 m A b a gai nst P D- 1 
C D X - 3 0 1: Rec o m bi na nt H u ma n Flt 3 Li ga n d (r h u Flt 3 L) 
I n dicati o n: 
Patie nts w it h u nresecta ble Sta ge III or Sta ge I V  mela n o ma  w h o ha ve pr o gresse d 
t hr o u g h or after sta n dar d t hera pies 
N u m ber of 
Patie nts:  
A p pr o xi matel y 1 6 0 patie nts will be e nr olle d : a p pr o xi matel y 6 0 patie nts will be e nr olle d  
i n t he gle m bat u m u ma b ve d oti n m o n ot hera p y ( Co h ort 1 ), a p pr oxi matel y 3 0 patie nts will 
be  e nr olle d  i n  t he  gle m bat u m u ma b  ve d oti n  a n d  varlil u ma b  c o m bi nati o n (C o h ort  2 ), 
a p pr o xi matel y 3 0 patie nts will be e nr olle d i n t he gle m bat u m u ma b ve d oti n a n d a P D - 1 
tar gete d C PI c o m bi nati o n ( C o h ort 3 ), a p pr o xi matel y 10- 1 2 patie nts will be e nr olle d i n 
t he gle m bat u m u ma b ve d oti n a n d C D X -3 0 1 c o m bi nati o n ( C o h ort 4) a n d , de pe n di n g o n a 
re vie w of t he safet y a n d acti vit y of t he pre vi o us c o h orts, a p pr o xi matel y 3 0 patie nts ma y 
s u bse q ue ntl y be e nr olle d i n t he gle m bat u m u ma b ve d oti n / C D X - 3 0 1/P D -1 tar gete d C PI  
c om bi nati o n ( C o h ort 5).  
N u m ber of 
St u d y Ce nters: 
A p pr o xi matel y 1 5 U S st u d y ce nters will partici pate. 
O bjecti ves:  
Pri mar y  
•  
T o  e val uate  t he  a nti -ca ncer  acti vit y  of gle m bat u m u ma b  ve d oti n  as  m o n ot hera p y  
( C o h ort 1), i n c o m bi nati on wit h varlil u ma b  ( C o h ort 2), i n c o m bi nati o n wit h a P D - 1 
tar gete d  c hec k p oi nt  i n hi bit or ( C PI) ( C o h ort  3), or  i n  c o m bi nati o n  wit h 
gle m bat u m u ma b  ve d oti n,  C D X -3 0 1,  a n d  a  P D - 1 t ar gete d C PI  ( C o h ort  5)  i n 
a d va nce d mela n o ma as meas ure d b y t he o bjecti ve res p o nse ra te ( O R R) per R E C I S T 
1. 1 . T o e val uate t he safet y a n d t olera bilit y of t he c o m bi nati o n of gle m bat u m u ma b 
ve d oti n a n d C D X- 3 0 1 ( C o h ort 4). 
Sec o n dar y 
•  
T o  f urt her  assess  t he  a nti -ca ncer  acti vit y  of gle m bat u m u ma b  ve d oti n  as 
m o n ot hera p y, i n c o m bi nati o n wit h varlil u ma b, i n c o m bi nati o n wit h a P D - 1 tar gete d 
C PI , or  i n  c o m bi nati o n  wit h  C D X -3 0 1  a n d  a  P D -1  tar get e d C PI i n  a d va nce d 
mela n o ma,  as  assesse d  b y pr o gressi o n- free  s ur vi val (P F S), d urati o n  of  res p o nse  
( D O R) a n d o verall  s ur vi val ( O S).  T o  assess  t he  a nti-ca ncer  acti vit y  of  t he 
c o m bi nati o n of gle m bat u m u ma b ve d oti n  a n d C D X - 3 0 1 i n a d va nce d mela n o ma, as 
assesse d b y O R R, P F S, D O R, a n d O S. 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 1  of 1 3 0  
•  
T o  i n vesti gate  if  t he  a nti -ca ncer  acti vit y  of gle m bat u m u ma b  ve d oti n  al o ne  or  i n 
c o m bi nati o n wit h i m m u n ot hera pies  i n a d va nce d mela n o ma is de pe n de nt u p o n t he 
de gree  of g p N M B  e x pressi o n i n t u m or tiss ue 
•  
T o f urt her c haracterize t he safet y of gle m bat u m u ma b ve d oti n as m o n ot hera p y  
•  
T o  c haracterize  t he  safet y  of  t he  c o m bi nati o n  of  gle m bat u m u ma b  ve d oti n wit h 
i m m u n ot hera pies i n a d va nce d mela n o ma 
E x pl or at or y 
•  
T o e xa mi ne t he ra n ge of g p N M B e x pressi o n i n a d va nce d mela n o ma, a n d t o assess 
w het her g p N M B e x pressi o n c ha n ges o ver ti me a n d/ or wit h s pecific pri or t hera pies  
•  
T o e xa mi ne p har mac o d y na mic effects of treat me nt, i ncl u di n g t y pes a n d n u m ber of 
i m m u ne  cells  infiltrati n g  t he t u m or; l ocalizati o n  of gle m bat u m u ma b  ve d oti n , 
C R 0 1 1 ,  a n d M M A E  i n t he  t u m or; s ol u ble  me diat ors, g p N M B  e x pressi o n  le vels 
a n d/ or  ot her  p ote ntial  bi o mar ker s  i n b ot h  n or mal  a n d  t u m or  tiss ue ; a nal ysis  of 
peri p heral  bl o o d  s u bsets ; t o  i n vesti gate  the  effect  of  C D X -3 0 1  o n  t he  t u m or 
micr oe n vir o n me nt,  i ncl u di n g  t he  effect  o n  i ntrat u m oral  de n dritic  cell  p o p ulati o ns 
( C o h orts 4 a n d 5) 
•  
T o  f urt her  c haracterize  t he  p har mac o ki netics  of  gle m bat u m u ma b  ve d oti n , 
varlil u ma b ,  a n d  C D X- 3 0 1, a n d  i m m u n o ge nicit y  of  gle mbat u m u ma b  ve d oti n , 
varlil u ma b , a n d C D X- 3 0 1 i n patie nts wit h a d va nce d mela n o ma a n d t o e x pl ore t he 
relati o ns hi ps bet wee n patie nt-s pecific meas ures of e x p os ure a n d safet y a n d acti vit y 
para meters  
•  
T o assess t he a nti -ca ncer acti vit y of t he c o m bi nati o n of gle m bat u m u ma b ve d oti n i n 
c o m bi nati o n wit h i m m u n ot hera p y as meas ure d b y t he O R R  a n d P F S per I m m u ne-
R elate d R E CI S T (ir R E CI S T )  
O ver vie w of 
st u d y desi g n: 
T his  is  a n  o pe n -la bel P hase  II st u d y  of  gle m bat u m u ma b  ve d oti n i n  patie nts  wit h 
u nresecta ble Sta ge III or I V mel a n o ma w h o ha ve pre vi o usl y recei ve d  C PIs . T his st u d y 
c o nsists  of 5 c o h orts.  I n  C o h ort  1,  gle m bat u m u ma b  ve d oti n  will  be  a d mi nistere d  as 
m o n ot hera p y. I n C o h ort 2, gle m bat u m u ma b ve d oti n will be c o m bi ne d wit h varlil u ma b. 
I n  C o h ort  3,  gle m bat u m u ma b  ve d oti n  will  be  c o m bi ne d  wit h a P D- 1 tar gete d  C PI, 
ni v ol u ma b or  pe m br oliz u ma b . I n  t his  c o h ort,  patie nts w h o se last treat me nt  re gi me n 
i ncl u de d ni v ol u ma b  or  pe m br oliz u ma b,  a n d  per  i nstit uti o nal  sta n dar d  of  care   w o ul d 
c onti n ue  t o  recei ve a P D - 1 tar gete d  t hera p y des pite  pr o gressi o n , will  recei ve eit her 
ni v ol u ma b  or  pe m br oliz u ma b  i n  c o m bi nati o n  wit h  gle m bat u m u ma b  ve d oti n, t o 
deter mi ne w het her t he a d diti o n of gle m bat u m u ma b ve d oti n ca n i n d uce a n effecti ve a nti -
mela n o ma i m m u ne res p o nse a n d i m pr o ve d a nti- ca ncer acti vit y. Patie nt s w h o pre vi o usl y 
recei ve d ni v ol u ma b i n c o m bi nati o n wit h i pili m u ma b a n d ha ve disc o nti n ue d i pili mu ma b 
w o ul d 
c o nti n ue  wit h  ni v ol u ma b ,  or  pe m br oliz u ma b, i n  c o m bi nati o n  wit h 
gle m bat u m u ma b ve d oti n.  Patie nts w h o e x perie nce d disease pr o gressi o n  o n ni v ol u ma b 
ma y  re cei ve  ni v ol u ma b  or  pe m br oliz u ma b  i n  c o m bi nati o n  wit h  gle m bat u m u ma b 
ve d oti n. Patie nts w h o e x perie nce d disease pr o gressi o n o n pe m br oliz u ma b ma y recei ve 
ni v ol u ma b or pe m br oliz u ma b i n c o m bi nati o n wit h gle m bat u m u ma b ve d oti n. 
I n C o h ort 4, gle m bat u m u ma b ve d oti n will be c o m bi ne d wit h C D X - 3 0 1 t o deter mi ne t he 
safet y a n d t olera bilit y of t he c o m bi nati o n a n d t o i n vesti gate t he effect of C D X-3 0 1 o n 
t he  t u m or  micr oe n vir o n me nt,  i ncl u di n g  t he  effect  o n  i ntrat u m oral  de n dritic  cell 
p o p ulati o ns . If gle m bat u m u ma b ve d oti n ca n be a d mi nistere d safel y i n c o m bi nati o n wit h 
C D X -3 0 1  ( C o h ort  4)  a n d  wit h  a  P D -1  tar gete d  C PI  ( C o h ort  3),  t he n  C o h ort  5  will 
e val uate w het her t he a nti -t u m or i m m u ne res p o nses w o ul d li kel y be f urt her a u g me nte d 
b y  c o m bi ni n g  all  t hree  a ge nts  i n  patie nts  w h o  ha ve  p re vi o usl y  faile d  a  C PI.  T h us, 
f oll o wi n g t he c o m pleti o n of C o h ort 4, t here will be a n e val uati o n peri o d w here b y t he 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 12 of 130 
Sponsor and the investigators will assess the safety and activity of both Cohorts 3 and 4; 
if the results are supportive, then enrollment in Cohort 5 will be initiated in patients who 
have previously failed a CPI.  
Patients will receive study treatment in an open-label fashion. Approximately 60 patients 
were enrolled and received glembatumumab vedotin in Cohort 1. Approximately 30 
patients were enrolled in Cohort 2 and received glembatumumab vedotin in combination 
with varlilumab. Approximately 30 patients will be enrolled in the glembatumumab 
vedotin and a PD-1 targeted CPI combination Cohort 3. Cohorts 2 and 3 enrolled patients 
in parallel. Approximately 10-12 patients will be enrolled in Cohort 4 (glembatumumab 
vedotin in combination with CDX-301) and, if the data is supportive in Cohorts 3 and 4, 
approximately 30 patients will be enrolled in Cohort 5 (glembatumumab vedotin in 
combination with both CDX-301 and a PD-1 targeted CPI). 
 
Cohort 
Treatment 
Glembatumumab 
Vedotin Dose 
Varlilumab 
Dose 
Patients (n) 
1 
Glembatumumab 
vedotin 
1.9 mg/kg 
- 
Approx. 60 
2 
Glembatumumab 
vedotin + Varlilumab 
1.9 mg/kg 
3.0 mg/kg* 
Approx. 30 
 
Cohort 
Treatment 
Glembatumumab 
Vedotin Dose 
PD-1 CPI Dose 
CDX-301 
Dose 
Patients 
(n) 
3 
Glembatumumab 
vedotin + PD-1 
targeted CPI** 
1.9 mg/kg 
As per 
institutional 
standard of care 
with reference to 
the package 
insert 
- 
Approx. 
30 
4 
Glembatumumab 
vedotin + CDX-301** 
1.9 mg/kg 
- 
75 μg/kg 
x 5 days 
Approx. 
10-12 
5 
Glembatumumab 
vedotin + CDX-301 + 
PD-1 targeted CPI** 
1.9 mg/kg 
As per 
institutional 
standard of care 
with reference to 
the package 
insert 
75 μg/kg 
x 5 days 
Approx. 
30 
*If >2 treatment-limiting toxicities occur in the first 10 patients, or in >20% of patients thereafter, all 
further patients enrolled will receive a varlilumab starting dose of 0.3 mg/kg and ongoing patients will 
also receive any further dosing of varlilumab at 0.3 mg/kg. 
**If >2 treatment-limiting toxicities occur in the first 10 patients, or in >20% of patients thereafter, then 
enrollment in Cohorts 3-5 will be interrupted pending evaluation by Celldex and the investigators. 
 
Study treatment, and associated study visits at 3 week intervals, will continue until 
disease progression or intolerance. In Cohort 3, patients who previously progressed on 
nivolumab or pembrolizumab will continue with a PD-1 targeted CPI, nivolumab or 
pembrolizumab, which will be administered with glembatumumab vedotin until disease 
progression (using study screening disease assessment as baseline reference) or 
intolerance. In Cohort 4, two priming cycles of CDX-301 will be administered 
subcutaneously for 5 consecutive days (Cycle 1 Days -6 to -2 and Cycle 1 Days 15-19) 
prior to glembatumumab vedotin on Day 1 in Cycles 1 and 2. Glembatumumab vedotin 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 13 of 130 
will continue to be administered at 3 week intervals until disease progression or 
intolerance. In Cohort 5, CDX-301 and glembatumumab vedotin will be administered in 
the same manner as in Cohort 4. Patients in Cohort 5 who previously progressed on 
nivolumab or pembrolizumab will continue with a PD-1 targeted CPI, nivolumab or 
pembrolizumab, similar to Cohort 3. Additional hematology and chemistry analyses as 
well as adverse event monitoring will be performed on Days 7 and 14 in Cycle 1 for 
patients in Cohorts 2-5. Patients in Cohort 1 should be monitored for at least 1 hour 
following the last administration of study drug to monitor for infusion reaction/cytokine 
release syndrome/hypersensitivity reaction. Patients in Cohorts 2, 3, and 5 should be 
observed on Cycle 1 Day 1 for at least 2 hours after the last study drug, and for at least 
1 hour at all subsequent dosing visits. In Cohorts 4 and 5, patients should also be 
observed for at least 1 hour after the first dose of CDX-301, at least 30 minutes for 
subsequent CDX-301 dosing visits, and for at least 1 hour at all other glembatumumab 
vedotin dosing visits.  Infusions should be given in a monitored setting that has ready 
access to an intensive care unit in case of a severe infusion reaction (see Section 8.8). 
Tumor assessments will be performed every 6 weeks (±1 week) for the first 6 months, 
and every 9 weeks (±2 weeks), thereafter, until documented progression of disease or 
initiation of alternate anticancer therapies. Tumor response will be assessed by the 
investigator in accordance with RECIST 1.1 guidelines (Appendix 3) (Eisenhauer, 
Therasse et al. 2009). For Cohorts 2-5, supplementary retrospective analyses of tumor 
response and progression may also be performed using Immune-Related RECIST 
(“irRECIST”) criteria (in which new lesions do not constitute progression, but contribute 
to the calculated sum of diameter of all measurable disease) (Nishino, Giobbie-Hurder 
et al. 2013). Patients who discontinue treatment in the absence of progression will 
continue to have tumor assessments until documented progression or initiation of 
alternate anti-cancer therapies.  
For Cohorts 2-5, in cases of apparent progression that may reflect enhanced 
inflammation and/or an initial imbalance in the kinetics of tumor growth and anti-cancer 
immune activity, continued combination treatment may be allowed with consent of the 
patient and permission granted from the Celldex Medical Monitor, until a second 
radiologic confirmation of progression performed at the next scheduled disease 
assessment (or sooner if clinically indicated). In addition, the following criteria must be 
met: 1) the patient experiences Investigator-assessed clinical benefit; and 2) the patient 
is tolerating the study treatment. (See Section 5.6.4 and Section 7.2.4.1.1). 
Continuous evaluation of toxicity will be performed by the investigators and Celldex 
throughout the entire course of patient treatment. Treatment-limiting toxicity (as defined 
in Section 8.7) will be reported to Celldex within 24 hours, and site teleconferences 
between Celldex and all participating sites will be held at frequent intervals to evaluate 
emerging safety data. In Cohort 2, if treatment-limiting toxicity occurs in >2 of the first 
10 patients, or in >20% of patients thereafter, all further patients enrolled will receive a 
varlilumab starting dose of 0.3 mg/kg and ongoing patients will also receive any further 
dosing of varlilumab at 0.3 mg/kg. If additional treatment-limiting toxicity occurs in 
>20% of patients receiving varlilumab at 0.3 mg/kg, enrollment will be interrupted 
pending evaluation by Celldex and the investigators. In Cohort 3-5, if treatment-limiting 
toxicity occurs in >2 of the first 10 patients or in >20% of patients thereafter, then 
enrollment for the entire cohort will be interrupted pending evaluation by Celldex and 
the investigators. The FDA and site IRBs will be notified of the analysis and 
determination regarding further enrollment. Enrollment in Cohort 5 will not commence 
until the evaluation of toxicity and activity in Cohorts 3 and 4 of all treated patients has 
been assessed and it has been determined that the combinations of glembatumumab 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 4  of 1 3 0  
ve d oti n wit h C D X -3 0 1 a n d gle m bat u m u ma b ve d oti n wit h P D -1 tar gete d C PI are safe 
a n d t olera ble.   
T reat me nt-Li miti n g T o xicit y  ( T L T) Defi niti o n  
A n y p ote ntial T L T  occ urri n g at a n y ti me d uri n g patie nt treat me nt i n C o h ort s 2- 5 will be 
re p orte d t o Cell de x  wit hi n 2 4 h o urs of t he site’s a ware ness of t he occ urre nce of t he e ve nt.  
A n y  patie nt  w h o e x perie nces  a T L T  t h o u g ht  relate d  t o  varlil u ma b, t he P D -1  tar gete d 
C PI , or C D X- 3 0 1 m ust disc o nti n ue d osi n g of t he s us pect dr u g  as d ose re d ucti o ns are n ot 
all o we d. Gle m bat u m u ma b ve d oti n -relate d t o xicit y, i ncl u di n g T L T, ma y be ma na ge d i n 
acc or da nce  wit h g ui da nce f or  gle m bat u m u ma b  ve d oti n  d ose  re d ucti o ns . Patie nts  w h o 
disc o nti n ue  varlil u ma b , t he P D -1  C PI ,  or  C D X- 3 0 1 ma y  c o nti n ue  gle m bat u m u ma b 
ve d oti n  as  m o n ot hera p y  at  t he  i n vesti gat or’s  discreti o n.  Patie nts  i n  C o h ort  2  w h o 
disc o nti n ue gle m bat u m u ma b ve d oti n s h o ul d disc o nti n ue varlil u ma b. Patie nts i n C o h ort s 
3 a n d 5 w h o disc o nti n ue gle m bat u m u ma b ve d oti n s h o ul d disc o nti n ue t he st u d y treat me nt 
p hase  a n d  ma y  c o nti n ue  P D -1  C PI  as  per  sta n dar d  of  care  d uri n g  st u d y  f oll o w  u p.  
Patie nts i n C o h ort s 4 a n d 5 w h o disc o nti n ue gle m bat u m u ma b ve d oti n s h o ul d disc o nti n ue  
C D X - 3 0 1.  
I n C o h ort 2 
•  
All Gra de 5 A Es attri b ute d t o st u d y treat me nt will  be c o nsi dere d T L Ts  
•  
A L T of > 3 x u p per li mit of n or mal ( U L N) wit h a c o nc urre nt t otal bilir u bi n ( T B L) 
> 2 x U L N will  be c o nsi dere d a T L T  if n o ot her reas o n ca n be f o u n d t o e x plai n t he 
c o m bi nati o n  of  i ncrease d  a mi n otra nsferase  ( A T)  a n d  ser u m  T B L,  s uc h  as  viral 
he patitis A, B, or C; pree xisti n g or ac ute li ver disease; or a n ot her dr u g ca pa ble of  
ca usi n g t he o bser ve d i nj ur y 
•  
A n y Gra de 4 A Es attri b ute d t o st u d y treat me nt will be c o nsi dere d T L Ts , a n d a n y 
Gra de  3 A Es  attri b ute d  t o  st u d y  treat me nt  will  be  e val uate d  b y  Cell de x  i n 
c olla b orati o n wit h t he i n vesti gat ors as p ote ntial T L Ts , wit h t he f oll o wi n g e xce pti o ns 
( w hic h d o n ot nee d t o be re p orte d wit hi n 2 4 h o urs as p ote ntial T L T ):  
o  L y m p h o pe nia or  a n y  i ncreases  i n  a m ylase  a n d/ or  li pase  n ot  ass ociate d  wit h 
cli nicall y si g nifica nt s y m pt o ms  
o  Is olate d  Gra de  3  or  4  electr ol yte  i m bala nces/a b n or malities  t hat  are  n ot 
ass ociate d  
wit h  
cli nical  
se q uelae  
a n d  
are  
c orrecte d  
wit h 
s u p ple me ntati o n/a p pr o priate ma na ge me nt wit hi n 7 2 h o urs of t heir o nset. 
o  A n y  Gra de  3  e n d ocri n o p at h y  t hat  is  a de q uatel y  c o ntr olle d  b y  h or m o nal 
re place me nt. 
o  Gra de 3 A E of t u m or flare ( defi ne d as l ocal pai n, irritati o n, or ras h l ocalize d at 
sites of k n o w n or s us pecte d t u m or). 
o  Gra de 3 i nf usi o n reacti o n t hat res ol ves wit hi n 6 h o urs t o ≤ Gra de 1. 
o  Gra de 3- 4 A Es e x pecte d as a res ult of gle m bat u m u ma b ve d oti n t hera p y, (e. g., 
ras h, ne ur o pat h y, ne utr o pe nia#) a n d n ot t h o u g ht t o be w orse ne d b y t he a d diti o n 
of varlil u ma b will n ot be c o nsi d ere d a T L T; s uc h e ve nts s h o ul d be ma na ge d i n 
acc or da nce  wit h  g ui da nce  f or  gle m bat u m u ma b  ve d oti n  d ose  re d ucti o ns.  T he 
o verall  i nci de nce  of  st u d y  treat me nt  disc o nti n uati o n  d ue  t o  gle m bat u m u ma b 
ve d oti n- relate d t o xicit y will be m o nit ore d o n a n o n g oi n g basis b y Cell de x a n d 
t he i n vesti gat ors. 
#I n vesti gat ors  are  referre d  t o t he  ta ble  e ntitle d  “ A d verse  Dr u g  Reacti o ns  ( A D R) 
O bser ve d wit h Gle m bat u m u ma b Ve d oti n ( P hase II D ose: 1. 8 8 m g/ k g, I. V., q 3 w)  i n 
Secti o n  6  of  t he  gle m bat u m u ma b  ve d oti n  i n vesti gat or ’s  br oc h ure;  t his ta ble 
s u m marizes  t he  a d verse  dr u g  reacti o ns/e x pecte d  a d verse  e ve nts  c o nsi dere d  b y 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 15 of 130 
Celldex to be causally related to glembatumumab vedotin based on clinical 
experience.  
For Cohorts 3-5, any treatment-related toxicity that warrants discontinuation of either 
the PD-1 targeted CPI, CDX-301, or glembatumumab vedotin will be considered a TLT. 
For all cohorts study analyses will include a retrospective assessment to define the range 
of gpNMB expression for all enrolled patients and to determine if outcome correlates 
with intensity or distribution of gpNMB expression. In Cohorts 2 and 3, normal skinfold 
biopsies are collected prior to study entry for retrospective assessment to identify patients 
predisposed to rash. Skinfold biopsies will be collected until such time Celldex informs 
the sites that further data is not needed.  
Patients who discontinue study prior to the first disease assessment for reasons unrelated 
to study treatment (i.e., adverse events deemed unrelated to study treatment, withdrawal 
of consent, lost to follow-up, withdrawal due to administrative reasons, etc.) will be 
excluded from the response-evaluable population and may be replaced. Patients who 
discontinue study prior to the first disease assessment due to treatment-related adverse 
events, symptomatic deterioration (adverse events due to progression), or death will be 
included in the response evaluable population.  
Study 
Treatment 
Dosing and 
Administration 
Glembatumumab vedotin will be administered on Day 1 of repeated 21 day cycles in 
Cohorts 1-5. The starting glembatumumab vedotin dose is 1.9 mg/kg, given as a 
90-minute intravenous infusion using a 0.22 micron in-line filter. Treatment will 
continue until progression or intolerance. 
In Cohort 2, varlilumab will be administered on Day 1 of Cycles 1, 2, 4, 6, 8, and 10 for 
a total of up to 6 doses. The dose of varlilumab will be 3.0 mg/kg (or 0.3 mg/kg in the 
event of treatment-limiting toxicity as described above), administered as a 90-minute 
intravenous infusion using a volumetric pump with a 0.2 micron pore size, low-protein 
binding polyethersulfone (PES) membrane in-line filter.  
In Cohort 2, glembatumumab vedotin and varlilumab will be administered as separate 
infusions. Varlilumab should be the first infusion and glembatumumab vedotin 
administered at least 30 minutes after varlilumab infusion. After cycle 10, 
glembatumumab vedotin treatment as a monotherapy will continue until confirmed 
progression or intolerance.  
In Cohort 3, the dose and dosing regimen for the PD-1 targeted CPI will continue per 
institutional standard of care with reference to the package insert. The first dose of PD-1 
targeted CPI may or may not be on the same day of the initiation of glembatumumab 
vedotin treatment. When both glembatumumab vedotin and the PD-1 targeted CPI are 
administered on the same day, the drugs will be administered as separate infusions. The 
PD-1 targeted CPI should be the first infusion and glembatumumab vedotin administered 
at least 30 minutes later as the second infusion. After initiation of glembatumumab 
vedotin treatment, CPI will be administered in combination with glembatumumab 
vedotin until disease progression (using study screening disease assessment as baseline 
reference) or intolerance.  
In Cohort 4, two priming cycles of CDX-301 will be administered subcutaneously at a 
dose of 75 μg/kg for 5 consecutive days (Cycle 1 Days -6 to -2 and Cycle 1 Days 15-19) 
prior to glembatumumab vedotin on Day 1 in Cycles 1 and 2. Glembatumumab vedotin 
treatment as a monotherapy will continue to be administered at repeated 21 day cycles 
until disease progression or intolerance.  
In Cohort 5, two priming cycles of CDX-301 will be administered subcutaneously at a 
dose of 75 μg/kg for 5 consecutive days (Cycle 1 Days -6 to -2 and Cycle 1 Days 15-19) 
prior to glembatumumab vedotin on Day 1 in Cycles 1 and 2. Glembatumumab vedotin 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 16 of 130 
treatment will continue to be administered at repeated 21 day cycles. The PD-1 targeted 
CPI will be administered per institutional standard of care with reference to the package 
insert. When both glembatumumab vedotin and the PD-1 targeted CPI are administered 
on the same day, the drugs will be administered as separate infusions. The PD-1 targeted 
CPI should be the first infusion and glembatumumab vedotin administered at least 30 
minutes later as the second infusion. After initiation of CDX-301 and glembatumumab 
vedotin treatment during Cycles 1 and 2, CPI will be administered in combination with 
glembatumumab vedotin until disease progression (using study screening disease 
assessment as baseline reference) or intolerance. 
Eligibility 
Criteria 
Inclusion Criteria 
Patients may be included in the study only if they meet all of the following inclusion 
criteria at the time of study enrollment: 
1. Read, understood, and provided written informed consent and, if applicable, Health 
Insurance Portability and Accountability Act (HIPAA) authorization after the nature 
of the study has been fully explained and must be willing to comply with all study 
requirements and procedures 
2. Advanced (unresectable Stage III or Stage IV) histologically-confirmed melanoma 
3. Documented progressive disease, based on radiographic, clinical or pathologic 
assessment, during or subsequent to the last anticancer therapy. For Cohorts 3 and 
5, progression (confirmed from two scans at least 4 weeks apart) must have occurred 
during the PD-1 targeted CPI treatment and the investigator has deemed it 
appropriate to continue to treat beyond confirmed disease progression. 
4. No more than 1 prior chemotherapy-containing regimen for advanced disease. For 
Cohorts 1, 2, and 4, prior treatments received must include at least one check-point 
inhibitor (e.g., anti-CTLA-4-, PD-1-, PD-L1-targeted immunotherapy) and for 
patients with a BRAF mutation, at least one BRAF- or MEK-targeted therapy, unless 
patients are not candidates for, or refused, these therapies. For Cohorts 3 and 5, prior 
treatment received must include a PD-1 targeted CPI (i.e., nivolumab or 
pembrolizumab) administered during the most recent disease progression and for 
patients with a BRAF mutation, at least one BRAF- or MEK-targeted therapy when 
appropriate. 
5. Pre-treatment tumor tissue, and for Cohorts 2 and 3 a skin fold biopsy, available for 
retrospective evaluation of gpNMB in tumor or normal epithelial cells, respectively, 
by central immunohistochemistry (IHC): 
a. All patients in Cohorts 1-3 must submit an archival formalin-fixed and paraffin-
embedded (FFPE) tumor tissue sample representative of advanced (Stage III or 
IV) disease, obtained more than 12 weeks prior to study entry (Historic sample).  
b. All patients in Cohorts 1-3 are also required to submit a second, recently-
obtained FFPE tumor tissue sample (Pre-entry sample). Tissue should be 
obtained within the 12 weeks prior to study entry, be subsequent to the last 
systemic anticancer therapy received, and be post-tumor progression. 
c. All patients in Cohorts 4-5 are required to submit a fresh Pre-entry tumor tissue 
sample as well as a fresh On-treatment tumor tissue sample. Pre-entry tissue 
should be obtained within the 12 weeks prior to study entry, be subsequent to 
the last systemic anticancer therapy received, and be post-tumor progression. 
Tumor tissue samples will be collected until such time Celldex informs the sites 
that further data is not needed. 
For patients who need to undergo a new biopsy to obtain a Pre-entry, or both 
Pre-entry and On-treatment sample, biopsy sites must be soft tissue or visceral 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 7  of 1 3 0  
t u m or lesi o ns t hat ca n be bi o psie d wit h acce pta ble cli nical ris k (as j u d ge d b y 
t he  i n vesti gat or). T he  bi o ps y  site  c h ose n  s h o ul d  ha ve  n ot  bee n  pre vi o usl y 
irra diate d. Bi o ps y sites m ust be disti nct fr o m R E CI S T 1. 1 tar get lesi o ns, u nless , 
i n t he case of t he Pre-e ntr y bi o ps y,  t he bi o ps y is o btai ne d m ore t ha n 1 0 da ys 
pri or  t o  t he  Scree ni n g  Disease  Assess me nt . Patie nts  m ust  be  se paratel y 
c o nse nte d  f or  c ollecti o n  of  a  fres h  Pre -e ntr y,  or  b ot h  Pre-e ntr y  a n d  O n -
treat me nt sa m ple. 
d.  All patie nts i n C o h ort s 2 a n d 3 m ust a gree t o s u b mit a rece ntl y -o btai ne d F F P E 
s ki n f ol d (a xilla or gr oi n) bi o ps y ( Pre-e ntr y sa m ple). Tiss ue ma y be o btai ne d b y 
p u nc h bi o ps y or b y s ur gical e xcisi o n.  S ki nf ol d bi o p sies will be c ollecte d u ntil 
s uc h ti me Cell de x i nf or ms t he sites t hat f urt her data is n ot nee de d.  
N O T E:  Patie nts w h o ca n n ot f ulfill t he re q uire me nt f or  eit her t he Hist oric , Pre -e ntr y, 
or O n -treat me nt t u m or sa m ple s u b missi o n i n C o h orts 1- 5 ma y be e nr olle d i n t he 
st u d y  wit h  pri or  per missi o n  of  t he  Cell de x  Me dical  M o nit or. I n  n o  case  will a 
patie nt be all o we d t o e nter t he st u d y wit h o ut at least o ne a vaila ble t u m or  sa m ple. 
6.  Male o r fe male patie nt ≥ 1 8 years of a ge  
7.  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us 0 t o 1  (A p pe n di x 
4 ) 
8.  Life e x pecta nc y of ≥ 1 2 wee ks 
9.  Meas ura ble (tar get) disease  b y  R E CI S T  1. 1  criteria   (Eise n ha uer,  T herasse  et  al. 
2 0 0 9 ) (A p pe n di x 3 ). T ar get lesi o ns selecte d f or t u m o r meas ure me nts s h o ul d be t h ose 
w here a d diti o nal (e. g., palliati ve) treat me nts are n ot i n dicate d or a ntici pate d.  
1 0.  Res ol uti o n of t o xiciti es relate d t o pri or t hera pies (i ncl u di n g ra di ot hera p y) t o ≤ N CI -
C T C A E  Gra de  1  se verit y,  e xce pt  f or  al o pecia, gra de  2  fati g ue, vitili g o,  or 
e n d ocri n o pat hies o n re place me nt t hera p y 
1 1.  Scree ni n g la b orat or y val ues m ust meet t he f oll o wi n g criteria:  
•  
A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1 5 0 0/ m m 3 
•  
He m o gl o bi n ≥ 9. 0 g/ d L 
•  
Platelet c o u nt ≥ 1 0 0, 0 0 0/ m m 3  
•  
C alc ulate d  creati ni ne  cleara nce >  4 0  m L/ mi n  per  t he  C oc kcr oft  a n d  Ga ult 
f or m ula (A p pe n di x 5 ) o r Ser u m Creati ni ne ≤ 2. 0 m g/ d L  
•  
A la ni ne tra nsa mi nase ( A L T) ≤ 3. 0 x u p per li mit of n or mal ( U L N) ( ≤ 5. 0 x U L N 
i n t he case of li ver metastases) 
•  
As partate tra nsa mi nase ( A S T) ≤ 3. 0 x U L N ( ≤ 5. 0 x U L N i n t he case of li ver 
metastases)  
•  
T otal  bilir u bi n ≤ 1. 5 x U L N ( ≤ 5. 0 x U L N i n t he case of li ver  metastases). 
Patie nts wit h k n o w n Gil bert’s s y n dr o me ma y be e nr olle d wit h t otal bilir u bi n 
≤ 3. 0 m g/ d L. 
1 2.  B ot h me n a n d w o me n e nr olle d i n t his trial m ust use effecti ve c o ntrace pti o n  d uri n g 
t he c o urse of t he trial a n d f or at least t w o m o nt hs after disc o nti n ui n g st u d y treat me nt. 
Effecti ve c o ntrace pti o n is defi ne d as d o u ble barrier c o ntrace pti o n (e . g., c o n d o m pl us 
s per mici de  i n  c o m bi nati o n  wit h  a  fe male  c o n d o m,  dia p hra g m,  cer vical  ca p, 
c o ntrace pti ve  s p o n ge   or va gi nal  ri n g),  i ntra -uteri ne  de vice  (I U D),  i m pla nts, 
i njecta bles, c o m bi ne d oral c o ntrace pti ves, se x ual a bsti ne nce (t otal a bsti ne nce fr o m 
se x ual i nterc o urse as t he preferre d lifest yle of t he patie nt; peri o dic a bsti ne nce is n ot 
acce pta ble), or se x ual i nterc o urse wit h o nl y a vasect o mize d part ner.  Patie nts a n d/ or 


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September 28, 2017 
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partners who are surgically sterile or postmenopausal are exempt from this 
requirement. 
Exclusion Criteria 
Patients will be excluded from the study for any of the following reasons: 
1. Received glembatumumab vedotin (CR011-vcMMAE; CDX-011) or other MMAE-
containing agents previously 
2. BRAF/MEK inhibitors within 2 weeks prior to the first dose of study treatment  
3. Use of any monoclonal based therapies within 4 weeks, except for the PD-1 targeted 
CPI (i.e., nivolumab or pembrolizumab) in Cohort 3, and all other immunotherapy 
(tumor vaccine, cytokine, or growth factor given to control the cancer) within 2 
weeks, prior to the first dose of study treatment  
4. Chemotherapy within 21 days or at least 5 half-lives (whichever is longer) prior to 
the planned start of study treatment 
5. [criterion deleted]  
6. Major surgery within 4 weeks prior to the first dose of study treatment. Surgery 
requiring local/epidural anesthesia must be completed at least 72 hours before study 
drug administration and patients should be recovered. 
7. Use of other investigational drugs within 2 weeks or 5 half-lives (whichever is 
longer) prior to study treatment administration 
8. Patients with ocular melanoma 
9. Neuropathy > NCI-CTCAE Grade 1 
10. Subjects with a history of allergic reactions attributed to compounds of similar 
composition to dolastatin or auristatin. Compounds of similar composition include 
Auristatin PHE as an anti-fungal agent, Auristatin PE (TZT-1027, Soblidotin, NSC-
654663) as an anti-tumor agent and symplostatin 1 as an anti-tumor agent. 
11. Active, untreated central nervous system metastases, except for patients with ≤ 3 
small (< 0.6 cm) asymptomatic lesions where treatment is not indicated. Patients 
with brain metastases identified at Screening may be rescreened after the lesion(s) 
have been appropriately treated; patients with treated brain metastases should be 
neurologically stable for 4 weeks post-treatment and prior to study enrollment, and 
off corticosteroids for at least 2 weeks before administration of study drugs.  
12. Women who are pregnant or lactating. All female patients with reproductive 
potential must have a negative pregnancy test prior to starting treatment. 
13. History of alternate malignancy except for adequately treated and cured basal or 
squamous cell skin cancer, curatively treated in situ disease, or any other cancer from 
which the patient has been disease-free for ≥ 3 years 
14. Significant cardiovascular disease including unstable angina pectoris, uncontrolled 
hypertension or arrhythmia, congestive heart failure (New York Heart Association 
Class III or IV) related to primary cardiac disease, ischemic or severe valvular heart 
disease or a myocardial infarction within 6 months prior to the first dose of study 
treatment 
15. Known alcohol or drug abuse 
16. Known infection with Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) 
or Hepatitis C (HCV) 
17. Any underlying medical condition that, in the investigator’s opinion, will make the 
administration of glembatumumab vedotin hazardous to the patient, or would 
obscure the interpretation of toxicity determination or adverse events 


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Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 19 of 130 
Additional Exclusion Criteria for Cohort 2 Only 
In addition to the exclusion criteria above, patients will be excluded from Cohort 2 for 
the following reason: 
18. Previous treatment with varlilumab or any other anti-CD27 mAb 
Additional Exclusion Criteria for Cohorts 2-5 
In addition to the exclusion criteria above, patients will be excluded from Cohorts 2-5 
for the following reasons:  
19. Active systemic infection requiring treatment. Infection controlled by oral therapy 
will not be exclusionary. Note: microscopic examination of urinalysis is required 
during screening. If urinary infection is suspected, then a negative urine culture is 
required prior to enrollment 
20. Use of immunosuppressive medications within 4 weeks or systemic corticosteroids 
within 2 weeks prior to first dose of study treatment. Topical, inhaled or intranasal 
corticosteroids (with minimal systemic absorption) may be continued if the patient 
is on a stable dose. Non-absorbed intraarticular corticosteroid and replacement 
steroids (≤10 mg/day prednisone or equivalent) will be permitted. 
21. Active autoimmune disease or a documented history of autoimmune disease, or 
history of potential autoimmune syndrome that required systemic steroids or 
immunosuppressive 
medications, 
except 
for 
patients 
with 
vitiligo, 
endocrinopathies, type 1 diabetes, or patients with resolved childhood asthma/atopy 
or other syndromes which would not be expected to recur in the absence of an 
external trigger (e.g., drug-related serum sickness or post-streptococcal 
glomerulonephritis). Subjects with mild asthma who require intermittent use of 
bronchodilators (such as albuterol) who have not been hospitalized for asthma in 
the preceding 3 years will not be excluded from this study.  
Additional Exclusion Criteria for Cohorts 3 and 5 Only 
In addition to the exclusion criteria above, patients will be excluded from Cohorts 3 and 
5 for the following reasons: 
22. Interstitial lung disease that is symptomatic or may interfere with the detection or 
management of suspected drug-related pulmonary toxicity. 
23. Active diverticulitis. 
Additional Exclusion Criteria for Cohorts 4 and 5 Only 
In addition to the exclusion criteria above, patients will be excluded from Cohorts 4 and 
5 for the following reasons: 
24. Any non-study vaccination within 4 weeks, or influenza vaccine within 2 weeks, 
prior to CDX-301 dosing  
Criteria for 
Evaluation 
Anti-tumor activity evaluations 
Anti-tumor activity will be assessed via ORR, PFS, DOR, and OS. Tumor response and 
progression will be defined by the investigator, according to RECIST 1.1 criteria. For 
Cohorts 2-5, supplementary retrospective analyses of tumor response and progression 
may also be performed using irRECIST criteria. 
Safety 
Safety will be assessed by vital sign measurements, clinical laboratory tests, physical 
exams, ECGs, ECOG performance status, and the incidence and severity of adverse 
events (graded according to National Cancer Institute Common Toxicity Criteria for 
Adverse Events (NCI-CTCAE v 4.0.)). Given the expected mechanism of action of 
varlilumab, the PD-1 targeted CPI, and CDX-301, particular attention will be given to 


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September 28, 2017 
Page 20 of 130 
adverse events in Cohorts 2-5 that may be secondary to activation of the immune system 
and have been observed with other immune-stimulatory antibodies (see Section 8.8). 
Immunogenicity 
Patients will be monitored for the development of anti-glembatumumab vedotin and anti-
CR011 antibodies. In addition, patients in Cohort 2 will be monitored for anti-varlilumab 
antibodies and patients in Cohorts 4 and 5 will be monitored for anti-CDX-301 
antibodies. Additional analyses will assess whether these antibodies are neutralizing.  
Pharmacokinetics (PK) 
Concentration of the glembatumumab vedotin antibody-drug conjugate (ADC), total 
antibody (TA), and free MMAE (Cohorts 1-5), varlilumab (Cohort 2), and CDX-301 
(Cohorts 4 and 5) will be determined using Good Laboratory Practices (GLP) compliant 
enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass 
spectrometry (LC-MS/MS) methods. The impact of circulating gpNMB levels or other 
soluble mediators on glembatumumab vedotin pharmacokinetic parameters may also be 
examined. 
Pharmacodynamic (PD) parameters 
Pharmacodynamic parameters will be evaluated via assessment of post-treatment tumor 
tissue obtained via voluntary biopsy or resection (Cohorts 1-3), mandatory pre-study 
and on-treatment biopsies (Cohorts 4 and 5), and blood samples. Parameters evaluated 
may include localization of glembatumumab vedotin, CR011, or MMAE at the tumor 
site and/or gpNMB expression levels in serum and tumor tissue, as well as evaluation 
of other soluble mediators, tumor infiltrating and peripheral leukocytes, circulating 
tumor cells, other immune response cells of interest such as gpNMB-expressing 
myeloid-derived suppressor cells, and to investigate the effect of CDX-301 on the 
tumor microenvironment, including the effect on intratumoral dendritic cell 
populations (Cohorts 4 and 5). Additional analysis may include immune response 
assessment to potentially relevant tumor antigens. 
Statistical 
Methods 
In Cohort 1, approximately 52 evaluable patients may be enrolled and treated with 
glembatumumab vedotin monotherapy with objective response rate (ORR) as the 
primary endpoint. As patients who discontinue study prior to the first disease assessment 
for reasons unrelated to study treatment will be excluded from the response-evaluable 
population, it is anticipated that approximately 60 patients will be enrolled in this cohort.  
For Cohort 1, the sample size was determined to estimate the ORR with one-sided 
significance level of 5% and power of 80%, using exact binomial test, to determine if 
the ORR exceeds a predefined minimum. A sample size of 52 patients will test the null 
hypothesis of an ORR of 5% versus 15% under the alternative hypothesis. If the number 
of responses (CR or PR) is 6 or more, the null hypothesis will be rejected with the actual 
error rate of 0.045. If the number of responses is 5 or less, the alternative hypothesis will 
be rejected with an actual error rate of 0.188. 
For Cohorts 2, 3, and 5, ORR by RECIST 1.1 remains the primary endpoint. 
Supplementary analyses of tumor response and progression may also be performed for 
Cohorts 2-5 using irRECIST criteria (in which new lesions do not necessarily constitute 
progression, but contribute to the calculated sum of diameter of all measurable disease) 
(Nishino, Giobbie-Hurder et al. 2013).  
For Cohorts 2, 3, and 5, approximately 30 patients per cohort, to achieve 25 evaluable, 
will be enrolled to have the maximum width of the 95% confidence interval (CI) of the 
estimated ORR to be no greater than 41%. If 7, 8, or 9 responses are observed (i.e., the 
estimated ORR is 28%, 32%, or 36%) among the 25 evaluable patients, then the lower 
limits of the two-sided 95% CIs of the estimated ORR are 12%, 15%, and 18% 


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Amendment 4 
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September 28, 2017 
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respectively. These calculations are based on the Clopper-Pearson method for exact 
confidence intervals. As a secondary consideration, 25 evaluable patients can achieve 
90% power for ORR of 25% comparing to 5% and 79% power comparing to 10% ORR 
with 1-sided type I error of 0.1 based on exact binomial test.  
Cohort 4 will enroll approximately 10-12 patients for safety and tolerability assessment 
of glembatumumab vedotin and CDX-301. Pre- and on-study tumor biopsies will be 
analyzed for the effect of CDX-301 on the tumor microenvironment, including the effect 
on intratumoral dendritic cell populations. The anti-tumor activity will also be explored 
as a secondary endpoint. 
Patients in Cohorts 2-5 who experience an event determined to be a treatment-limiting 
toxicity will not be replaced and will be considered evaluable.  
All statistical analyses will be performed separately for each treatment cohort, unless 
specified differently. Given the timing of different cohorts, statistical analyses will be 
performed for each cohort when sufficient data is available upon completion of 
enrollment. 
ORR will be estimated as the proportion of patients who achieve best overall response 
of CR or PR per RECIST 1.1 that are confirmed at an interval of at least 28 days. 
Secondary analyses of ORR will include responses observed at a single-time point. The 
final analysis of ORR will be based on the investigator assessment of response. However, 
in the event of a positive study outcome, an additional assessment of ORR may be 
performed by an independent review committee (IRC). The estimate of the objective 
response rate will be accompanied by one- and two-sided exact 95% Clopper-Pearson 
confidence interval for each cohort. In addition, one-sample exact binomial test will be 
used to test the null hypotheses of ORR (Cohort 1: ORR <5%; Cohorts 2, 3, and 5: both 
ORR <5%, and ORR <10%) with one-sided significance level of 0.05 for Cohort 1 and 
0.1 for Cohorts 2, 3, and 5. The primary ORR analyses will be based on respective 
evaluable population and the secondary analysis will be based on respective ITT 
population. Supplementary analyses of tumor response and progression may also be 
performed using irRECIST criteria (in which new lesions do not constitute progression, 
but contribute to the calculated sum of diameter of all measurable disease). Exploratory 
analysis will be performed for comparing the three cohorts on efficacy endpoints, and no 
adjustment for multiple testing will be considered. 
Waterfall plots will be used to depict graphically the maximum decrease from baseline 
in the sum of longest diameters of target lesions. Correlation between the degree of 
gpNMB expression and maximum decrease from baseline in the sum of longest 
diameters of target lesions will be evaluated. For this analysis, all patients will be used, 
with gpNMB expression measured on a continuous scale (percentage of gpNMB-
positive tumor cells). Further, to explore the predictive power of various cut-off values 
for gpNMB expression, a receiver operating curve (ROC) analysis for the response data 
(Gönen and SAS Institute. 2007) will be performed. 
The duration of objective response, PFS, and OS will be summarized descriptively for 
all patients, using the Kaplan-Meier method. The association between the degree of 
gpNMB expression and PFS will be evaluated using a Cox proportional hazards model. 
For this analysis, all patients will be used, with gpNMB expression measured on a 
continuous scale (percentage of gpNMB-positive tumor cells). When a factor is 
continuous, the hazard ratio is interpreted as the change in risk for each 1-unit increase 
in the factor. For example, a hazard ratio of 0.99 indicates the hazard for the event 
decreases by 1% for each 1%-unit increase in gpNMB expression level. For Cohort 1, if 
a true hazard ratio of 0.99 is assumed and the standard deviation for gpNMB expression 
level is ± 35%, 36 PFS events from among the 52 evaluable patients (70% event rate) 


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September 28, 2017 
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will provide approximately 80% power with one-sided significance level of 10% (Hsieh 
and Lavori 2000). The predictive power of various cut-off values for gpNMB expression 
will be explored based on a receiver operating curve (ROC) analysis for censored data 
(Gönen and SAS Institute. 2007). Similar analyses will be performed for Cohorts 2, 3, 
and 5 separately. 
For the above analyses, the most recent tumor sample will be utilized to determine the 
tumor gpNMB expression level for each patient. Additional exploratory analyses may 
be performed to examine the distribution and intensity of gpNMB expression (i.e., 
staining intensity and percentage of positive tumor and stromal cells) relative to outcome, 
as well as comparison of Historic and Pre-Study samples to determine whether gpNMB 
expression changes over time and/or with specific prior therapies.  


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September 28, 2017 
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4.  SCHEDULE OF ASSESSMENTS 
Table 1:  Schedule of Assessments (Cohorts 1-3) 
Visit 
Screening2 
Treatment Visits3 
Disease Assessment  
Visit5 
Survival 
Assessment6 
Cycle 1/ 
Day 1 
Cycle 1/ 
Day 7 
(Cohorts 2 
and 3) 
Cycle 1/ 
Day 14 
(Cohorts 2 
and 3) 
Cycle 2/ 
Day 1 
Cycle 3, 4, 5, etc./ 
Day 1 
End of 
Treatment4 
Every 6 (±1) weeks for 
6 months then every 9 
(±2) weeks thereafter 
Every 12 (±2) 
weeks until 
study closure 
Visit window1   
Day -28 to 
Day -1 
 
+/- 1 day 
+/- 1 day 
+/-3 days 
+/-3 days 
Within 28 days 
post-dosing 
Informed Consent, and, if applicable, 
HIPAA 
X 
 
 
 
 
 
 
 
Tumor tissue7 
X8 
 
X9 
Skin fold biopsy7 
X8 
 
 
 
 
 
 
 
Medical history10 
X 
X 
 
 
 
 
 
 
Physical examination11 
X 
X12 
 
 
X 
X 
X 
 
 
Vital signs13 
X 
X 
 
 
X 
X 
X 
 
 
ECOG performance status 
X 
X12 
 
 
X 
X 
X 
 
 
Electrocardiogram (ECG)  
X 
 
 
 
 
 
X 
 
 
Pregnancy test14 
X 
X12 
 
 
 
 
 
 
 
Hematology15 
X 
X12 
X 
X 
X 
X 
X 
 
 
Blood chemistry15 
X 
X12 
X 
X 
X 
X 
X 
 
 
Urinalysis/dipstick15 
X 
X12 
 
 
 
 
X 
 
 
Thyroid function test (Cohort 2)15 
X 
X12 
 
 
 
X (Odd cycles) 
X 
 
 
Immunogenicity16, 17 
 
X 
 
 
 
X (Odd cycles) 
X 
 
 
PBMC collection17, 18  
 
X 
 
 
X 
X (Cohorts 2 and 3, 
Cycle 5 only) 
 
 
 
PK sample collection17, 19 
 
X 
 
 
X 
X (Odd cycles)  
X  
 
 
PD sample collection17 
 
X 
 
 
X 
 
X  
 
 
Disease assessment20 
X 
 
 
 
 
 
 
X 
 
Administration of glembatumumab 
vedotin21 
 
X 
 
 
X 
X 
 
 
 
Administration of varlilumab22 
(Cohort 2) 
 
X 
 
 
X 
X21 
 
 
 
Administration of PD-1 targeted CPI 
(Cohort 3)23  
 
X 
X23 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
X 
Concomitant medication review24 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring25 
 
X 
X26 
X26 
X 
X 
X 
X27 
X27 
(footnotes on next page) 


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Amendment 4 
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September 28, 2017 
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Table 1 - Footnotes: 
1. A delay in study treatment or performance of study visits due to holidays, weekends, inclement weather or other unforeseen circumstances will be permitted 
and not considered a protocol violation. However, significant delays (i.e., greater than one week) due to these reasons should be discussed with the study 
medical monitor to reach consensus on subsequent scheduling. See (Section 8.6) and (Section 8.8) for management of dosing delays due to toxicity. 
2. Informed consent may be signed at any time prior to or during the screening period. No study-specific procedures will be performed prior to receipt of signed 
Informed Consent. However, assessments performed according to standard of care prior to receipt of Informed Consent may be utilized to fulfill the screening 
requirement, if completed within the required window for screening.  
3. Patients will receive study treatment until intolerance, progression of disease, or any of the other criteria for discontinuation of study treatment (Section 
7.2.4.1.1) are met. All cohorts will receive glembatumumab vedotin on a three-week cycle. Cohort 2 patients will also receive varlilumab on Day 1 of Cycles 
1, 2, 4, 6, 8, and 10. Cohort 3 patients will also receive a PD-1 targeted CPI per institutional standard of care.  
4. The End of Treatment Visit should be performed within 28 days after last dose of study treatment and prior to initiation of alternate therapies.  
5. Disease assessments will be performed every 6 weeks (±1 week) for 6 months and every 9 weeks (±2 weeks) thereafter, scheduled based on the first dose of 
glembatumumab vedotin at C1D1, until documented progression of disease or initiation of alternate anticancer therapies. For Cohorts 2 and 3, in cases of 
apparent progression that may reflect enhanced inflammation and/or an initial imbalance in the kinetics of tumor growth and anti-cancer immune activity, 
continued combination treatment may be allowed with permission granted from the Celldex Medical Monitor, until a second radiologic confirmation of 
progression performed at the next scheduled disease assessment (or sooner if clinically indicated) (Section 5.6.4 and Section 7.2.4.1.1). If a partial or complete 
response is noted, a follow-up disease assessment must be done no sooner than 28 days later to confirm response. Patients who discontinue treatment in the 
absence of progression will continue to have tumor assessments until documented progression or initiation of alternate anti-cancer therapies. If surgical 
intervention or localized radiation are indicated (either for palliation or down-staging of previously non-resectable tumor), these interventions should be 
avoided if clinically feasible until after the 12 week response assessment. Prior to any intervention (such as surgical resection, palliative radiation or alternate 
anti-cancer therapy), every effort should be made to perform a tumor response assessment in order to document progression and/or confirm an objective 
response. Patients who undergo surgical resection or radiation in the absence of progression may continue to receive study treatment until remaining lesions 
meet criteria for progression of disease. 
6. Subsequent to disease progression, all patients will be followed at 12 (±2) week intervals until study closure. Patients who discontinue treatment in the absence 
of progression will continue to have tumor assessments until documented progression or initiation of alternate anti-cancer therapies. These visits may be 
performed by telephone.  
7. Assessment of gpNMB expression will be performed by IHC, retrospectively, at a central laboratory on FFPE Historic and Pre-entry (tumor and skin fold 
[axilla or groin] biopsy) samples. Skin biopsy should be 3-5 mm in diameter. Additional analyses performed centrally may also include, but are not limited to, 
gpNMB expression by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR), examination of tumor markers using IHC or other molecular analyses, 
evaluation of tumor infiltrating leukocyte populations, biomarkers related to immune activation and localization of glembatumumab vedotin, CR011, or MMAE 
at the tumor site in post-treatment samples. Sample collection, processing and shipping instructions will be provided separately.  
8. Historic FFPE samples must represent the advanced stage of disease (Stage III or IV). Pre-entry FFPE samples must be obtained within 12 weeks prior to 
study entry, be subsequent to the last systemic anticancer therapy received, and be post-tumor progression. For patients who must undergo biopsy to obtain a 
FFPE Pre-entry sample, biopsy sites must be soft tissue tumor or visceral lesions that can be biopsied with acceptable clinical risk (as judged by the 
investigator). The biopsy site chosen should not have been previously irradiated and must be distinct from RECIST 1.1 target lesions. Tissue from multiple 
previous collection dates should also be submitted, when available/feasible, in order to further understand how gpNMB levels may change over time and/or 
with cancer stage. Skin biopsies (Cohorts 2 and 3) must be obtained within 12 weeks of study entry. 
9. At recurrence, biopsy and central analysis of recurrent tumor is optional but strongly encouraged. Similarly, in the event of tumor resection or biopsy performed 
per standard of care anytime during treatment or following tumor progression, submission of these tissue samples for central analysis is strongly encouraged. 
 
 


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September 28, 2017 
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10. Medical history includes demography, melanoma history, previous surgeries/therapy, and pre-existing diseases. At Cycle 1, Day 1, medical history is updated 
prior to administration of study drug.  
11. Complete physical exam should be performed at screening; thereafter, symptom-directed exams are acceptable.  
12. Assessments do not need to be repeated if completed within the previous 24 hours as part of the screening assessment.  
13. Vital signs to include height (at screening only), weight, respiration, pulse, temperature, and resting systolic and diastolic blood pressure. In Cohort 2 on 
glembatumumab vedotin and varlilumab dosing days, vital signs should be assessed pre-infusion, at 45 (±15) minutes during each infusion, and within one-
half hour following completion of each infusion. In Cohort 3, vital signs should be assessed for each glembatumumab vedotin infusion as follows: pre-infusion, 
at 45 (±15) minutes during the infusion, and within one-half hour following completion of the glembatumumab vedotin infusion. Additionally, when the PD-
1 targeted CPI is administered with or without glembatumumab vedotin dosing, vital signs should be assessed prior to each PD-1 targeted CPI infusion and 
additionally, as necessary, per clinical and institutional standards. (Note: weight is only assessed once per visit.)  
14. Serum or urine pregnancy test only for women of childbearing potential. Patients of non-childbearing potential include those who are ≥60 years, surgically 
sterilized, or postmenopausal with absence of menses for at least 1 year. However, women <60 with therapy-induced amenorrhea will require a pregnancy test 
unless additional evidence (oophorectomy or serial measurement of FSH and/or estradiol) are available to ensure postmenopausal status. 
15. Laboratory assessments must include the following, when indicated. Hematology results must be reviewed prior to dosing. For patients in Cohort 2, liver 
function tests (i.e., ALT, AST, and total bilirubin) and creatinine must also be reviewed prior to dosing. In addition, in Cohort 2, thyroid function tests must 
be performed at screening, at Cycle 1, at every odd cycle (i.e., Cycles 3, 5, 7, etc.), and at End of Treatment.  
 
Hematology: 
Clinical Chemistry: 
Urinalysis  
Hemoglobin 
Sodium 
pH 
Hematocrit 
Potassium 
Protein 
Mean corpuscular volume (MCV) 
Chloride  
Glucose 
Erythrocyte count (RBC) 
Bicarbonate  
Specific gravity 
Leukocytes (WBC) 
Glucose (nonfasting)  
Blood 
Platelets 
Differential:  
Neutrophils  
Lymphocytes 
Monocytes 
Eosinophils 
 
Differential should be reported consistently 
throughout the study as either an absolute 
count (preferred) or as a percentage. 
Blood urea nitrogen (BUN) 
 
Creatinine 
Calcium 
Phosphate 
Alkaline phosphatase 
Alanine transaminase (ALT/SGPT) 
Aspartate transaminase (AST/SGOT) 
Total protein 
Albumin 
Lactate Dehydrogenase (LDH) 
Total Bilirubin 
       Microscopic examination must be performed at 
baseline and, if clinically indicated, at subsequent 
visits (if urinary infection is suspected then a negative 
urine culture is required prior to enrollment.) 
 
Thyroid Function Test (Cohort 2 only) 
TSH 
Free T4 and T3 
 
Free T4 and free T3 performed at screening, and then 
only if TSH is abnormal at subsequent visits. 
16. Samples for immunogenicity will be collected prior to dosing on Day 1 of “odd” cycles (i.e., Cycles 1, 3, 5, 7, etc.).  
17. Analyses will be performed centrally. Sample collection, processing and shipping instructions will be provided separately.  


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 26 of 130 
18. For Peripheral Blood Mononuclear Cell (PBMC) collection on Cycle 1/Day 1 and Cycle 2/Day 1, samples are collected prior to dosing. For Cohort 1 an 
additional sample is collected at End of Treatment. For Cohorts 2 and 3 an additional sample is collected on Cycle 5/Day 1 prior to dosing. Analyses may 
include (but are not limited to) examination of gpNMB expression (and/or potential binding partners for gpNMB) on myeloid suppressor cells; peripheral 
leukocytes; circulating tumor cells; and other immune response cells of interest. Additional analysis may include response assessment to potentially relevant 
tumor antigens and analysis of myeloid derived suppressor cells. Details on sample collection and handling will be provided separately. PBMC samples will 
be collected until such time Celldex informs the sites that further data is not needed.  
19. Cohort 1: On Day 1 of Cycle 1 and 2 only, glembatumumab vedotin PK samples will be collected prior to dosing and at end of infusion (at or within 30 minutes 
after completion of infusion). A PK sample will also be collected at the End of Treatment visits.  
Cohort 2: On Day 1 of Cycles 1, 2, and 5, a total of three PK samples will be collected on each day for glembatumumab vedotin and varlilumab PK analysis. 
PK samples will be collected prior to dosing of varlilumab, at end of varlilumab infusion (at or within 10 minutes after completion of infusion), and at end of 
glembatumumab vedotin infusion (at or within 10 minutes after completion of infusion). On Day 1 of Cycles 3, 7, and subsequent odd cycles, only one PK 
sample will be collected prior to the first infusion. An additional sample should be drawn as soon as possible for any patients who experience an infusion 
reaction. A PK sample will also be collected at the End of Treatment visits. 
Cohort 3: On Day 1 of Cycles 1, 2, and 5, a total of two PK samples will be collected on each day for glembatumumab vedotin PK analysis. PK samples will 
be collected prior to dosing of glembatumumab vedotin and at end of infusion (at or within 10 minutes after completion of infusion). On Day 1 of Cycles 3, 7, 
and subsequent odd cycles, only one PK sample will be collected prior to the first infusion. An additional sample should be drawn as soon as possible for any 
patients who experience an infusion reaction. A PK sample will also be collected at the End of Treatment visits. 
For Cohorts 1, 2, and 3, analysis may also include circulating soluble gpNMB levels or other soluble molecules. 
20. Imaging-based evaluation per RECIST 1.1 should be performed. Contrast-enhanced Computed Tomography (CT) of the chest, abdomen, and pelvis, as well 
as all other suspected disease sites is required. Magnetic Resonance Imaging (MRI) exams of the brain, abdomen, and pelvis can be performed in lieu of a CT; 
however, MRI exams of the chest are not recommended. In the event that a chest MRI is performed, a non-contrast chest CT is strongly recommended to 
evaluate the lung parenchyma. Brain and/or bone scans are required for any patients with a history of metastases to bone and/or brain or where symptomatology 
raises the suspicion for bone and/or brain metastases. Lesions identified on bone scans should be confirmed by a CT or MRI at baseline, and, if identified as 
target lesions due to soft tissue component, they should continue to be followed by the same methodology (i.e., CT or MRI scan). However, bone lesions 
followed as non-target disease may be subsequently followed by bone scans only. Lesions that cannot be imaged but are assessable by clinical exam may be 
assessed by color photography including a ruler (preferred method) or measured with calipers. Normally, all target and non-target disease sites should be 
evaluated at each assessment. However, for patients with non-target bone disease, bone scans need only be repeated every twelve to eighteen weeks, or more 
frequently if clinically indicated. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at 
baseline and during follow-up. Target lesions selected for tumor measurements should be those where surgical resection or radiation are not indicated or 
anticipated.  
21. Unless otherwise specified, all study assessments should be performed prior to administration of study treatment(s), and may be performed up to 24 hours 
prior to treatment administration if assessments remain within the specified visit window.  
22. In Cohort 2, varlilumab and glembatumumab vedotin will be administered as separate infusions with a break of at least 30 minutes between infusions. 
Varlilumab should be infused over 90 (±10) minutes and administered before glembatumumab vedotin, also infused over 90 (±10) minutes. Varlilumab will 
be administered on Day 1 of Cycles 1, 2, 4, 6, 8, and 10 only. Patients in Cohort 1 should be monitored for at least 1 hour following the last administration of 
study drug to monitor for infusion reaction/cytokine release syndrome/hypersensitivity reaction. Patients in Cohort 2 should be observed on Cycle 1 Day 1 for 
at least 2 hours after the last study drug, and for at least 1 hour at all subsequent dosing visits. Infusions should be given in a monitored setting that has ready 
access to an intensive care unit in case of a severe infusion reaction. 
 
 


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Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 27 of 130 
23. Administration of the PD-1 targeted CPI should be continuous from the prior standard of care treatment regimen during which the most recent disease 
progression occurred. No more than 3 doses of nivolumab or 2 doses of pembrolizumab should be missed between the most recent disease progression and 
initiation of treatment on study. Day 1 of Cycle 1 occurs with the first dose of glembatumumab vedotin which is administered on the same day as the PD-1 
targeted CPI. When both glembatumumab vedotin and the PD-1 targeted CPI are administered on the same day, the drugs will be administered as separate 
infusions. The PD-1 targeted CPI should be the first infusion and glembatumumab vedotin administered at least 30 minutes later as the second infusion. 
Patients in Cohort 3 should be observed on Cycle 1 Day 1 for at least 2 hours after the last study drug, and for at least 1 hour at all subsequent dosing visits. 
Infusions should be given in a monitored setting that has ready access to an intensive care unit in case of a severe infusion reaction. The PD-1 targeted CPI 
will be administered in combination with glembatumumab vedotin until disease progression (using study screening disease assessment as baseline reference) 
or intolerance.  
Additional clinic visits and monitoring (such as laboratory assessments) relevant to the administration of the PD-1 targeted CPI will be conducted in accordance 
with standard of care when appropriate. However, all CPI dosing and adverse events occurring between study visits will be documented in the eCRF. 
24. All concomitant medication will be documented in the Case Report Form (CRF) if taken within 28 days prior to Study Day 1, and either (whichever occurs 
sooner): a) 28 days after last dose of study treatment or b) initiation of alternate anti-cancer therapy. In addition, all anti-cancer medications should be recorded 
throughout the duration of study follow-up.  
25. For patients who develop grade 3 treatment-related rash and who provide appropriate consent, punch biopsies and photographs of the rash, as well as uninvolved 
skin, are strongly encouraged. Samples may be analyzed centrally; in these cases, collection, processing and shipping instructions will be provided separately.  
26. Adverse event monitoring on Cycle 1 Day 7 and Cycle 1 Day 14 for patients in Cohorts 2 and 3 can be performed in person or by telephone to determine if 
the patient is experiencing any adverse events.  
27. Events occurring >28 days after discontinuation of glembatumumab vedotin, >70 days after discontinuation of varlilumab (Cohort 2), or >70 days after 
discontinuation of the PD-1 targeted CPI (Cohort 3) are only reportable if both serious (SAE) and potentially treatment-related. 
 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 28 of 130 
Table 2. Schedule of Assessments (Cohorts 4 and 5)  
Visit 
Screening2 
Treatment Visits3 
Disease 
Assessment 
Visit5 
Survival 
Assessment6 
Cycle 1/ Day 
-6 to Day -2 
Cycle 1 
/ Day 1 
Cycle 1 
/ Day 7 
Cycle 1 / 
Day 15-19 
Cycle 2 
/ Day 1 
Cycle 3, 4, 5, etc. 
/ Day 1 
End of 
Treatment4 
Every 6 (±1) 
weeks for 6 
months then 
every 9 (±2) 
weeks thereafter 
Every 12 (±2) 
weeks until study 
closure 
Visit window1 
Day -35 to 
Day -7 
 
+3/- 1 
days 
+/- 1 
day 
 
+3/- 1 
days 
+/- 3 days 
Within 28 
days post-
dosing 
Informed Consent, and, if 
applicable, HIPAA 
X 
 
 
 
 
 
 
 
 
 
Tumor tissue7 
X8 
 
 
X8 
X9 
Medical history10 
X 
X (Day -6 
only) 
 
 
 
 
 
 
 
 
Physical examination11 
X 
X12 
X 
 
X 
X 
X 
X 
 
 
Vital signs13 
X 
X 
X 
 
X 
X 
X 
X 
 
 
ECOG performance status 
X 
X12 
 
 
 
X 
X 
X 
 
 
Electrocardiogram (ECG)  
X 
 
 
 
 
 
 
X 
 
 
Pregnancy test14 
X 
X12 
 
 
 
 
 
 
 
 
Hematology15 
X 
X12 (Day -6 
only) 
X 
X 
X (Day 15 
only) 
X 
X 
X 
 
 
Blood chemistry15 
X 
X12 (Day -6 
only) 
X 
X 
X (Day 15 
only) 
X 
X 
X 
 
 
Urinalysis/dipstick15 
X 
X12 
 
 
 
 
 
X 
 
 
Immunogenicity16, 17 
 
X 
 
 
 
 
X (Odd cycles) 
X 
 
 
PBMC collection17, 18 
 
 
X  
(Day -6 only) 
 
 
X (Day 15 
only) 
X  
X (Cycle 3 only) 
 
 
 
PK sample collection17, 19 
 
X (Days -6 
and -2 only) 
X 
 
X (Days 
15 and 19 
only) 
X 
X (odd cycles) 
X 
 
 
PD sample collection17 
 
X 
X 
 
 
X 
 
X 
 
 
Disease Assessment20 
X 
 
 
 
 
 
 
 
X 
 
Administration of 
glembatumumab vedotin21 
 
 
X 
 
 
X 
X 
 
 
 
Administration of 
CDX-30121, 22 
 
X 
 
 
X 
 
 
 
 
 
Administration of PD-1 
targeted CPI (Cohort 5)23 
 
 
X 
X 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
X 
Concomitant medication 
review24 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Monitoring25 
 
X 
X 
X26 
X 
X 
X 
X 
X27 
X27 
(footnotes on next page) 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 29 of 130 
 
Table 2 - Footnotes: 
1. A delay in study treatment or performance of study visits due to holidays, weekends, inclement weather or other unforeseen circumstances will be permitted 
and not considered a protocol violation. However, significant delays (i.e., greater than one week) due to these reasons should be discussed with the study 
medical monitor to reach consensus on subsequent scheduling. See (Section 8.6) and (Section 8.8) for management of dosing delays due to toxicity. 
2. Informed consent may be signed at any time prior to or during the screening period. No study-specific procedures will be performed prior to receipt of signed 
Informed Consent. However, assessments performed according to standard of care prior to receipt of Informed Consent may be utilized to fulfill the screening 
requirement, if completed within the required window for screening.  
3. Patients will receive study treatment until intolerance, progression of disease, or any of the other criteria for discontinuation of study treatment (Section 
7.2.4.1.1) are met. Both cohorts will receive glembatumumab vedotin on a three-week cycle. Patients will also receive CDX-301 on 5 consecutive days from 
Cycle 1 Days -2 to -6 and Cycle 1 Days 15-19. Cohort 5 patients will also receive a PD-1 targeted CPI per institutional standard of care.  
4. The End of Treatment Visit should be performed within 28 days after last dose of study treatment and prior to initiation of alternate therapies.  
5. Disease assessments will be performed every 6 weeks (±1 week) for 6 months and every 9 weeks (±2 weeks) thereafter, scheduled based on the first dose of 
glembatumumab vedotin at C1D1, until documented progression of disease or initiation of alternate anticancer therapies. In cases of apparent progression that 
may reflect enhanced inflammation and/or an initial imbalance in the kinetics of tumor growth and anti-cancer immune activity, continued combination 
treatment may be allowed with permission granted from the Celldex Medical Monitor, until a second radiologic confirmation of progression performed at the 
next scheduled disease assessment (or sooner if clinically indicated) (Section 5.6.4 and Section 7.2.4.1.1). If a partial or complete response is noted, a follow-
up disease assessment must be done no sooner than 28 days later to confirm response. Patients who discontinue treatment in the absence of progression will 
continue to have tumor assessments until documented progression or initiation of alternate anti-cancer therapies. If surgical intervention or localized radiation 
are indicated (either for palliation or down-staging of previously non-resectable tumor), these interventions should be avoided if clinically feasible until after 
the 12 week response assessment. Prior to any intervention (such as surgical resection, palliative radiation or alternate anti-cancer therapy), every effort should 
be made to perform a tumor response assessment in order to document progression and/or confirm an objective response. Patients who undergo surgical 
resection or radiation in the absence of progression may continue to receive study treatment until remaining lesions meet criteria for progression of disease. 
6. Subsequent to disease progression, all patients will be followed at 12 (±2) week intervals until study closure. Patients who discontinue treatment in the absence 
of progression will continue to have tumor assessments until documented progression or initiation of alternate anti-cancer therapies. These visits may be 
performed by telephone.  
7. Assessment of gpNMB expression and/or dendritic cells will be performed by IHC, retrospectively, at a central laboratory on FFPE Pre-entry and On-treatment 
tumor samples. Additional analyses performed centrally may also include, but are not limited to, gpNMB expression by Reverse Transcriptase Polymerase 
Chain Reaction (RT-PCR), examination of tumor markers using IHC or other molecular analyses, evaluation of tumor infiltrating leukocyte populations, 
biomarkers related to immune activation and localization of glembatumumab vedotin, CR011, or MMAE at the tumor site in post-treatment samples. For these 
analyses, fresh Pre-entry and On-treatment samples will need to be cut into two pieces. Sample collection, processing and shipping instructions will be provided 
separately. Tumor tissue samples will be collected until such time Celldex informs the sites that further data is not needed. 
8. Fresh pre-entry samples must be obtained within 12 weeks prior to study entry, be subsequent to the last systemic anticancer therapy received, and be post-
tumor progression. On-treatment biopsies must be obtained on Cycle 1 Day 7 (+/- 1 day). On-treatment biopsies in Cohort 5 may be collected at a different 
time point depending on the results obtained in Cohort 4. If so, then any change will be communicated to the Investigators and sites. Sites of sample collection 
must be soft tissue tumor or visceral lesions that can be attained with acceptable clinical risk (as judged by the investigator). The site chosen should not have 
been previously irradiated and must be distinct from RECIST 1.1 target lesions.  
9. At recurrence, biopsy and central analysis of recurrent tumor is optional but strongly encouraged. Similarly, in the event of tumor resection or biopsy performed 
per standard of care anytime during treatment or following tumor progression, submission of these tissue samples for central analysis is strongly encouraged. 
10. Medical history includes demography, melanoma history, previous surgeries/therapy, and pre-existing diseases. At Cycle 1, Day -6, medical history is updated 
prior to administration of study drug.  


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 30 of 130 
11. Complete physical exam should be performed at screening; thereafter, symptom-directed exams are acceptable.  
12. Assessments do not need to be repeated if completed within the previous 24 hours as part of the screening assessment.  
13. Vital signs to include height (at screening only), weight, respiration, pulse, temperature, and resting systolic and diastolic blood pressure. Vital signs should 
be assessed for each glembatumumab vedotin infusion as follows: pre-infusion, at 45 (±15) minutes during the infusion, and within one-half hour following 
completion of the glembatumumab vedotin infusion. On CDX-301 dosing days, vital signs should be performed prior to dosing and 60 (±10) minutes after the 
first dose of CDX-301, and prior to dosing and 30 (±10) minutes after subsequent doses of CDX-301. Additionally, when the PD-1 targeted CPI is administered 
with or without glembatumumab vedotin dosing, vital signs should be assessed prior to each PD-1 targeted CPI infusion and additionally, as necessary, per 
clinical and institutional standards. (Note: weight is only assessed once per visit.)  
14. Serum or urine pregnancy test only for women of childbearing potential. Patients of non-childbearing potential include those who are ≥60 years, surgically 
sterilized, or postmenopausal with absence of menses for at least 1 year. However, women <60 with therapy-induced amenorrhea will require a pregnancy test 
unless additional evidence (oophorectomy or serial measurement of FSH and/or estradiol) are available to ensure postmenopausal status. 
15. Laboratory assessments must include the following, when indicated. Hematology results must be reviewed prior to dosing.  
 
Hematology: 
Clinical Chemistry: 
Urinalysis  
Hemoglobin 
Sodium 
pH 
Hematocrit 
Potassium 
Protein 
Mean corpuscular volume (MCV) 
Chloride  
Glucose 
Erythrocyte count (RBC) 
Bicarbonate  
Specific gravity 
Leukocytes (WBC) 
Glucose (nonfasting)  
Blood 
Platelets 
Differential:  
Neutrophils  
Lymphocytes 
Monocytes 
Eosinophils 
 
Differential should be reported consistently 
throughout the study as either an absolute 
count (preferred) or as a percentage. 
Blood urea nitrogen (BUN) 
 
Creatinine 
Calcium 
Phosphate 
Alkaline phosphatase 
Alanine transaminase (ALT/SGPT) 
Aspartate transaminase (AST/SGOT) 
Total protein 
Albumin 
Lactate Dehydrogenase (LDH) 
Total Bilirubin 
       Microscopic examination must be performed at 
baseline and, if clinically indicated, at subsequent 
visits (if urinary infection is suspected then a negative 
urine culture is required prior to enrollment.) 
 
 
 
 
 
 
16. Samples for CDX-301 and glembatumumab vedotin immunogenicity will be collected prior to dosing on Day -6 of Cycle 1 and Day 1 of “odd” cycles (i.e., 
Cycles 1, 3, 5, 7, etc.), and at the End of Treatment Visit.  
17. Analyses will be performed centrally. Sample collection, processing and shipping instructions will be provided separately.  
18. For Peripheral Blood Mononuclear Cell (PBMC) collection on Cycle 1/Day -6, Cycle 1/Day 15, Cycle 2/Day 1, and Cycle 3/Day 1, samples are collected prior 
to dosing. Analyses may include (but are not limited to) examination of gpNMB expression (and/or potential binding partners for gpNMB) on myeloid 
suppressor cells; peripheral leukocytes; circulating tumor cells; and other immune response cells of interest. Additional analysis may include response 
assessment to potentially relevant tumor antigens and analysis of myeloid derived suppressor cells. Details on sample collection and handling will be provided 
separately. PBMC samples will be collected until such time Celldex informs the sites that further data is not needed.  
19. On Cycle 1 Days -2, -6, 15, and 19, sample for CDX-301 PK is collected prior to CDX-301 dose. On Day 1 of Cycle 1 and 2 only, glembatumumab vedotin 
PK samples will be collected prior to any dosing and at the end of infusion (at or within 30 minutes after completion of infusion). A PK sample for both 
analytes will also be collected prior to dosing on Day 1 of “odd” cycles (i.e., Cycles 3, 5, 7, etc.) and at the End of Treatment visits.  


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 31 of 130 
20. Imaging-based evaluation per RECIST 1.1 should be performed. Contrast-enhanced Computed Tomography (CT) of the chest, abdomen, and pelvis, as well 
as all other suspected disease sites is required. Magnetic Resonance Imaging (MRI) exams of the brain, abdomen, and pelvis can be performed in lieu of a CT; 
however, MRI exams of the chest are not recommended. In the event that a chest MRI is performed, a non-contrast chest CT is strongly recommended to 
evaluate the lung parenchyma. Brain and/or bone scans are required for any patients with a history of metastases to bone and/or brain or where symptomatology 
raises the suspicion for bone and/or brain metastases. Lesions identified on bone scans should be confirmed by a CT or MRI at baseline, and, if identified as 
target lesions due to soft tissue component, they should continue to be followed by the same methodology (i.e., CT or MRI scan). However, bone lesions 
followed as non-target disease may be subsequently followed by bone scans only. Lesions that cannot be imaged but are assessable by clinical exam may be 
assessed by color photography including a ruler (preferred method) or measured with calipers. Normally, all target and non-target disease sites should be 
evaluated at each assessment. However, for patients with non-target bone disease, bone scans need only be repeated every twelve to eighteen weeks, or more 
frequently if clinically indicated. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at 
baseline and during follow-up. Target lesions selected for tumor measurements should be those where surgical resection or radiation are not indicated or 
anticipated.  
21. Unless otherwise specified, all study assessments should be performed prior to administration of study treatment(s), and may be performed up to 24 hours 
prior to treatment administration if assessments remain within the specified visit window.  
22. The intent is for CDX-301 to be administered for 5 consecutive days on Monday through Friday, followed by glembatumumab vedotin treatment (and PD-1 
targeted CPI for Cohort 5) on the following Monday. CDX-301 administration is allowed on weekend days if the site has the ability to do so. Ideally, CDX-
301 should be administered at approximately the same time each day. Patients should be observed on Day -6 prior to Cycle 1 for at least 1 hour after CDX-
301 injection, and for at least 30 minutes at all subsequent CDX-301 doses.   
23. In Cohort 5, administration of the PD-1 targeted CPI should be continuous from the prior standard of care treatment regimen during which the most recent 
disease progression occurred. No more than 3 doses of nivolumab or 2 doses of pembrolizumab should be missed between the most recent disease progression 
and initiation of treatment on study. Day 1 of Cycle 1 occurs with the first dose of glembatumumab vedotin which, in Cohort 5, is administered on the same 
day as the PD-1 targeted CPI. When both glembatumumab vedotin and the PD-1 targeted CPI are administered on the same day, the drugs will be administered 
as separate infusions. The PD-1 targeted CPI should be the first infusion and glembatumumab vedotin administered at least 30 minutes later as the second 
infusion. Patients should be observed on Cycle 1 Day 1 for at least 2 hours after administration of the last study drug, and for at least 1 hour at all subsequent 
dosing visits. Infusions should be given in a monitored setting that has ready access to an intensive care unit in case of a severe infusion reaction. The PD-1 
targeted CPI will be administered in combination with glembatumumab vedotin until disease progression (using study screening disease assessment as baseline 
reference) or intolerance.  
Additional clinic visits and monitoring (such as laboratory assessments) relevant to the administration of the PD-1 targeted CPI will be conducted in accordance 
with standard of care when appropriate. However, all CPI dosing and adverse events occurring between study visits will be documented in the eCRF. 
24. All concomitant medication will be documented in the Case Report Form (CRF) if taken within 28 days prior to Study Day 1, and either (whichever occurs 
sooner): a) 28 days after last dose of study treatment or b) initiation of alternate anti-cancer therapy. In addition, all anti-cancer medications should be recorded 
throughout the duration of study follow-up.  
25. For patients who develop grade 3 treatment-related rash and who provide appropriate consent, punch biopsies and photographs of the rash, as well as uninvolved 
skin, are strongly encouraged. Samples may be analyzed centrally; in these cases, collection, processing and shipping instructions will be provided separately 
26. Adverse event monitoring on Cycle 1 Day 7 can be performed in person or by telephone to determine if the patient is experiencing any adverse events.  
27. Events occurring >28 days after discontinuation of glembatumumab vedotin, >28 days after discontinuation of CDX-301, or >70 days after discontinuation of 
the PD-1 targeted CPI (Cohort 5 only) are only reportable if both serious (SAE) and potentially treatment-related. 




























































Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 6 1  of 1 3 0  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
6.   S T U D Y O B J E C TI V E S  
T he pri mar y o bjecti ve of t he st u d y is t o e val uat e t he a nti -ca n cer acti vit y of gle m b at u m u ma b 
ve d oti n as m o n ot hera p y ( C o h ort 1),  i n c o m bi nati o n wit h varlil u ma b ( C o h ort 2), i n c o m bi nati o n 
wit h a P D - 1 tar gete d  c hec k p oi nt  i n hi bit or ( C PI) ( C o h ort  3), or  i n  c o m bi nati o n  wit h 
gle m bat u m u ma b  v e d oti n,  C D X -3 0 1,  a n d  a  P D -1  tar gete d  C PI  ( C o h ort  5)  i n  a d va n ce d 
mela n o ma as meas ure d b y t he O R R per R E CI S T 1. 1 . I n C o h ort 4, t he pri mar y o bj ecti ve is to 
e valuate  t he  saf et y  a n d  t olera bilit y  of  t he  c o m bi nati o n  of  gle m bat u m u ma b  ve d oti n  a n d 
C D X - 3 0 1. 
Sec o n dar y o bjecti ves ar e:  
•  T o f urt her assess t he a nti -ca ncer acti vit y of gl e m bat u m u ma b ve d oti n as m o n ot hera p y , i n 
c o m bi nati o n wit h varlil u ma b , i n c o m bi nati o n wit h a P D- 1 tar gete d C PI, or i n c o m bi nati o n 
wit h C D X -3 0 1 a n d a P D -1 tar get e d C PI i n a d va nce d mela n o ma, as assesse d b y P F S, D O R 
a n d O S . T o assess t he a nti-ca ncer acti vit y of t he c o m bi nati o n of gle m bat u m u ma b ve d oti n 
a n d C D X- 3 0 1 i n a d va n ce d mela n o ma, as assess e d b y O R R, P F S, D O R, a n d O S. 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 6 2  of 1 3 0  
•  T o  i n vesti gat e  if  t he  a nti -ca ncer  acti vit y  of  gle m bat u m u ma b  v e d oti n al o ne  or  i n 
c o m bi nati o n wit h i m m u n ot hera pies i n a d v a nce d mela n o ma is de pe n de nt u p o n t he de gree 
of g p N M B e x pressi o n i n t u m or tiss ue 
•  T o f urt her c har acterize t he safet y of gl e m bat u m u ma b ve d oti n as m o n ot hera p y  
•  T o  c haracterize  t he  safet y  of  t he  c o m bi nati o n  of  gle m bat u m u ma b  ve d oti n  wit h 
i m m u n ot hera pies i n a d va nce d mela n o ma 
E x pl orat or y o bjecti ves ar e:  
•  T o e x a mi ne t he ra n ge of g p N M B e x pressi o n i n a d va nce d mela n o ma, a n d t o asse ss w het her 
g p N M B e x pressi o n c ha n ges o v er ti me a n d/ or wit h s pecific pri or t h era pies  
•  T o e x a mi ne p har mac o d y na mic  eff ects of treat me nt, i ncl u di n g t y p es a n d n u m ber of i m m u ne 
cells i nfiltrati n g t he t u m or; l ocalizati o n of gle m b at u m u ma b ve d oti n, C R 0 1 1, a n d M M A E 
i n t he  t u m or;  s ol u ble  me diat ors, g p N M B  e x pressi o n  le vels  a n d/ or  ot her p ote ntial 
bi o mar kers  i n  b ot h n or mal  a n d  t u m or  tiss ue;  a nal ysis  of  peri p heral  bl o o d  s u bsets; t o 
i n vesti gate t he eff ect of C D X-3 0 1 o n t he t u m or micr oe n vir o n me nt, i ncl u di n g t he effect o n 
i ntrat u m oral de n dritic cell p o p ulati o ns ( C o h orts 4 a n d 5). 
•  T o  f urt her  c h aracterize  t he  p har mac o ki n etics  a n d  i m m u n o ge nicit y  of  gle m bat u m u ma b 
ve d oti n, varlil u ma b , a n d C D X- 3 0 1 i n patie nts wit h a d va nce d mela n o ma , a n d t o e x pl ore t he 
relati o ns hi ps  bet wee n  p atie nt-specific  m eas ures  of  e x p os ure  a n d  safet y  a n d  acti vit y 
para meters  
•  T o  assess  t he  a nti -ca ncer  acti vit y  of  t he  c o m bi n ati o n  of  gl e m bat u m u ma b  ve d oti n  a n d 
i m m u n ot hera pies as meas ure d b y t he O R R a n d P F S per ir R E CI S T 
7.   IN V E S TI G A TI O N A L P L A N  
7. 1.    
O ver all Desi g n a n d Pl a n of t he St u d y 
T his  is  a n  o pe n -la bel  P hase  II  st u d y  of  gle m b at u m u ma b  ve d oti n  as  m o n ot hera p y  or  i n 
c o m bi nati o n wit h varlil u ma b , or i n c o m bi nati o n wit h ot her i m m u n ot hera pies, i n patie nts wit h 
u nresect a ble Sta ge III or I V mela n o ma  w h o ha v e pre vi o usl y recei ve d  c he c k p oi nt i n hi bit ors . 
Patie nts will recei ve st u d y treat me nt  i n a n o pe n-la bel fas hi o n. A p pr o xi matel y 6 0 patie nts  wer e 
e nr olle d a n d  recei ved gl e m bat u m u ma b ve d oti n m o n ot hera p y  i n C o h ort 1. A p pr o xi matel y 3 0 
patie nts  were e nr olle d i n C o h ort 2 a n d recei ved gl e m bat u m u ma b ve d oti n i n c o m bi nati o n wit h 
varlil u ma b. I n C o h ort 3, a p pr o xi ma tel y 3 0 p atie nts will recei ve gle m bat u m u ma b ve d oti n i n 
c o m bi nati o n wit h a P D- 1 tar gete d c hec k p oi nt i n hi bit or  ( C PI); ni v ol u ma b a n d pe m br oliz u ma b. 
I n t his c o h ort, p atie nts w h ose last treat me nt re gi me n i ncl u de d ni v ol u ma b or pe m br oliz u ma b, 
a n d per i nstit uti o nal sta n dar d of care  w o ul d c o nti n ue t o recei ve a P D -1 tar get e d t hera p y  des pite 
pr o gressi o n, will  recei ve 
eit her  ni v ol u ma b  or  pe m br oliz u ma b  i n  c o m bi nati o n  wit h 
gle m bat u m u ma b ve d oti n, t o deter mi ne w het her t he a d diti o n of gle m b at u m u ma b ve d oti n ca n 
i n d uce a n  eff ecti ve  a nti -mela n o ma  i m m u ne  res p o nse  a n d  i m pr o ve d  a nti -ca ncer  acti vit y.  
Patie nts  w h o  pre vi o usl y  recei ve d  ni v ol u ma b  i n  c o m bi nati o n  wit h  i pili m u ma b  a n d  ha v e 
disc o nti n ue d i pili m u ma b w o ul d c o nti n ue wit h ni v ol u ma b , or pe m br oliz u ma b, i n c o m bi nati o n 
wit h  gle m bat u m u ma b  ve d oti n.  Patie nts w h o e x perie nce d  diseas e  pr o gressi o n  o n  ni v ol u ma b 
ma y  recei ve  ni v ol u ma b  or  pe m br oliz u ma b  i n  c o m bi nati o n  wit h  gle m bat u m u ma b  ve d oti n. 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 63 of 130 
Patients who experienced disease progression on pembrolizumab may receive nivolumab or 
pembrolizumab in combination with glembatumumab vedotin. 
In Cohort 4, approximately 10-12 patients will receive glembatumumab vedotin combined 
with CDX-301 to determine the safety and tolerability of the combination and to investigate 
the effect of CDX-301 on the tumor microenvironment, including the effect on intratumoral 
dendritic cell populations. Following this pilot cohort, an evaluation period will occur whereby 
the Sponsor and Investigators will assess the safety and activity of glembatumumab vedotin in 
combination with CDX-301 (Cohort 4) and with a PD-1 targeted CPI (Cohort 3). If the results 
are supportive in Cohorts 3 and 4, then enrollment of approximately 30 patients in Cohort 5 
will begin to evaluate whether the anti-tumor immune responses would likely be further 
augmented by combining all three agents in patients who have previously failed a CPI.  
Study treatment, and associated study visits at 3 week intervals, will continue until disease 
progression or intolerance. In Cohort 2, varlilumab will be administered on Day 1 of Cycles 1, 
2, 4, 6, 8, and 10 for a total of up to 6 doses. In Cohort 3, patients who experienced disease 
progression on nivolumab or pembrolizumab will continue with a PD-1 targeted CPI, 
nivolumab or pembrolizumab, which will be administered with glembatumumab vedotin until 
disease progression (using study screening disease assessment as baseline reference) or 
intolerance. In Cohort 4, two priming cycles of CDX-301 will be administered subcutaneously 
for 5 consecutive days (Cycle 1 Days -6 to -2 and Cycle 1 Days 15-19) prior to 
glembatumumab vedotin on Day 1 in Cycles 1 and 2. Glembatumumab vedotin will continue 
to be administered at 3 week intervals until disease progression or intolerance. Patients in 
Cohort 5 who previously progressed on nivolumab or pembrolizumab will continue with a 
PD-1 targeted CPI, nivolumab or pembrolizumab, similar to Cohort 3. The PD-1 targeted CPI 
will be administered according to institutional standard of care with reference to the package 
insert. In Cohort 5, CDX-301 and glembatumumab vedotin will be administered in the same 
manner as in Cohort 4. 
Additional hematology and chemistry analyses as well as adverse event monitoring will be 
performed on Days 7 and 14 in Cycle 1 for patients in Cohorts 2-5. Patients in Cohort 1 should 
be monitored for at least 1 hour following the last administration of study drug to monitor for 
infusion reaction/cytokine release syndrome/hypersensitivity reaction. Patients in Cohorts 2 
and 3 should be observed on Cycle 1 Day 1 for at least 2 hours after the last study drug, and 
for at least 1 hour at all subsequent dosing visits. Patients in Cohorts 4 and 5 should be observed 
on Cycle 1 Day -6 and Cycle 1 Day 1 for at least 2 hours after the last study drug, and for at 
least 1 hour at all other dosing visits. Infusions should be given in a monitored setting that has 
ready access to an intensive care unit in case of a severe infusion reaction (see Section 8.8). 
Tumor assessments will be performed every 6 weeks (±1 week) for the first 6 months, and 
every 9 weeks (±2 weeks) thereafter, until documented progression of disease or initiation of 
alternate anticancer therapies. Tumor response will be assessed by the investigator in 
accordance with RECIST 1.1 guidelines (Appendix 3) (Eisenhauer, Therasse et al. 2009) . For 
Cohorts 2-5, supplementary retrospective analyses of tumor response and progression may also 
be performed using Immune-Related RECIST (“irRECIST”) criteria (in which new lesions do 
not constitute progression, but contribute to the calculated sum of diameter of all measurable 
disease) (Nishino, Giobbie-Hurder et al. 2013). Patients who discontinue treatment in the 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 64 of 130 
absence of progression will continue to have tumor assessments until documented progression 
or initiation of alternate anti-cancer therapies.  
For Cohorts 2-5, in cases of apparent progression that may reflect enhanced inflammation 
and/or an initial imbalance in the kinetics of tumor growth and anti-cancer immune activity, 
continued combination treatment may be allowed with permission granted from the Celldex 
Medical Monitor, until a second radiologic confirmation of progression performed at the next 
scheduled disease assessment (or sooner if clinically indicated) (Section 7.2.4.1.1). The 
following criteria must be met: 1) the patient experiences investigator-assessed clinical benefit; 
and 2) the patient is tolerating the study treatment. The patient must sign an informed consent 
form for continued treatment after apparent disease progression.  
Continuous evaluation of toxicity will be performed by the investigators and Celldex 
throughout the entire course of patient treatment. Treatment-limiting toxicity (as defined in 
Section 8.7) will be reported to Celldex within 24 hours, and site teleconferences between 
Celldex and all participating sites will be held at frequent intervals to evaluate emerging safety 
data. In Cohort 2, if treatment-limiting toxicity occurs in >2 of the first 10 patients, or in >20% 
of patients thereafter, all further patients enrolled will receive a varlilumab starting dose of 
0.3 mg/kg and ongoing patients will also receive any further dosing of varlilumab at 0.3 mg/kg. 
If additional treatment-limiting toxicity occurs in >20% of patients receiving varlilumab at 
0.3 mg/kg, enrollment will be interrupted pending evaluation by Celldex and the investigators. 
In Cohorts 3-5, if >2 of the first 10 patients experience treatment-limiting toxicities, or in >20% 
of patients thereafter, then enrollment in the cohort will be interrupted pending evaluation by 
Celldex and the investigators. The FDA and site IRBs will be notified of the analysis and 
determination regarding further enrollment. Enrollment in Cohort 5 will not commence until 
the evaluation of toxicity and activity in Cohorts 3 and 4 of all treated patients has been 
assessed and it has been determined that the combinations of glembatumumab vedotin with 
CDX-301 and glembatumumab vedotin with PD-1 targeted CPI are safe and tolerable. 
For all cohorts, study analyses will include a retrospective assessment to define the range of 
gpNMB expression for all enrolled patients and to determine if outcome correlates with 
intensity or distribution of gpNMB expression. In Cohorts 2 and 3, normal skinfold biopsies 
are collected prior to study entry for retrospective assessment to identify patients predisposed 
to rash. Skinfold biopsies will be collected until such time Celldex informs the sites that further 
data is not needed.  
Patients who discontinue study prior to the first disease assessment for reasons unrelated to 
study treatment (i.e., adverse events deemed unrelated to study treatment, withdrawal of 
consent, lost to follow-up, withdrawal due to administrative reasons, etc.) will be excluded 
from the response-evaluable population and may be replaced. Patients who discontinue study 
prior to the first disease assessment due to treatment-related adverse events, symptomatic 
deterioration (adverse events due to progression), or death will be included in the response 
evaluable population.  


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 65 of 130 
7.2.  
Selection of Study Population 
7.2.1.  
Number of Patients 
Approximately 160 patients will be enrolled: approximately 60 patients enrolled in Cohort 1, 
approximately 30 patients enrolled in Cohort 2, approximately 30 patients will be enrolled in 
Cohort 3, approximately 10-12 patients will be enrolled in Cohort 4, and approximately 30 
patients will be enrolled in Cohort 5. Cohorts 2 and 3 enrolled patients in parallel. 
7.2.2.  
Subject Eligibility 
7.2.2.1.  
Inclusion Criteria 
Patients may be included in the study only if they meet all of the following inclusion criteria 
at the time of study enrollment: 
1. Read, understood, and provided written informed consent and, if applicable, Health 
Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the 
study has been fully explained and must be willing to comply with all study requirements 
and procedures. 
2. Advanced (unresectable Stage III or Stage IV) histologically-confirmed melanoma. 
3. Documented progressive disease, based on radiographic, clinical or pathologic assessment, 
during or subsequent to the last anticancer therapy. For Cohorts 3 and 5, progression 
(confirmed from two scans at least 4 weeks apart) must have occurred during the PD-1 
targeted CPI treatment and the investigator has deemed it appropriate to continue to treat 
beyond confirmed disease progression. 
4. No more than 1 prior chemotherapy-containing regimen for advanced disease. For Cohorts 
1, 2, and 4, prior treatments received must include at least one check-point inhibitor (e.g., 
anti-CTLA-4-, PD-1-, PD-L1-targeted immunotherapy) and for patients with a BRAF 
mutation, at least one BRAF- or MEK-targeted therapy, unless patients are not candidates 
for, or refused, these therapies. For Cohorts 3 and 5, prior treatment received must include 
a PD-1 targeted CPI (i.e., nivolumab or pembrolizumab) administered during the most 
recent disease progression and for patients with a BRAF mutation, at least one BRAF- or 
MEK-targeted therapy when appropriate. 
5. Pre-treatment tumor tissue, and for Cohorts 2 and 3 a skin biopsy, available for 
retrospective evaluation of gpNMB in tumor or normal epithelial cells, respectively, by 
central immunohistochemistry (IHC): 
a. All patients in Cohorts 1-3 must submit an archival FFPE tumor tissue sample 
representative of advanced (Stage III or IV) disease, obtained more than 12 weeks 
prior to study entry (Historic sample).  
b. All patients in Cohorts 1-3 are also required to submit a second, recently-obtained 
FFPE tumor tissue sample (Pre-entry sample). Tissue should be obtained within the 
12 weeks prior to study entry, be subsequent to the last systemic anticancer therapy 
received, and be post-tumor progression.  
c. All patients in Cohorts 4-5 are required to submit a fresh Pre-entry tumor tissue sample 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 6 6  of 1 3 0  
as  well  as  a  fr es h  O n -treat me nt  t u m or  tiss ue  sa m ple.  Pre-e ntr y  tiss ue  s h o ul d  be 
o btai ne d wit hi n t he 1 2 wee ks pri or t o st u d y e ntr y, be s u bse q ue nt t o t he last s yst e mic 
a ntica ncer t her a p y recei v e d, a n d be p ost -t u m or pr o gressi o n. T u m or tiss ue sa m ples will 
be c ollecte d u ntil s uc h ti me Cell de x i nf or ms t he sites t hat f urt her dat a is n ot nee de d.  
F or patie nts w h o n ee d t o u n der g o a n e w bi o ps y t o o btai n a Pre -e ntr y, or b ot h Pre -e ntr y 
a n d O n-treat me nt, sa m pl e, bi o ps y sites m ust be s oft tiss ue or visceral t u m or lesi o ns 
t hat ca n be bi o psie d wit h acce pt a ble cli nical ris k (as j u d ge d b y t he i n vesti gat or). T he 
bi o ps y site c h ose n s h o ul d ha ve n ot bee n pre vi o usl y irra diate d. Bi o ps y sit es m ust be 
disti nct fr o m R E CI S T 1. 1 tar get l esi o ns, u nless, i n t he case of t he Pre -e ntr y bi o ps y,  
t he bi o ps y is o btai ne d m ore t ha n 1 0 da ys pri or t o t he Scree ni n g Disease Assess me nt. 
Patie nts m ust be se paratel y c o ns e nte d f or c ollecti o n of a fres h Pre -e ntr y, or b ot h Pre -
e ntr y a n d O n-treat me nt s a m ple. 
d.   All patie nts i n C o h ort s 2 a n d 3 m ust a gree t o s u b mit a rece ntl y-o btai ne d F F P E s ki n 
f ol d  (a xilla  or  gr oi n)  bi o ps y  ( Pre-e ntr y  sa m ple).  Tiss ue  ma y  b e  o btai ne d  b y  p u n c h 
bi o ps y or s ur gical e x cisi o n.  S ki nf ol d bi o psies will  be c ollecte d u ntil s uc h ti me Cell de x 
i nf or ms t he sites t hat f urt her data is n ot nee de d. 
N O T E:  Patie nts w h o ca n n ot f ulfill t he re q uire me nt f or eit her t he Hist oric , Pre -e ntr y, or 
O n -treat me nt s a m ple s u b missi o n i n C o h orts 1- 5 ma y b e e nr olle d i n t he st u d y wit h pri or 
per missi o n of t he Cell de x Me dical M o nit or.  I n n o case will a patie nt be all o we d t o e nter 
t he st u d y wit h o ut at least o ne a vaila ble t u m or s a m ple. 
6.  Male or  fe m ale patie nt ≥ 1 8 years of a ge 
7.  Easter n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us 0 t o 1 ( A p pe n di x 4 ) 
8.  Lif e e x pecta nc y of ≥ 1 2 wee ks 
9.  Meas ura ble  (tar get)  disease  b y  R E CI S T  1. 1  crit eria   (Eise n h a uer,  T herasse  et  al.  2 0 0 9 ) 
(A p pe n di x  3 ).  Tar get  lesi o ns  selecte d  f or  t u m or  meas ure me nts  s h o ul d  be  t h ose  w here 
a d diti o nal (e. g., palliati ve) treat me nts are n ot i n di cate d or a ntici pate d.   
1 0.  Res ol uti o n  of  t o xicities  relate d  t o  pri or  t hera pies  (i ncl u di n g  ra di ot hera p y) t o 
≤ N CI -C T C A E  Gr a de  1  se verit y,  e x ce pt  f or  al o pecia,  gra d e  2  fati g ue,  vitili g o,  or 
e n d ocri n o pat hies o n r e pl ace me nt t hera p y 
1 1.  Scree ni n g la b or at or y val ues m ust meet t he f oll o wi n g criteria:  
•  A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1 5 0 0/ m m 3 
•  He m o gl o bi n ≥ 9. 0 g/ d L 
•  Platelet c o u nt ≥ 1 0 0, 0 0 0/ m m 3 
•  Cal c ulate d  creati ni ne  cleara nce > 4 0  m L/ mi n  per  t he  C oc kcr oft  a n d  Ga ult  f or m ula 
(A p pe n di x 5 ) or Ser u m Creati ni ne ≤ 2. 0 m g/ d L 
•  Ala ni ne tra nsa mi nas e ( A L T) ≤ 3. 0 x u p per li mit of n or mal ( U L N) ( ≤ 5. 0 x U L N i n t he 
case of li ver metastases)  
•  As partate  tra ns a mi nase  ( A S T) ≤ 3. 0 x U L N ( ≤ 5. 0 x U L N i n t he c as e  of  li ver 
metastases)  


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 6 7  of 1 3 0  
•  T otal bilir u bi n  ≤ 1. 5 x U L N ( ≤ 5. 0 x U L N i n t he cas e of li ver m etastases). Patie nts 
wit h k n o w n Gil bert’s s y n dr o me ma y be e nr olle d wit h t otal bilir u bi n ≤ 3. 0 m g/ d L  
1 2.  B ot h  me n  a n d  w o me n  e nr olle d  i n  t his  trial  m ust  use  effecti ve  c o ntrac e pti o n  d uri n g  t he 
c o urse of t he trial a n d f or at least t w o m o nt hs after disc o nti n ui n g st u d y treat me nt. Effecti ve 
c o ntrace pti o n is  defi ne d as d o u ble barrier c o ntrace pti o n (e . g., c o n d o m pl us s per mici de i n 
c o m bi nati o n  wit h  a  fe m ale  c o n d o m,  dia p hra g m,  cer vical  ca p, c o ntrace pti ve  s p o n ge  or 
va gi n al  ri n g ), i ntr a-ut eri ne  d e vice  (I U D), 
i m pla nts,  i njecta bles,  c o m bi ne d  oral 
c o ntrace pti ves, se x ual a bsti ne nce ( t otal a bsti ne n ce fr o m se x ual i nterc o urse as t he preferre d 
lifest yle of t he p atie nt; p eri o dic a bsti ne n ce is n ot acce pta ble), or se x ual i nterc o urs e wit h 
o nl y  a  vas ect o mize d  part ner.  Patie nts  a n d/ or  part ners  w h o  are  s ur gi call y  sterile  or 
p ost me n o pa usal are e x e m pt fr o m t his re q uire me nt. 
7. 2. 2. 2.   
E xcl usi o n Criteri a  
Patie nts will be e x cl u de d fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns:  
1.  Recei ve d  gle m bat u m u m a b  ve d oti n  ( C R 0 1 1 -vc M M A E;  C D X -0 1 1)  or  ot her  M M A E -
c o ntai ni n g a ge nts pre vi o usl y  
2.  B R A F/ M E K i n hi bit ors wit hi n 2 wee ks pri or t o t he first d ose of st u d y treat me nt.  
3.  Use of a n y m o n ocl o n al base d t hera pies wit hi n 4 wee ks,  e x ce pt f or t he P D - 1 tar gete d C PI 
(i.e.,  ni v ol u ma b  or  p e m br oliz u ma b) i n  C o h ort  3, a n d  all  ot her  i m m u n ot hera p y  (t u m or 
vacci ne, c yt o ki ne, or gr o wt h fact or gi ve n t o c o ntr ol t he ca ncer) wit hi n 2 wee ks, pri or t o t he 
first d ose of st u d y treat m e nt.  
4.  C he m ot hera p y  wit hi n  2 1  da ys  or  at  least  5  h alf -li ves  ( w hic he v er  is l o n ger)  pri or  t o  t h e 
pla n ne d start of st u d y treat me nt 
5.  [ criteri o n delete d] 
6.  Maj or s ur ger y wit hi n 4 wee ks pri or t o t he first d ose of st u d y treat me nt. S ur ger y re q uiri n g 
l ocal/e pi d ural  a nest hesi a  m ust  be  c o m plete d  at  least  7 2  h o urs  bef ore  st u d y  dr u g 
a d mi nistrati o n a n d patie nts s h o ul d be rec o vere d. 
7.  Use of ot her i n vesti gati o n al dr u gs wit hi n 2 wee ks or 5 half -li ves ( w hic h e ver is l o n ger) pri or 
t o st u d y treat me nt a d mi nistrati o n 
8.  Patie nts wit h oc ular mela n o ma  
9.  Ne ur o pat h y > N CI - CT C A E Gra d e 1  
1 0.  S u bjects wit h a hist or y of aller gic reacti o ns attri b ut e d t o c o m p o u n ds of si milar c o m p ositi o n 
t o d olastati n or a uristati n. C o m p o u n ds of si milar c o m p ositi o n i ncl u de A uristati n P H E as 
a n a nti-f u n gal a ge nt, A uristati n P E ( T Z T-1 0 2 7, S o bli d oti n, N S C -6 5 4 6 6 3) as a n a nti -t u m or 
a ge nt a n d s y m pl ostati n 1 as a n a nti-t u m or a ge nt. 
1 1.  Acti ve,  u ntreate d  ce ntral  ner v o us  s yste m  metastases,  e x ce pt  f or  patie nts  wit h  ≤  3  s mall  
( < 0. 6  c m)  as y m pt o matic  lesi o ns  w here  treat me nt  is  n ot  i n dicate d.  Patie nts  wit h  brai n 
metasta ses  i de ntifie d  at  Scree ni n g  ma y  be  res cree n e d  after  t h e  lesi o n(s)  ha ve  bee n 
a p pr o priatel y tr eate d; p atie nts wit h treate d brai n metastases s h o ul d be ne ur ol o gicall y sta bl e 
f or 4 wee ks p ost-tr eat me nt a n d pri or t o st u d y e nr oll me nt, a n d off c ortic oster oi ds f or at least 
2 wee k s bef ore a d mi nistrati o n of st u d y dr u gs.  


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 68 of 130 
12. Women who are pregnant or lactating. All female patients with reproductive potential must 
have a negative pregnancy test prior to starting treatment. 
13. History of alternate malignancy except for adequately treated and cured basal or squamous 
cell skin cancer, curatively treated in situ disease, or any other cancer from which the 
patient has been disease-free for ≥ 3 years 
14. Significant cardiovascular disease including unstable angina pectoris, uncontrolled 
hypertension or arrhythmia, congestive heart failure (New York Heart Association Class 
III or IV) related to primary cardiac disease, ischemic or severe valvular heart disease or a 
myocardial infarction within 6 months prior to the first dose of study treatment 
15. Known alcohol or drug abuse 
16. Known infection with Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) or 
Hepatitis C (HCV) 
17. Any underlying medical condition that, in the investigator’s opinion, will make the 
administration of glembatumumab vedotin hazardous to the patient, or would obscure the 
interpretation of toxicity determination or adverse events 
Additional Exclusion Criteria for Cohort 2 Only 
In addition to the exclusion criteria above, patients will be excluded from Cohort 2 for the 
following reason: 
18. Previous treatment with varlilumab or any other anti-CD27 mAb 
Additional Exclusion Criteria for Cohorts 2-5 
In addition to the exclusion criteria above, patients will be excluded from Cohorts 2-5 for the 
following reasons: 
19. Active systemic infection requiring treatment. Infection controlled by oral therapy will not 
be exclusionary. Note: microscopic examination of urinalysis is required during screening. 
If urinary infection is suspected, then a negative urine culture is required prior to 
enrollment. 
20. Use of immunosuppressive medications within 4 weeks or systemic corticosteroids within 
2 weeks prior to first dose of study treatment. Topical, inhaled or intranasal corticosteroids 
(with minimal systemic absorption) may be continued if the patient is on a stable dose. 
Non-absorbed intraarticular corticosteroid and replacement steroids (≤10 mg/day 
prednisone or equivalent) will be permitted. 
21. Active autoimmune disease or a documented history of autoimmune disease, or history of 
potential autoimmune syndrome that required systemic steroids or immunosuppressive 
medications, except for patients with vitiligo, endocrinopathies, type 1 diabetes, or patients 
with resolved childhood asthma/atopy or other syndromes which would not be expected to 
recur in the absence of an external trigger (e.g., drug-related serum sickness or post-
streptococcal glomerulonephritis). Subjects with mild asthma who require intermittent use 
of bronchodilators (such as albuterol) who have not been hospitalized for asthma in the 
preceding 3 years will not be excluded from this study. 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 6 9  of 1 3 0  
A d diti o nal E x cl usi o n Criteria f or C o h orts 3 a n d 5 O nl y  
I n a d diti o n t o t he e x cl usi o n criteria a b o ve, patie nts will be e x cl u de d fr o m C o h orts 3 a n d 5 f or 
t he f oll o wi n g r eas o ns: 
2 2.  I nterstitial  l u n g  disease  t hat  is  s y m pt o matic  or  ma y  i nterfere  wit h  t he  detecti o n  or 
ma na ge me nt of s us pecte d dr u g-relat e d p ul m o nar y t o xicit y 
2 3.  A cti ve di vertic ulitis    
A d diti o nal E x cl usi o n Criteria f or C o h orts 4 a n d 5 O nl y 
I n a d diti o n t o t he e x cl usi o n criteria a b o ve, patie nts will be e x cl u de d fr o m C o h orts 4 a n d 5 f or 
t he f oll o wi n g r eas o ns: 
2 4.  A n y n o n -st u d y vacci nati o n wit hi n 4 wee ks, or i nfl ue nza vacci ne wit hi n 2 wee ks, pri or t o 
C D X - 3 0 1 d osi n g 
7. 2. 3.   Me as ures t o Mi ni mize Bi as  
T his is n o n -ra n d o mize d o pe n -la bel st u d y. T he a n al ysis of t u m or res p o nse  a n d pr o gressi o n-free 
s ur vi val will be base d o n t u m or res p o nse assess me nts perf or me d b y t h e i n vesti gat or acc or di n g 
t o sta n dar dize d, o bjecti ve res p o nse criteria ( R E CI S T 1. 1). I n a d diti o n, i n t he e ve nt of a p ositi ve 
st u d y o ut c o me, a n a d diti o nal assess me nt of t u m or res p o nse a n d pr o gressi o n ma y  be perf or me d 
b y a n i n d e pe n de nt r e vie w c o m mittee (I R C) bli n de d t o i n vesti gat or assess me nts.  
7. 2. 4.   Wit h dr a w als a n d Re pl ace me nt of P atie nts  
E ver y eff ort s h o ul d b e m a de wit hi n t he b o u n ds of safet y a n d patie nt c h oi ce t o ha ve eac h p atie nt 
c o m plete t he st u d y.  A n e x pla nati o n will be rec or d e d f or eac h patie nt ta ke n off st u d y treat me nt 
or disc o nti n ui n g t he st u d y. 
Patie nts w h o disc o nti n ue st u d y pri or t o t he first disease assess me nt  f or reas o ns u nrelate d t o 
st u d y  tr eat me nt  (i.e., a d verse  e ve nts  dee m e d  u nrelate d  t o  st u d y  treat me nt, wit h dra wal  of 
c o nse nt, l ost t o f oll o w -u p, wit h dra wal d u e t o  a d mi nistrati ve reas o ns,  etc.) will  be  e x cl u de d 
fr o m t he res p o ns e-e v al ua ble p o p ulati o n  a n d ma y be re place d . Patie nts w h o disc o nti n ue st u d y 
pri or  t o  t he  first  dis ease  assess me nt d ue  t o  treat me nt -relate d  a d verse  e v e nts,  s y m pt o matic 
deteri orati o n ( a d vers e e v e nts d ue t o pr o gressi o n), or deat h  will be  i ncl u de d i n t he res p o nse 
e val ua ble p o p ulati o n. 
7. 2. 4. 1.   Disc o nti n u ati o n of St u d y Tre at me nt  
Reas o ns f or disc o nti n uati o n of st u d y treat me nt i ncl u de:  
•  Pr o gr essi ve disease, as assesse d b y t he treati n g i n vesti gat or i n acc or da n ce wit h R E CI S T 
1. 1  criteria  ( A p pe n di x  3 );  i n  C o h orts  2- 5 a n  e x ce pti o n  ma y  be  gra nte d  as  descri be d  i n 
Secti o n  7. 2. 4. 1. 1 . 
•  S y m pt o matic d eteri or ati o n (cli nical pr o gressi o n) : 
o  N ote:  T his cate g or y is a p plica ble t o patie nts wit h a gl o bal deteri orati o n of healt h stat us 
re q uiri n g  disc o nti n uati o n  of  treat me nt.  H o w e ver, per  R E CI S T  1. 1  ( A p pe n di x  3 ), 
s y m pt o matic deteri orati o n is n ot a descri pt or of a n o bjecti ve res p o ns e; it is a reas o n 
f or  st o p pi n g  st u d y  t her a p y.  T h us,  e ver y  eff ort  s h o ul d  be  ma de  t o c o nti n ue  disease 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 7 0  of 1 3 0  
assess me nts  per  pr ot oc ol u ntil  d oc u me nte d  o bj ecti ve  pr o gressi o n  or  i nitiati o n  of 
alter nate t hera p y.   
•  Recei pt of alter n ate a nti -ca ncer treat me nts  
•  Wit h dra wal r e q uest b y  t h e patie nt or t he patie nt’s l e gal re prese ntati ve 
o  N ote: Wit h dra wal of c o nse nt f or c o nti n ue d treat me nt s h o ul d  be differe ntiate d fr o m 
wi t h dra wal of c o ns e nt f or st u d y f oll o w-u p, a n d e ver y eff ort s h o ul d be ma de wit hi n t he 
b o u n ds of safet y a n d p atie nt c h oice t o ha ve eac h p atie nt c o m plete t he st u d y f oll o w - u p.  
•  A d verse E v e nt   
•  P h ysicia n D ecisi o n  
•  N o n -c o m plia nce of t he p atie nt  
•  Pre g n a nc y  
•  Deat h, ot her wis e n ot e x plai na ble b y t he a b o v e o pti o ns 
•  Patie nt l ost t o f oll o w - u p (see bel o w)  
•  Treat me nt -li miti n g t o xicit y ( C o h orts 2- 5) 
Patie nts w h o disc o nti n ue st u d y treat me nt s h o ul d be see n f or a n E n d of Treat me nt Visit. Patie nts 
w h o  disc o nti n ue  st u d y  tr eat me nt  wit h o ut  pr o gressi o n  of  disease  as  per  R E CI S T  1. 1  s h o ul d 
c o nti n ue Diseas e Assess me nt Visits u ntil criteria f or diseas e pr o gressi o n are met  or alter n ate 
t hera pies are i nitiate d (see Ta ble 1 , a n d Ta ble 2 ).  
7. 2. 4. 1. 1  
All o w a nce f or Per mitti n g C o nti n ue d St u d y Dr u g  Tre at me nt i n C ases of 
A p p are nt Pr o gressi ve Dise ase  
As descri be d i n Secti o n 5. 6. 4 , acc u m ulati n g e vi d e nce i n dicates a mi n orit y of patie nts treat e d 
wit h  i m m u n ot hera p y  ma y  deri ve  cli nical  be n efit  des pite  i nitial  e vi de nce  of  pr o gressi o n  per 
R E CI S T ( A p pe n di x 3 ). T heref ore, i n or d er t o ascertai n w het her tr u e pr o gressi o n has occ urre d, 
or  w het her  a  treat me nt  me diate d  i nfla m mat or y/i m m u ne  me di ate d  a ntit u m or  reacti o n 
( pse u d o pr o gr essi o n) mi g ht ha ve pr ece de d a t u m or res p o nse, p atie nts wit h a p pare nt pr o gressi o n 
w h o  ha v e  n o  a d diti o nal  c o n ve nti o nal  treat me nt  o pti o ns  ma y  c o nti n ue  st u d y  treat me nt  a n d 
c o m plete t he s u bse q ue nt disease assess me nt o n sc he d ule, pr o vi de d t he f oll o wi n g criteri a are 
met:  
•  I n v esti gat or-ass esse d cli nical be nefit. T he assess me nt of cli nical be nefit s h o ul d ta ke i nt o 
acc o u nt w het her t he patie nt is cli nicall y d eteri orati n g a n d u nli kel y t o recei ve f urt her be nefit 
fr o m c o nti n ue d treat me nt. 
•  Patie nt is t olerati n g st u d y dr u g.  
•  All decisi o ns t o c o nti n ue treat me nt be y o n d i nitial pr o gressi o n m ust be disc usse d wit h t he 
Cell de x Me dical M o nit or a n d t he patie nt, a n d t he patie nt m ust si g n a n i nf or me d c o nse nt 
f or m f or  c o nti n ue d  treat me nt  after  i nitial  pr o gressi o n.  Patie nts  ca n  o nl y  c o nti n ue  st u d y 
treat me nt  be y o n d  i nitial  pr o gressi o n  if  t h e y  ha v e  n o  a d diti o nal  c o n v e nti o nal  treat me nt 
o pti o ns. 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 7 1  of 1 3 0  
•  Patie nts  s h o ul d  disc o nti n ue  st u d y  t hera p y  u p o n  f urt her  e vi de nce  of  f urt h er pr o gressi o n, 
defi ne d  as  a n  a d diti o nal  1 0 %  or  greater  i ncrease  i n  t u m or  b ur de n  v ol u me  fr o m  ti me  of 
i nitial  pr o gr essi o n  (i ncl u di n g  all  tar get  lesi o ns  a n d  ne w  meas ura ble  lesi o ns).  F or  t his 
assess me nt, ne w lesi o ns are c o nsi d ere d meas ura bl e at t he ti me of i niti al pr o gressi o n if t he 
l o n gest dia meter is at least 1 0 m m (e x ce pt f or pat h ol o gical l y m p h n o des, w hic h m ust ha ve 
a s h ort a xis of at least 1 5 m m). A n y ne w lesi o ns c o nsi dere d n o n- meas ura bl e at t he ti me of 
i nitial  pr o gressi o n  ma y  bec o me  meas ura ble  a n d  t heref ore i ncl u de d  i n  t he  t u m or  b ur de n 
meas ure me nt if t he l o n gest dia meter i ncreas es t o at least 1 0 m m (e x ce pt f or pat h ol o gical 
l y m p h n o des, w hic h m ust ha ve a n i ncreas e i n s h ort a xis t o at least 1 5 m m). 
•  F or statistical a nal yses t h at i ncl u de t he i n v esti gat or -assessed pr o gressi o n d ate, patie nts w h o 
c o nti n ue  treat me nt  be y o n d  i nitial  i n vesti gat or -assesse d,  m o difie d  R E CI S T  1. 1  defi ne d 
pr o gressi o n will be c o nsi dere d t o ha ve i n vesti gat or -assesse d pr o gressi ve disease at t he ti me 
of t he i nitial pr o gr essi o n e ve nt.  
7. 2. 4. 2.   
Disc o nti n u ati o n f r o m St u d y  
Reas o ns f or patie nt r e m o val fr o m t he st u d y i n cl u de: 
•  Re q uest of t he patie nt or t he patie nt’s le gal re prese ntati ve ( wit h dra wal of c o nse nt f or t he 
st u d y f oll o w- u p) 
•  Patie nt l ost t o f oll o w - u p 
o  A s u bject s h o ul d b e c o nsi dere d l ost t o f oll o w u p o nl y after m ulti ple eff orts ha ve bee n 
ma de t o c o ntact t he s u bject t o assess his/ her healt h stat us after fail ure of t he s u bject t o 
atte n d sc he d ule d visits.  If after t w o d oc u me nte d p h o ne calls t he i n vesti gati ve site is 
still u na ble t o c o ntact t he s u bject, a certifie d letter s h o ul d be se nt t o his/ her h o me f or 
i m me diate res p o nse. If t here is still n o res p o nse, t he s u bject is t o be c o nsi dere d l ost t o 
f oll o w u p. A rec or d of t he s u bject bei n g l ost t o f oll o w u p s h o ul d be n ote d i n t he s o urce 
d oc u me nts al o n g wit h t he p h o ne c o ntacts a n d t he ret ur ne d certifi e d mail (if se nt bac k).  
7. 2. 5.   C o m pleti o n of St u d y  
It is a ntici pate d t hat t h e e nr oll me nt peri o d will be a p pr o xi matel y 5 4 m o nt hs. All  patie nts will 
be  f oll o we d  wit h  re gar d  t o  s ur vi val  u ntil  deat h,  disc o nti n uati o n  fr o m  st u d y f oll o w-u p,  or 
ter mi nati o n/c o m pleti o n of st u d y. Patie nts w h o die or c o m plete t he st u d y  f oll o w -u p t hr o u g h 
st u d y cl os ur e will be c o nsi dere d t o ha ve “c o m plet e d” t he st u d y.  
T he st u d y will be declar e d c o m plete w he n s ufficie nt data is o btai ne d t o c o ncl u de t he st u d y; 
t his is esti mate d at a p pr o xi matel y t w o years fr o m t he date w he n t he l ast patie nt i n t he st u d y 
disc o nti n ues  st u d y  tr eat me nt.  Pre mat ure  ter mi nati o n  of  t his  st u d y  ma y  o cc ur  beca use  of  a 
re g ulat or y a ut h orit y decisi o n, dr u g safet y iss u es, or at t he dis creti o n of Cell de x . I n a d diti o n, 
Cell de x retai ns t he ri g ht t o disc o nti n ue de vel o p me nt of gle m bat u m u ma b ve d oti n or varlil u ma b 
at a n y ti me.  


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 72 of 130 
8.  STUDY TREATMENT 
  
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
  
 
 
  
 
  
  
 
 
 
 
  
 
 
  
 
 






Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 75 of 130 
 
  
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.  Nivolumab 
8.3.1.  Description, Packaging, and Labeling 
Nivolumab will be obtained from commercial supply and handled/stored in a fashion 
consistent with packet insert and institutional policies. The following sections are based on 
package insert (dated July 2017). However, investigators are responsible for referencing the 
complete and most current package insert for full guidance regarding potential toxicity and 
dosing of nivolumab. 
Nivolumab is available as 40 mg/4 mL and 100 mg/10 mL solution in a single-dose vial. 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 7 6  of 1 3 0  
8. 3. 2.   St or a ge a n d H a n dli n g  
Ni v ol u ma b d oes n ot c o ntai n a preser v ati ve. St ore ni v ol u ma b u n der refri gerati o n at 2 °C t o 8 °C 
( 3 6°F t o 4 6 °F). Pr otect fr o m li g ht b y st ori n g i n ori gi nal pac ka ge u ntil ti me of use. D o n ot freeze 
or s ha ke. 
After pr e par ati o n, st ore t he ni v ol u ma b i nf usi o n eit her: 
•  At r o o m te m perat ur e f or n o m ore t ha n 8 h o urs fr o m t he ti me of pre parati o n. T his i ncl u des 
r o o m te m perat ure st or a ge of t he i nf usi o n i n t he I V c o ntai ner a n d ti me f or a d mi nistrati o n of 
t he i nf usi o n or 
•  U n der r efri gerati o n at 2° C t o 8° C ( 3 6° F t o 4 6° F) f or n o m ore t ha n 2 4 h o urs fr o m t he ti me 
of i nf usi o n pre parati o n. 
D o n ot freeze.  
8. 3. 3.    Pre p ar ati o n a n d A d mi nistr ati o n 
Pre parati o n of t he Dil uti o n 
Vis uall y  i ns pect  ni v ol u ma b  s ol uti o n  f or  p arti c ular  matter  a n d  disc ol orati o n  pri or  t o 
a d mi nistrati o n. Ni v ol u ma b is a clear t o o palesce nt, c ol orless t o pale -yell o w s ol uti o n. Discar d 
t he vial if t h e s ol uti o n is cl o u d y, disc ol ore d, or c o ntai ns e xtra ne o us partic ulate matter ot her 
t ha n a fe w tra nsl uce nt-t o- w hite, pr otei nace o us particles. D o n ot s ha ke t he vial. 
•  Wit h dra w t he re q uire d v ol u me of ni v ol u ma b a n d tra nsfer i nt o a n i ntra ve n o us c o ntai ner 
•  Dil ute  ni v ol u ma b  wit h  eit her  0. 9 %  S o di u m  C hl ori de  I njecti o n,  U S P  or  5 %  De xtr ose 
I njecti o n, U S P t o pre par e a n i nf usi o n wit h a fi nal c o nce ntrati o n ra n gi n g fr o m 1 m g/ m L to 
1 0 m g/ m L. 
•  Mi x dil ute d s ol uti o n b y ge ntle i n versi o n. D o n ot s ha ke. 
•  Discar d partiall y us e d vials or e m pt y vi als of ni v ol u ma b. 
A d mi nistrati o n  
A d mi nister t he i nf usi o n o ver 6 0 mi n utes t hr o u g h a n i ntra ve n o us li ne c o ntai ni n g a sterile, n o n -
p yr o ge nic, l o w pr otei n bi n di n g i n -li ne filter ( p ore size of 0. 2 micr o meter t o 1. 2 micr o meter). 
D o n ot c o -a d mi nister ot her dr u gs t hr o u g h t he sa m e i ntra ve n o us li ne. Fl us h t he i ntra ve n o us li ne 
at t he e n d of i nf usi o n.  
Gle m bat u m u ma b  ve d oti n  a n d  ni v ol u ma b  will  b e  a d mi nistere d  as  se p arate  i nf usi o ns  w h e n 
d osi n g occ urs o n t he sa me da y. Ni v ol u ma b s h o ul d be t he first i nf usi o n a n d gle m bat u m u ma b 
ve d oti n  a d mi nistere d  at  least  3 0  mi n utes  later  as  t he  sec o n d  i nf usi o n.  Patie nts  s h o ul d  be 
o bser ve d o n C ycle 1 Da y 1 f or at least 2 h o urs aft er t he last st u d y dr u g, a n d f or at least 1 h o ur 
at  all  s u bse q ue nt  d osi n g  visits.  F or  a d diti o nal  details  o n  gle m bat u m u ma b  ve d oti n 
a d mi nistrati o n please see S ecti o n 8. 1. 3 . 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 7 7  of 1 3 0  
8. 4.   Pe m b r oliz u m a b  
8. 4. 1.    Descri pti o n, P ac k a gi n g, a n d L a beli n g 
Pe m br oliz u ma b  will  be  o btai ne d  fr o m  c o m merci al  s u p pl y  a n d  h a n dle d/st ore d  i n  a  fas hi o n 
c o nsiste nt wit h pac ket i nsert a n d i nstit uti o nal p olicies. T he  f oll o wi n g secti o ns are base d o n 
pac ka ge i nsert ( dat e d J ul y 2 0 1 7). H o we ver, i n vesti gat ors are res p o nsi ble f or refere n cin g t he 
c o m plete a n d m ost c urre nt pac ka ge i nsert f or f ull g ui d a nce re gar di n g p ote ntial t o xicit y a n d 
d osi n g of pe m br oliz u ma b. 
Pe m br oliz u ma b is a vaila ble as 5 0 m g l y o p hilize d p o w der i n si n gle -use vi al f or rec o nstit uti o n 
a n d as 1 0 0 m g/ 4 m L ( 2 5 m g/ m L) s ol uti o n i n si n gle-use vials.  
8. 4. 2.   St or a ge a n d H a n dli n g  
Pe m br oliz u ma b d oes n ot c o ntai n a preser vati ve. St ore t he rec o nstit ute d a n d dil ute d s ol uti o n 
fr o m t he pe m br oliz u ma b 5 0 m g vial eit her: 
•  At r o o m te m perat ure f or n o m ore t ha n 6 h o urs fr o m t he ti me of rec o nstit uti o n. T his i ncl u des 
r o o m te m perat ure st ora ge of rec o nstit ute d vials, st ora ge of t he i nf usi o n s ol uti o n i n t he I V 
ba g, a n d t he d ur ati o n of i nf usi o n. 
•  U n der r efri gerati o n at 2° C t o 8° C ( 3 6° F t o 4 6° F) f or n o m ore t ha n 2 4 h o urs fr o m t he ti me 
of rec o nstit uti o n. If refri gerati o n, all o w t he dil ute d s ol uti o n t o c o me t o r o o m te m perat ure 
pri or t o a d mi nistrati o n.  
St ore t he dil ute d s ol uti o n fr o m t he 1 0 0 m g/ 4 m L vial eit her:  
•  At r o o m te m perat ure f or n o m ore t ha n 6  h o urs fr o m t he ti me of dil uti o n.  T his i ncl u des 
r o o m te m perat ure stora ge of rec o nstit ute d vials, st ora ge of t he i nf usi o n s ol uti o n i n t he I V 
ba g, a n d t he d ur ati o n of i nf usi o n. 
•  U n der r efri gerati o n at 2° C t o 8° C ( 3 6° F t o 4 6° F) f or n o m ore t ha n 2 4 h o urs fr o m t he ti me 
of rec o nstit uti o n. If refri gerati o n, all o w t he dil ute d s ol u ti o n t o c o me t o r o o m te m perat ure 
pri or t o a d mi nistrati o n.  
D o n ot freeze.  
8. 4. 3.    Pre p ar ati o n a n d A d mi nistr ati o n 
Pre parati o n of t he Dil uti o n 
Rec o nstit uti o n of pe m br oliz u ma b f or i njecti o n (l y o p hilize d p o w der): 
•  A d d 2. 3 m L of Sterile Water f or I nje cti o n, U S P b y i njecti n g t he wat er al o n g t he w alls of 
t he vial a n d n ot directl y o n t he l y o p hilize d p o w der (res ulti n g c o nce ntrati o n 2 5 m g/ m L). 
•  Sl o wl y s wirl t he vial. All o w u p t o 5 mi n utes f or t h e b u b bles t o clear. D o n ot s ha ke t he vial.  


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 7 8  of 1 3 0  
Pre parati o n f or i ntra ve n o us i nf usi o n: 
•  Vi s uall y  i ns pect  t h e  s ol uti o n  f or  partic ulate  matter  a n d  disc ol orati o n  pri or  t o 
a d mi nistrati o n.  T he  s ol uti o n  is  clear  t o  sli g htl y  o palesce nt,  c ol orless  t o  sli g htl y  yell o w. 
Discar d t he vial if visi ble particles are o bser v e d.  
•  Dil ute  pe m br oliz u ma b  i njecti o n  (s o l uti o n)  or  rec o nstit ute d  l y o p hilize d  p o w der  pri or  t o 
i ntra ve n o us a d mi nistrati o n. 
•  Wit h dra w  t he  re q uire d  v ol u me  fr o m  t he  vial(s)  of  pe m br oliz u ma b  a n d  tra nsfer  i nt o  a n 
i ntra ve n o us (I V) ba g c o ntai ni n g 0. 9 % S o di u m C hl ori de  I nj ecti o n,  U S P or 5 % De xtr ose 
I njecti on, U S P. Mi x dil ute d s ol uti o n b y ge ntle i n versi o n.  T he fi nal c o nce ntrati o n of t he 
dil ute d s ol uti o n s h o ul d be bet wee n 1 m g/ m L t o 1 0 m g/ m L. 
•  Discar d a n y u n us e d p orti o n left i n t he vial. 
A d mi nistrati o n  
A d mi nister  i nf usi o n  s ol uti o n  i ntra ve n o usl y  o ver  3 0  mi n utes  t hr o u g h  a n  i ntra ve n o us  li ne 
c o ntai ni n g a sterile, n o n -p yr o ge nic, l o -pr ot ei n bi n di n g 0. 2 micr o n t o 5 micr o n i n -li ne or a d d-
o n filter. D o n ot c o-a d mi nister ot her dr u gs t hr o u g h t he sa me i nf usi o n li ne. 
Gle m bat u m u ma b ve d oti n a n d pe m br oliz u ma b will be a d mi nister e d as s e parate i nf usi o ns w he n 
d osi n g  occ urs  o n  t he  sa me  da y.  Pe m br oliz u ma b  s h o ul d  be  t he  first  i nf usi o n  a n d 
gle m bat u m u ma b ve d oti n a d mi nistere d at least 3 0 mi n utes later as t he sec o n d i nf usi o n.  Patie nts 
s h o ul d be o bser ve d o n C ycl e 1 Da y 1 f or at least 2 h o urs after t he last st u d y dr u g, a n d f or at 
least 1 h o ur at all s u bs e q ue nt d osi n g visits. F or a d diti o nal details o n gle m b at u m u ma b ve d oti n 
a d mi nistrati o n please see  S ecti o n 8. 1. 3 . 
 
 
 
 
 
 
   
 
 
 
 
 
 
e 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 7 9  of 1 3 0  
 
   
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
   
8. 6.    
D ose M o dific ati o ns 
8. 6. 1.   
Gle m b at u m u m a b ve d oti n 
G le m bat u m u ma b  ve d oti n d ose  re d ucti o n s  i n  i n di vi d ual  patie nts  f or  t o xicit y  are  per mitte d; 
i ntra-patie nt d ose escal ati o ns are n ot.  A n y patie nt w h o re q uires a d ose re d u cti o n will c o nti n ue 
t o recei ve a r e d uce d d ose f or t he re m ai n der of t he st u d y. A ma xi m u m of t w o d ose re d ucti o ns 
are all o we d.  If a patie nt r e q uires m or e t ha n t w o d ose re d u cti o ns, t he y s h o ul d be disc o nti n ue d 
fr o m treat me nt. 
D ose re d u cti o n le vels ar e as f oll o ws:  
•  Starti n g d ose: 1. 9 m g/ k g  
•  First d ose re d u cti o n: 1. 3 m g/ k g 
•  Sec o n d d ose re d u cti o n: 1. 0 m g/ k g 
Patie nts e x perie nci n g t he f oll o wi n g r e q uire d ose re d ucti o n: 
•  Gra de 3 or 4 n o n -h e mat ol o gical dr u g -relate d t o xicit y n ot res ol vi n g t o Gra de 2 or less wit hi n 
7 2 h o urs of i nitiati o n of s u p p orti ve care. E x ce pti o ns t o t his criteri o n i ncl u de al o pecia  a n d 
ot her t o xicities of n o n- vital or ga ns aft er disc ussi o n wit h t he me dical m o nit or 
•  Gra de 4 n e utr o pe nia l asti n g > 5 d a ys or ass o ciate d wit h fe ver > 1 0 0. 5˚ F 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 8 0  of 1 3 0  
•  Gra de 4 t hr o m b o c yt o p e nia 
•  Patie nts  t hat  de vel o p  Gr a de  2  or  3  ne ur o pat h y  will  ha ve  d osi n g  hel d  u ntil  ne ur o pat h y 
i m pr o ves t o ≤ Gra de 1, a n d will be restarte d wit h a d ose re d ucti o n.  Patie n ts wit h Gra de 4 
ne ur o pat h y s h o ul d ha ve treat me nt disc o nti n ue d alt o get h er.  
•  Ot her e ve nts t hat, i n t he o pi ni o n of t he treati n g i n vesti gat or, warra nt d ose m o dificati o n 
8. 6. 2.   
V arlil u m a b  
M o dificati o ns t o t he a d mi nistere d d ose of varlil u ma b is n ot all o we d. Patie nts w h o e x perie nce 
a n  e ve nt  deter mi ne d  t o  be  a treat me nt-li miti n g  t o xicit y  (Secti o n  8. 7 )  will  per ma ne ntl y 
disc o nti n ue  st u d y  treat me nt,  i ncl u di n g  gl e m bat u m u ma b  ve d oti n , a n d  n ot  be  re pl ace d. If 
treat me nt-li miti n g  t o xicit y  occ urs  i n  > 2  of  t he  first  1 0  patie nts,  or  i n  > 2 0 %  of  p atie nts 
t hereafter, all f urt her patie nts e nr olle d will recei ve a varlil u ma b starti n g d ose of 0. 3 m g/ k g a n d 
o n g oi n g patie nts will als o recei v e a n y f urt her d osi n g of varlil u ma b at 0. 3 m g/ k g.  If a d ditio nal 
treat me nt-li miti n g  t o xicit y  occ urs  i n  > 2 0 %  of  p atie nts  recei vi n g  varlil u ma b  at  0. 3  m g/ k g, 
e nr oll me nt will be i nterr u pte d pe n di n g e val uati o n b y Cell de x  a n d t he i n vesti gat ors.  
A dj ust me nts t o t he d osi n g sc h e d ule (tr eat me nt del a ys, i nf usi o n i nterr u pti o ns a n d i nf usi o n rat e 
a dj ust me nts) are all o we d f or treat me nt -relat e d t o xicit y as f oll o ws: 
•  Pri or t o eac h varlil u ma b  a d mi nistrati o n at C ycle 2 a n d be y o n d,  patie nts m ust be recei vi n g 
< 1 0 m g/ da y pre d nis o ne or e q ui vale nt f or treat me nt of dr u g relate d t o xicit y, a n d all t o xicit y 
relate d t o pri or treat me nt (i ncl u di n g la b orat or y a b n or malities) m ust res ol ve t o ≤ gra de  1 
wit h t he f oll o wi n g e x ce pti o ns:  
o  S u bjects ma y r es u me treat me nt i n t he prese n ce of g ra de 2 fati g u e  
o  S u bjects  w h o  ha ve  n ot  e x perie nce d  a g ra de  3  dr u g-relat e d  s ki n  A E  ma y  res u me 
treat me nt i n t he pres e nce of gra de 2 s ki n t o xicit y  
o  S u bjects wit h baseli ne g r a de 1 A S T/ A L T or t otal bilir u bi n w h o re q uire d ose dela ys f or 
reas o ns ot her t ha n a 2-gr a de s hift i n A S T/ A L T or t otal bilir u bi n ma y res u me treat me nt 
i n t he prese nce of gr a de 2 A S T/ A L T or t otal bilir u bi n 
o  Gra de 2 d r u g-r elate d p ul m o nar y t o xicit y, diarr hea, or c olitis, m ust ha ve res ol ve d t o 
baseli ne bef ore tr eat me nt is res u me d  
o  Patie nts  wit h  dr u g -r elate d  e n d ocri n o pat hies  a de q uatel y  c o ntr olle d  wit h  o nl y 
p h ysi ol o gic h or m o ne r e place me nt ma y res u me treat me nt  
o  Patie nts ma y c o nti n ue t r eat me nt wit h ≥ gra de 2 l y m p h o pe nia 
o  Treat me nt ma y c o nti n ue wit h o ut i nterr u pti o n f or li pase a n d/ or a m yl ase i ncrease at t he 
i n vesti gat or’s discr eti o n if n ot ass oci ate d wit h s y m pt o ms. Gra de 4 i ncreases s h o ul d be 
disc usse d wit h t he Cell de x me dical m o nit or.  
•  Tre at me nt ma y b e dela ye d f or u p t o t hree wee ks t o t he ne xt pla n ne d a d mi nistrati o n t o all o w 
s ufficie nt ti me f or rec o v er y  fr o m treat me nt-relat e d  t o xicities. If  a  dela y  greater  t ha n  si x 
wee ks  is  re q uir e d,  t he  I n v esti gat or  s h o ul d  c o nfer  wit h  Cell de x  t o  deter mi ne 
t he 
a p pr o priate n ess of c o nti n ue d treat me nt.  


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 8 1  of 1 3 0  
8. 6. 3.    P D- 1 T ar get e d C hec k p oi nt I n hi bit or  
T he P D - 1 tar gete d  C PI s h o ul d  be  a d mi nistere d  i n  acc or d a nce  wit h i nstit uti o nal  sta n dar d 
practice wit h ref ere n ce t o t he ma n ufact urer’s p ac k a ge i nsert . D osi n g of t hes e C PIs s h o ul d n ot 
be o mitte d or si g nifica ntl y d ela ye d t o acc o m m o dat e ot her st u d y treat me nts b ei n g a d mi nistere d 
i n  t his  st u d y. I n  C o h orts  3 a n d  5,  no m ore  t ha n  3  d oses  of  ni v ol u ma b  or  2  d oses  of 
pe m br oliz u ma b s h o ul d be misse d pri or t o i nitiati o n of gle m b at u m u ma b ve d oti n t hera p y.   
8. 6. 4.  C D X - 3 0 1 
T here  will  be  n o  C D X -3 0 1  d ose  m o dificati o ns.  If  disc o nti n ue d,  C D X-3 0 1  will  n ot  be 
rei nstit ute d. C D X- 3 0 1 s h o ul d n ot be a d mi nistere d if mar ke d le u k o c yt osis, e. g., W B Cs greater 
t ha n 5 0, 0 0 0 cells/ m m3, is o bser ve d. A n y  ≥ Gra de 3  i njecti o n site reacti o ns t h o u g ht relat e d t o 
C D X - 3 0 1 warra nt disc o nti n uati o n of C D X- 3 0 1 treat me nt.  
D oses  misse d  f or  a n y  r eas o n  s h o ul d  n ot  be  ma de  u p;  t he  ne xt  C D X -3 0 1  d ose  s h o ul d  be 
a d mi nistere d as per t he tr eat me nt pla n.  
8. 7.   Tre at me nt - Li miti n g T o xicit y ( T L T) 
A n y  p ote ntial T L T  o cc urri n g  at  a n y  ti me  d uri n g  patie nt  treat me nt  i n  C o h ort s  2- 5 will be 
re p orte d t o Cell de x  wit hi n 2 4 h o urs of t h e site’s a ware n ess of t he o cc urre n ce of t he e ve nt.  A n y 
patie nt  w h o  e x perie nces  a T L T  t h o u g ht  rel ate d  t o  varlil u ma b, t he P D -1  tar gete d  C PI ,  or 
C D X - 3 0 1 m ust  disc o nti n ue  d osi n g  of  t he  s us pect  dr u g  as  d ose  re d u cti o ns  are  n ot  all o we d . 
Gle m bat u m u ma b ve d oti n -relate d t o xicit y, i ncl u di n g T L T, ma y be m a na ge d i n acc or da nce wit h 
g ui da n ce f or gle m bat u m u ma b ve d oti n d ose re d ucti o ns . Patie nts w h o disc o nti n ue varlil u ma b , 
t he P D - 1 tar get e d C PI , or C D X- 3 0 1 ma y c o nti n u e gle m bat u m u ma b ve d oti n as m o n ot hera p y 
at t he i n vesti gat or’s discr eti o n. Patie nts i n C o h ort 2 w h o disc o nti n ue gl e m bat u m u ma b ve d oti n 
s h o ul d disc o nti n ue varlil u ma b. Patie nts i n C o h orts 3 a n d 5 w h o disc o nti n ue gle m bat u m u ma b 
ve d oti n s h o ul d disc o nti n ue t he st u d y treat me nt p hase a n d ma y c o nti n ue t he P D - 1 tar gete d C PI 
as per sta n d ar d of care d uri n g st u d y f oll o w u p . P atie nts i n C o h ort s 4 a n d 5 w h o disc o nti n ue 
gle m bat u m u ma b v e d oti n s h o ul d disc o nti n ue C D X- 3 0 1. 
I n C o h ort 2,  
•  All Gra de 5 A Es attri b ute d t o st u d y treat me nt will  be c o nsi dere d T L Ts . 
•  A L T of > 3 x u p per li mit of n or mal ( U L N) wit h a c o nc urre nt t otal bilir u bi n ( T B L) > 2 x 
U L N will  be c o nsi dere d a T L T  if n o ot her reas o n ca n be f o u n d t o e x plai n t he c o m bi nati o n 
of  i ncrease d  a mi n otr a nsf erase  ( A T)  a n d  ser u m  T B L,  s uc h  as  viral  he patitis  A,  B,  or  C; 
pree xisti n g or ac ut e li ver disease; or a n ot her dr u g ca pa ble of  ca usi n g t he o bser ve d i nj ur y 
•  A n y Gra d e 4 A Es attri b ute d t o st u d y treat me nt will be  c o nsi dere d T L Ts , a n d a n y Gra de 3 
A Es attri b ute d t o st u d y treat me nt will be e val uate d b y C ell de x i n c olla b orati o n wit h t he 
i n vesti gat ors as p ote ntial T L Ts , wit h t he f oll o wi n g e x ce pti o ns ( w hic h d o n ot nee d t o be 
re p orte d wit hi n 2 4 h o urs as p ote ntial T L T ):  
o  L y m p h o pe nia or a n y i n cr eases i n a m ylas e a n d/ or li pase n ot ass ociat e d wit h cli nicall y 
si g nifica nt s y m pt o ms 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 82 of 130 
o Isolated Grade 3 or 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset. 
o Any Grade 3 endocrinopathy that is adequately controlled by hormonal replacement. 
o Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor). 
o Grade 3 infusion reaction that resolves within 6 hours to ≤ Grade 1. 
o Grade 3-4 AEs expected as a result of glembatumumab vedotin therapy, (e.g., rash, 
neuropathy, neutropenia#) and not thought to be worsened by the addition of 
varlilumab will not be considered a TLT; such events should be managed in 
accordance with guidance for glembatumumab vedotin dose reductions. The overall 
incidence of study treatment discontinuation due to glembatumumab vedotin-related 
toxicity will be monitored on an ongoing basis by Celldex and the investigators. 
#Investigators are referred to the table entitled “Adverse Drug Reactions (ADR) Observed 
with Glembatumumab Vedotin (Phase II Dose: 1.88 mg/kg, I.V., q3w) in Section 6 of the 
glembatumumab vedotin investigator’s brochure; this table summarizes the adverse drug 
reactions/expected adverse events considered by Celldex to be causally related to 
glembatumumab vedotin based on clinical experience.  
For Cohorts 3-5, any treatment-related toxicity that warrants discontinuation of the PD-1 
targeted CPI, CDX-301, or glembatumumab vedotin will be considered a TLT.  
8.8.  Potential Toxicity and Management of Toxicity 
Potential toxicity and guidance for the management of toxicity is summarized below. However, 
the glembatumumab vedotin, varlilumab, and CDX-301 Investigator’s Brochures, and the 
PD-1 targeted CPI package insert, are the Single Reference Safety Documents that provides 
complete and relevant information about the known safety profile of each agent. Updates to 
these data will be provided as revisions to the Investigator’s Brochures and through 
Investigational New Drug (IND) Safety Reports submitted to the investigator by Celldex, 
rather than by amendment to this section of the protocol.  
Glembatumumab vedotin-related toxicities observed in previous studies have included 
neutropenia, alopecia, rash, pruritus, diarrhea, nausea, vomiting, constipation, fatigue/asthenia, 
pyrexia, anorexia, neuropathy and dysgeusia. Serious hematologic, gastrointestinal and 
dermatologic toxicity have occurred in 3-4% of treated patients. Infrequent but serious events 
have included fatal cases of toxic epidermal necrolysis and renal failure; severe or fatal sepsis 
(some cases were associated with pneumonia or urinary tract infection); and infusion site 
extravasation.  
Toxicity related to varlilumab has been generally low-grade, and has included fatigue, 
arthralgia, nausea, decreased appetite, diarrhea, headache, vomiting, pyrexia, rash, pruritus, 
cough and neuropathy. Asymptomatic laboratory changes including lymphopenia, changes in 
liver function tests, and increases in lipase and amylase have occurred. Additional events 
consistent with an immune-mediated mechanism, such as hyperthyroidism, hypothyroidism, 
colitis, and infusion reaction, have been infrequently reported.  


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 8 3  of 1 3 0  
C D X - 3 0 1 was  ge n erall y well -t olerate d i n all pri or st u dies. I n t h e Cell de x-s p o ns ore d p has e 1 
st u d y i n 3 0 healt h y v ol u nteers, treat me nt-rel ate d t o xicit y was i nfre q u e nt, a n d re p orte d o nl y at 
t he 2 5 a n d 7 5 µ g/ k g/ da y d ose le vels. O ne Gra de 3 e ve nt, c o m m u nit y ac q uire d p ne u m o nia, was 
c o nsi dere d  treat me nt -rel ate d. N o  a d diti o nal  i nfecti o ns,  D L T, treat me nt-relate d S A E,  or 
treat me nt-r elate d Gr a de  3 t o xicit y w ere  re p orte d. All ot her treat me nt -relat e d a d vers e e ve nts 
were  Gra de  1  a n d  i ncl u de d  l y m p ha de n o p at h y, diarr h ea,  i njecti o n  site  er yt he ma,  f ollic ulitis , 
a n d dr y m o ut h. 
I n v esti gat ors s h o ul d be c o g niza nt of t he p ote ntial f or u n pre dicte d ac ute a n d c hr o nic t o xicit y 
ass ociate d  wit h  t he  c o m bi nati o n  of  gle m bat u m u ma b  ve d oti n  a n d  i m m u n ot hera p y. Patie nts 
recei vi n g  gle m bat u mu ma b  ve d oti n  a n d  i m m u n ot hera p y s h o ul d  be  cl osel y  m o nit ore d  f or 
t o xicit y. Patie nts  s h o ul d  be  a d vise d  t o  i m me diatel y  re p ort  s y m pt o ms  s u c h  as  u n e x plai ne d 
a b d o mi nal  pai n,  diarr hea,  na usea  or  v o miti n g,  se vere  ras h , visi o n  c ha n ges  or  si g ns  of  a 
p ote ntial i nfecti o n, s uc h as a fe ver of 1 0 0. 5° F or greater, c hills, c o u g h, or pai n o n uri nati o n. 
Patie nts  wit h  u ne x plai ne d  s y m pt o ms  s uc h  as  fati g ue,  m yal gias,  i m p ot e nce,  me ntal  stat us 
c ha n ges, or c o nsti pati o n s h o ul d be i n vesti gate d f or t he prese n ce of t h yr oi d, pit uitar y or  a dre nal 
e n d ocri n o pat hies. Vis ual c o m plai nts  s h o ul d be i n v esti gate d b y a n o p ht hal m ol o gist. La b orat or y 
tests m ust be perf or me d as o utli ne i n Sc he d ule of Assess me nts a n d res ults re vie w e d pri or t o 
d osi n g. Patie nts  i n  C o h ort  1  s h o ul d  be  m o nit ore d  f or  at  least  1  h o ur  f oll o wi n g  t he  last 
a d mi nistrati o n  of  st u d y  dr u g  t o  m o nit or  f or  i nf usi o n  reacti o n/c yt o ki ne  releas e 
s y n dr o me/ h y p erse nsiti vit y  reacti o n.  Patie nts  i n  C o h orts  2- 5 s h o ul d  be  o bser ve d  o n  C ycl e  1 
Da y 1 f or at least 2 h o urs after t he last st u d y dr u g, a n d f or  at least 1 h o ur at all s u bse q ue nt 
d osi n g visits.  I n C o h orts 4 a n d 5, patie nts s h o ul d als o be o bser ve d f or at least 2 h o urs after t he 
first d ose of C D X- 3 0 1, t he first d ose of gle m bat u m u ma b ve d oti n, a n d f or at least 1 h o ur at all 
ot her d osi n g visits. I nf usio ns s h o ul d be gi ve n i n a m o nit ore d setti n g t hat has rea d y access t o 
a n i nte nsi ve care u nit i n case of a se vere i nf usi o n reacti o n.  
T o xicit y  s h o ul d  be  a g gr essi vel y w or ke d- u p  a n d  a p pr o priatel y  ma na ge d  per  t he  g ui d eli nes 
pr o vi de d  i n  t he G le m bat u m u ma b Ve d oti n 
I n vesti gat or’s  Br o c h ure,  t he  Varlil u ma b 
I n v esti gat or’s Br oc h ur e, t he pac ka ge i nsert f or t he P D - 1 tar gete d c hec k p oi nt i n hi bit or, a n d t he 
C D X -3 0 1 I n vesti gat or’s Br oc h ure  t o i ncl u de t he f oll o wi n g:  
•  Pr urit us a n d dr y s ki n m a y b e ma n a ge d wit h e m ollie nts. A nti his ta mi nes ma y be us e d f or 
pr urit us as i n dicate d. Less e xte nsi ve ras h m a y be treate d wit h t o pical c orti c oster oi ds a n d 
m ore  e xte nsi ve/se ver e  r as hes  ma y  b e  treate d  wit h  s yste mic  c ortic oster oi ds.   P ossi ble 
pre ve ntati ve meas ur es i n cl u de t he mai nte n a nce of clea n a n d dr y s ki n i n f ol ds u n der t he 
breast, a xillae, a n d gr oi n. Patie nts s h o ul d be c o u ns ele d re gar di n g t he p ote ntial f or al o pecia.  
Sites are e nc o ur a ge d t o c ollect p h ot o gra p hic rec or ds of ras hes f or t he me di cal rec or d a n d 
der mat ol o gi cal c o ns ults as nee de d; bi o ps y  c ollecti o n a n d q ua ntitati o n of g p N M B b y t he 
ce ntral la b orat or y is str o n gl y e n c o ura ge d.  
•  Earl y a n d a g gressi ve ma na ge me nt of all i nfecti o ns, partic ularl y p ne u m o nias a n d uri nar y 
tract  i nfecti o ns  is  rec o m me n de d,  i ncl u di n g  t he  use  of  G-C S F  a n d  e m piric  a nti bi oti c 
acc or di n g t o N C C N g ui d eli nes. T he use of pr o p h yl actic a nti bi otics s h o ul d be c o nsi dere d 
f or  patie nts  wit h  p ote nti al  i m m u ne  s u p pressi o n  (e. g.,  t h ose  re q uiri n g  c ortic oster oi ds  or 
ot her  i m m u n os u p pressi ve  a ge nts  [e x cl u di n g  patie nts  i n  C o h ort  2  w h o  are  s u bjec t  t o 
e x cl usi o n criteria # 2 0]). Baseli ne ris k fact ors s u c h as pri or c he m ot hera p y a n d ra diati o n, 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 8 4  of 1 3 0  
t u m or b ur de n, perf or ma n ce stat us, a n d c o nc o mita nt use of ster oi ds s h o ul d be e val uat e d a n d 
earl y si g n of i nfecti o ns a n d fe ver s h o ul d b e cl osel y m o nit ore d.  
•  Patie nt s wit h ne utr o pe nia s h o ul d be treate d wit h st a n dar d s u p p orti ve care  
•  Pa tie nts  ma y  recei ve  a ntie metic  pr o p h yl a xis  acc or di n g  t o  A merica n  S ociet y  of  Cli nical 
O nc ol o g y  ( R o bert,  T h o mas  et  al. )  g ui deli nes  (Kris,  H es ket h  et  al.  2 0 0 6 ) or  l o cal 
i nstit uti o nal  sta n dar ds.  All  patients  s h o ul d  be  treate d  f or  di arr h ea  or  c o nsti pati o n  wit h 
sta n dar d meas ures, as i n dicate d. 
•  Aceta mi n o p he n  ma y  b e  use d  t o  ma na ge  dr u g -relate d  a d v erse  e ve nts  s uc h  as  fe v er, 
m yal gias or art hr al gi as.  Ster oi ds ma y b e use d t o m a na ge m ore se vere t o xicit y.  
•  M e dicati o n t o treat a na p h ylactic or a na p h yl act oi d reacti o ns s h o ul d be rea dil y a vaila ble at 
t he ti me of t he st u d y dr u g i nf usi o n. Patie nts w h o d o e x perie nce a n i nf usi o n reacti o n ma y 
be pre -me dicat e d wit h a nti hista mi nes, aceta mi n o p he n/ paraceta m ol a n d/ or c ortic oster oi ds 
pri or t o s u bse q ue nt i nf usi o ns. Patie nts w h o e x perie nce a  Gra de 4 i nf usi o n reacti o n s h o ul d 
disc o nti n ue  st u d y  treat m e nt.  F urt her  g ui da n ce  f or  ma na ge me nt  of  i nf usi o n  reacti o ns  is 
pr o vi de d i n t he varlil u ma b I n v esti gat ors Br o c h ure, a n d ma y be m o difie d base d o n l ocal 
treat me nt sta n dar ds a n d g ui deli nes, as a p pr o pri ate.  
•  Detaile d  g ui da n ce  f or  m a na ge me nt  of i m m u ne-me diate d  a d verse  e ve nts  (ir A Es)  are 
pr o vi de d i n t he varlil u ma b I n v esti gat ors Br oc h ure.  
•  Detaile d g ui da n ce f or ma na ge me nt of ir A Es f oll o wi n g ni v ol u ma b treat me nt are pr o vi d e d 
i n t he pac ka ge i nsert. Ma na ge me nt of s u c h i ncl u de a d mi nistrati o n of c ortic oster oi ds base d 
o n t he se verit y of t he reacti o n.  I n a d diti o n, ni v ol u ma b treat me nt s h o ul d be wit h hel d f or: 
m o derate  i m m u ne -m e diate d  p ne u m o nitis,  he patitis, a dre n al  i ns ufficie n c y, ne p hritis, or 
re nal  d ysf u ncti o n;  m o derate or  se v ere  i m m u ne-me diate d  c olitis ,  h y p o p h ysitis,  or  n e w-
o nset ne ur ol o gical si g ns or s y m pt o ms; se v ere i m m u ne -me diate d h y p er gl yce mia or ras h . If 
a n y of t hese e ve nts i ncr ease i n s e verit y or b ec o me life -t hreate ni n g, or if i m m u ne-me diate d 
e nce p h alitis or  se ver e  i nf usi o n  reacti o n occ urs, t he n  ni v ol u ma b  treat me nt  s h o ul d  be 
per ma ne ntl y disc o nti n ue d.  Ma na ge c h a n ges i n t h yr oi d f u n cti o n wit h i nitiati o n of t h yr oi d 
h or m o ne re place me nt as nee de d ( ni v ol u ma b p ac k a ge i nsert, J ul y 2 0 1 7 ). 
•  Detaile d  g ui da nce  f or  ma na ge me nt  of ir A Es  f oll o wi n g  pe m br oliz u ma b  treat me nt  are 
pr o vi de d  i n  t he  pac ka ge  i nsert.  Ma na ge me nt  of  s uc h  i ncl u de  a d mi nistrati o n  of 
c ortic oster oi ds base d o n t he se verit y of t he reacti o n.  C ha n ges i n li ver e nz y m e el e vati o ns 
d ue  t o  i m m u ne -me diate d  he patitis  s h o ul d  be m o nit ore d, wit h  treat me nt  wit h hel d  or 
disc o nti n ue d base d o n se verit y. I n a d diti o n, pe m br oliz u ma b treat me nt s h o ul d be wit h hel d 
f or:  m o derate  i m m u ne-me diate d  p ne u m o nitis,  ne p hritis,  or  h y p o p h ysitis; m o derat e  or 
se vere c olitis; se ver e h y p er gl yce mia or h y p ert h yr oi dis m. If a n y of t hes e e ve nts i ncreas e i n 
se verit y or bec o me life-t hreate ni n g, or if se vere or life-t hreate ni n g i nf usi o n reacti o n or s ki n 
reacti o ns i ncl u di n g Ste ve ns-J o h ns o n s y n dr o m e a n d t o xic e pi der mal necr ol ysis occ ur, t he n 
ni v ol u ma b  treat me nt  s h o ul d  be  per ma ne ntl y  dis c o nti n ue d.  Ma na ge  c ha n ges  i n  t h yr oi d 
f u ncti o n  wit h  i nitiati o n  of  t h yr oi d  h or m o ne  re place me nt  as  nee de d  (p e m br oliz u ma b  
pac ka ge i nsert, J ul y 2 0 1 7 ). 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 8 5  of 1 3 0  
•  Le u k o c yt osis, es peciall y m o n oc yt osis, is e x pecte d d uri n g a d mi nistrati o n of C D X- 3 0 1 a n d 
ma y b e partic ularl y pr o n o u nce d w he n c o m bi ne d wit h ot her he mat o p oietic gr o wt h fact ors. 
He mat ol o gi cal  para meters,  i ncl u di n g  W B C  a n d  differe ntial,  s h o ul d  be  m o nit ore d  i n 
s u bjects recei vi n g C D X-3 0 1. C D X -3 0 1 s h o ul d n ot be a d mi nistere d if mar k e d le u k oc yt osis, 
e. g. W B Cs gr eater t ha n 5 0, 0 0 0 cells/ m m 3, is o bser ve d. 
•  Pre -me dicati o n  wit h  di p he n h y dra mi ne  has  bee n  re p orte d  effecti ve  i n  t he  pre ve nti o n  of 
pr uritic  a n d  er yt h e mic  r eacti o ns   (M ors e,  Nair  et  al.  2 0 0 0 ),  a n d  ma y  b e  c o nsi dere d  f or 
patie nts  w h o  e x perie nce  l ocal  reacti o ns  after  treat me nt  wit h  C D X -3 0 1.  I njecti o n  site 
reacti o ns ma y als o be treate d wit h a nal gesics. 
8. 9.   Acc o u nt a bilit y  
G le m bat u m u ma b ve d oti n, varlil u ma b , a n d C D X- 3 0 1 will be  s u p plie d b y Cell de x as o pe n-la bel 
st oc k. T he i n vesti gati o nal pr o d uct is t o be us e d o nl y f or t his pr ot oc ol a n d n ot f or a n y ot her 
p ur p ose, a n d m ust be ke pt i n a n a p pr o priate, sec ure area (e. g. , l oc k e d refri gerat or/ca bi net) a n d 
st ore d i n acc or da nce wit h t he c o n diti o ns s pecifie d i n t his pr ot oc ol/ o n t he la bels. 
T he in vesti gat or  will  ass u me  res p o nsi bilit y  f or  a d mi nistrati o n  a n d  dis pe nsati o n  of  st u d y 
me dicati o n. A n acc urate rec or d of all st u d y dr u gs recei v e d, dis pe nse d, ret ur ne d, a n d destr o ye d 
m ust be mai ntai ne d.  Dr u g s u p plies will be i n ve nt orie d a n d acc o u nte d f or t hr o u g h o ut t he st u d y, 
a n d acc o u nta bilit y rec or ds m ust be a v aila ble f or i ns pecti o n at a n y ti me a n d pr o vi de d t o Cell de x 
u p o n t he c o m pleti o n of t he st u d y. 
U p o n recei pt of a n y i n vesti gati o nal pr o d uct, a n i n ve nt or y m ust be c o n d uct e d t o c o nfir m t he 
q ua ntit y a n d c o n diti o n of material r ecei ve d, a n d v erificati o n of recei pt m ust be c o m plete d a n d 
ret ur ne d i n acc or d a nce wit h i nstr ucti o ns pr o vi de d b y Cell de x.  
Re -s u p pl y of st u d y m e di cati o n ma y b e re q uest e d i n acc or da n ce wit h i nstr ucti o ns pr o vi de d b y 
Cell de x.  Use d,  partl y  us e d  a n d/ or  r e mai ni n g  u n use d  i n vesti gati o nal  pr o d uct  will  be  eit her 
ret ur ne d t o Cell de x or destr o ye d acc or di n g t o t he site’s Sta n dar d O perati n g Pr oce d ures ( S O Ps), 
as directe d b y Cell de x, a n d a rec or d o f t his dis p ositi o n will be mai ntai ne d. 
T he  P D - 1 tar get e d  C PI  will  be  o bt ai ne d  b y  eac h  st u d y  site  as c o m mercial  s u p pl y  a n d 
ha n dle d/st ore d i n a f as hi o n c o nsiste nt wit h pac ka ge i nsert a n d i nstit uti o nal p olicies.  
8. 1 0.   C o m pli a nce  
G le m bat u m u ma b ve d oti n, varlil u ma b , t he P D- 1 tar gete d c hec k p oi nt i n hi bit or, a n d C D X- 3 0 1 
will al wa ys b e a d mi nistere d b y st u d y st aff at t he cli nic.  
9.   C O N C O MI T A N T T H E R A P Y  
W hile  o n  st u d y,  w he n  cli nicall y  a p pr o priat e,  p atie nts  s h o ul d  strictl y  f oll o w  t he  st u d y -
prescri be d treat me nt r e gi me n.  T her ef ore, p atie nts s h o ul d n ot recei ve a d diti o nal i n vesti gati o nal 
a ge nts  or  a nti -ca ncer  t hera pies,  u nless  rec urre nce/ pr o gressi o n  of  disease  warra nts 
disc o nti n uati o n of st u d y treat me nt a n d c o m me nce me nt of alter nate t h era pi es.  


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 86 of 130 
Subjects may continue to use any ongoing medications not prohibited by the 
inclusion/exclusion criteria. During study treatment, patients may receive supportive care to 
include bisphosphonates, hematologic and anti-infectious support and pain management. Anti-
emetics and steroids, if needed, for chemotherapy premedication are also permitted. 
Growth factor support is permitted and should be administered with consideration to the 
American Society of Clinical Oncology (Robert, Thomas et al.) guideline on the use of 
hematopoietic colony-stimulating factors (Smith, Khatcheressian et al. 2006). If growth factor 
support for neutropenia is required while the patient is also being treated with CDX-301 
(Cohorts 4 and 5), then white blood cell counts and differentials should be closely followed. 
Efforts should be made to maintain stable doses of concomitant medications during the course 
of treatment with glembatumumab vedotin, varlilumab, the PD-1 targeted checkpoint inhibitor, 
and CDX-301. 
If surgical intervention or localized radiation become indicated (either for palliation or down-
staging of previously non-resectable tumor), these interventions are permitted, but should be 
avoided if clinically feasible until after the 12 week response assessment. A tumor response 
assessment should be conducted prior to any intervention, in order to document progression 
and/or confirm an objective response. Patients who undergo surgical resection or radiation in 
the absence of progression may continue to receive study treatment until remaining lesions 
meet criteria for progression of disease. 
All concomitant medication will be documented in the CRF if taken within 28 days prior to 
initiation of study treatment, and either (whichever occurs sooner): 1) 28 days after last dose 
of study treatment (glembatumumab vedotin), or 70 days after last dose varlilumab (the latter 
whichever occurs later in Cohort 2), or 70 days after last dose of the PD-1 targeted checkpoint 
inhibitor (the latter whichever occurs later in Cohort 3); or 2) initiation of alternate anti-cancer 
therapy. In addition, all anti-cancer medications should be recorded throughout the duration of 
study follow-up. 
9.1.  
Glembatumumab vedotin 
The effect of glembatumumab vedotin on the absorption, metabolism, or excretion of other 
drugs has not been studied. Drugs known to strongly inhibit CYP3A4 should be used with 
caution, and drugs known to be potent CYP3A4 inducers should be avoided, if at all possible, 
while patients are exposed to glembatumumab vedotin. (See Section 8.8 for further 
information.) 
A 
table 
listing 
P450 
enzyme-drug 
interactions 
is 
available 
at: 
http://medicine.iupui.edu/clinpharm/ddis/main-table). 
Prolonged use of systemic corticosteroids above the physiologic dose (5 mg prednisone or 
equivalent) should be avoided during the study as this may increase the risk of infection and 
sepsis (see Section 8.8). 
9.2.  
Varlilumab 
Any vaccination containing live, attenuated, or inactivated virus may be permitted if clinically 
indicated. However, this must be discussed with the Celldex Medical Monitor prior to 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 8 7  of 1 3 0  
a d mi nistrati o n a n d ma y r e q uire a st u d y dr u g was h o ut peri o d pri or t o a n d after a d mi nistrati o n 
of t he vacci ne.  I n acti vate d i nfl ue nza vacci nati o n is per mitte d o n st u d y wit h o ut restricti o n. 
I m m u n os u p pr essi ve a ge nts are pr o hi bite d d uri n g t he st u d y, wit h t he f oll o wi n g e x ce pti o ns:  
•  Im m u n os u p pr essi ve  a ge nts  a n d  t he  use  of  s yste mic  c ortic oster oi ds  are  p er mitte d  i n  t he 
c o nte xt of treati n g a d vers e e ve nts.  Patie nts recei vi n g c ortic oster oi ds f or treat me nt of dr u g-
relate d a d vers e e v e nts m ust be at ≤ 1 0 m g/ da y pre d nis o ne or e q ui val e nt pri or t o re -i nitiati o n 
of st u d y t hera p y 
•  Patie nts are per mitte d t he use of t o pical, oc ular, i ntra -artic ular, i ntra n asal, a n d i n halati o nal 
c ortic oster oi ds ( wit h mi ni mal s yste mic a bs or pti o n).   
P re-me dica ti o n as pr o p h yl a xis f or i nf usi o n reacti o n s h o ul d o nl y be i nitiate d if cli nicall y 
i n dicate d. 
9. 3.   P D -1 T ar get e d C hec k p oi nt I n hi bit or  
T he  ma n ufact ur er’s  pac ka ge  i nsert  f or  t he  P D -1  tar get e d  c hec k p oi nt  i n hi bit or  s h o ul d  be 
c o ns ulte d f or g ui da nce o n c o nc o mita nt me d icati o ns a n d a n y k n o w n or t he oretical ris ks. 
9. 4.  C D X - 3 0 1 
T he eff ect of C D X -3 0 1 o n t he a bs or pti o n, meta b olis m, or e x creti o n of ot her dr u gs has n ot bee n 
st u die d. I nitiati o n  of  a n y  n e w  m e dicati o n  d uri n g  t he  c o urs e  of  t he  st u d y treat me nt  is 
disc o ura ge d a n d s h o ul d o nl y be d o ne f or a me di call y i n dicate d a d vers e e ve nt or ne w c o n diti o n. 
A n y vacci nati o n is pr o hi bite d u ntil at least 2 8 d a ys after t he last d os e of C D X - 3 0 1. If gr o wt h 
fact or s u p p ort f or ne utr o p e nia is re q uire d w hile t he patie nt is als o bei n g treate d wit h C DX- 3 0 1 
( C o h orts 4 a n d 5), t he n w hite bl o o d cell c o u nts a n d differe ntials s h o ul d be cl osel y f oll o we d. 
1 0.   S T U D Y P R O C E D U R E S  
1 0. 1.    Sc he d ule of I n vesti g ati o ns a n d D at a C ollecti o n 
T he  st u d y  is  di vi de d  i nt o  p hases  wit h  ass ociate d  e val uati o ns  a n d  pr oce d ures  t hat  m ust  be 
p erf or me d  at  s p ecific  ti me  p oi nts,  as  descri be d  i n  t he  f oll o wi n g  secti o ns.  T he  St u d y 
Assess me nt Sc he d ule ( T a ble 1  a n d Ta ble 2 ) s u m marizes t he fre q ue n c y a n d ti mi n g of vari o us 
efficac y, safet y, a n d ot her meas ure m e nts. 
1 0. 1. 1.   Scree ni n g Peri o d  
Pri or t o t he p erf or ma nce of a n y st u d y -s pecifi c pr o ce d ures, t he patie nt will ha ve t he nat ure of 
t he  st u d y  e x plai ne d  t o  t he m,  a n d  will  be  as k e d  t o  gi ve  writte n  i nf or m e d  c o nse nt  a n d,  if 
a p plica ble,  HI P A A  a ut h orizati o n.  I nf or me d  c o ns e nt/ HI P A A  a ut h orizati o n  m ust  be  o btai ne d 
pri or  t o  a n y  st u d y -s pecific  pr oce d ur es  t hat  d o  n ot  f or m  a  part  of  t he  patie nt’s  n or mal  care. 
H o we ver, assess me nts perf or me d  acc or di n g  t o sta n dar d of care pri or t o recei pt of i nf or med 
c o nse nt ma y be utilize d t o f ulfill t he scree ni n g re q uire me nt, if c o m plete d wit hi n t he re q uire d 
wi n d o w f or scr ee ni n g. 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 88 of 130 
The assessments outlined for the Screening Visit in the Study Assessment Schedule (Table 1 
and Table 2) will be completed for each patient prior to inclusion in the study, and results will 
be evaluated to verify entry criteria prior to study enrollment. 
10.1.2. Study Enrollment 
Patients who are screened and do not meet all entry criteria will not be entered in the clinical 
database. Once assigned, numbers for any screening failures, non-treated, non-evaluable, or 
discontinued patients will not be re-used. 
Enrollment should occur in accordance with instructions provided by Celldex, only after 
confirming all inclusion criteria and none of the exclusion criteria have been met. Following 
the completion of Cohort 4, there will be an evaluation period whereby the Sponsor and the 
investigators will assess the safety and activity of both Cohorts 3 and 4.  If the results are 
supportive, then enrollment in Cohort 5 will be initiated.   
10.1.3. Treatment Phase 
Specific procedures to be performed at each visit during the treatment phase are illustrated in 
the Study Assessment Schedule (Table 1 and Table 2).  
The End of Treatment Visit should be performed within 28 days after last study drug dosing 
and prior to initiation of alternate therapies. As described in Section 10.2.2.3, any abnormalities 
(adverse events) attributed to study drug dosing, including laboratory abnormalities, should be 
subsequently followed until the event or its sequelae resolve or stabilize. 
10.1.4.  Disease Assessment Visits 
Tumor assessments will be performed every 6 weeks (±1 week) for the first 6 months and 
every 9 weeks (±2 weeks) thereafter, until documented progression of disease or initiation of 
alternate anticancer therapies. Patients who discontinue treatment in the absence of progression 
will continue to have tumor assessments until documented progression or initiation of alternate 
anti-cancer therapies.  
10.1.5.  Survival Follow-up 
Subsequent to progression of disease, all patients will be followed at 12 week intervals until 
study closure.  
10.2.  
Methods of Assessment 
10.2.1.  Activity  
10.2.1.1.  Anti-tumor Activity 
Anti-tumor activity will be assessed via ORR, PFS, DOR and OS. Tumor response and 
progression will be defined by the investigator according to RECIST 1.1 criteria. In addition, 
in the event of a positive study outcome, an additional assessment of tumor response and 
progression may be performed by an IRC, blinded to investigator assessments. For Cohorts 
2-5, supplementary retrospective analyses of tumor response and progression may also be 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 8 9  of 1 3 0  
perf or me d usi n g ir R E CI S T criteria (i n w hic h ne w lesi o ns d o n ot c o nstit ute pr o gressi o n, b ut 
c o ntri b ute t o t he calc ul ate d s u m of dia meter of all meas ura ble disease).  
1 0. 2. 1. 2.   I m m u n o ge nicit y 
Patie nts  will  be  m o nit ore d  f or  t he  d e vel o p me nt  of  a nti -gle m bat u m u ma b  ve d oti n  a n d a nti-
C R 0 1 1 a nti b o dies.  I n  a d diti o n , patie nts  i n  C o h ort  2  will  be  m o nit ore d  f or a nti-varlil u ma b 
a nti b o dies, a n d patie nts i n C o h orts 4 a n d 5 will be m o nit ore d f or a nti -C D X -3 0 1 a nti b o dies. 
A d diti o nal a nal ys es will assess  w het her t hese a nti b o dies are n e utralizi n g.  
1 0. 2. 1. 3.    P h ar m a c o ki netic E v al u ati o ns 
C o nce ntrati o n  of  t he  gle m bat u m u ma b  ve d oti n A D C, T A , a n d  free  M M A E   ( C o h orts  1- 5), 
varlil u ma b ( C o h ort  2),  a n d  C D X-3 0 1  ( C o h orts  4  a n d  5)  will  be  d eter mi ne d  usi n g  G L P 
c o m plia nt E LI S A a n d L C -M S/ M S me t h o ds. T he i m pact of circ ulati n g g p N M B le v els or ot her 
s ol u ble  me diat ors o n gl e m bat u m u ma b  ve d oti n p har mac o ki netic  para meters  ma y  als o  be 
e x a mi ne d.  
1 0. 2. 1. 4.    P h ar m a c o d y n a mi cs 
P har mac o d y na mic  p ara m eters  will be e v al uate d vi a assess me nt of p ost- treat me nt t u m or tiss ue 
o btai ne d  via  v ol u ntar y  bi o ps y  or  res ecti o n  ( C o h orts  1-3),  ma n d at or y pre -st u d y  a n d  o n-
treat me nt bi o psies ( C o h orts 4 a n d 5), a n d bl o o d sa m ples . Para meters e val uate d ma y i ncl u de 
l ocalizati o n of gle m bat u m u ma b ve d oti n, C R 0 1 1 , or M M A E at t he t u m or site a n d/ or g p N M B 
e x pressi o n le vels i n ser u m a n d t u m or tiss ue, as w ell as e val uati o n of ot her s ol u ble me diat ors, 
t u m or  i nfiltrati n g  a n d  peri p her al  le u k oc ytes,  circ ulati n g  t u m or  cells  a n d  ot her  i m m u ne 
res p o nse  cells  of  i nterest s uc h as g p N M B-e x pressi n g  m yel oi d -d eri ve d  s u p press or  cells , a n d 
t he effect of C D X-3 0 1 o n t he t u m or micr o e n vir o n me nt, i ncl u di n g t h e effect o n i ntrat u m oral 
de n dritic  cell  p o p ulati o ns. ( C o h orts  4 a n d  5). A d diti o nal  a nal ysis  ma y  i ncl u de  i m m u ne 
res p o nse ass ess me nt t o p ote ntiall y rel e va nt t u m or a nti ge ns. 
1 0. 2. 2.    S af et y V ari a bles 
1 0. 2. 2. 1.   A d verse E ve nts: D efi niti o n  
A n  a d verse  e ve nt  is  a n y  u nt o w ar d  me dical  o cc urre nce  i n  a  p atie nt  a d mi nistere d  a  st u d y 
treat me nt.  A n  a d verse  e ve nt  ( A E)  ca n  t heref ore  be  a n y  u nfa v ora ble  a n d  u ni nte n de d  si g n 
(i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociat e d wit h 
t he use of a st u d y tr eat me nt, w het her or n ot relate d t o t he st u d y treat me nt. All o bser ve d or 
v ol u nteere d a d verse e ve nts re gar dless of s us pect e d ca usal relati o ns hi p t o t he st u d y treat me nt 
will be re p orte d , as descri be d i n t he f oll o wi n g secti o ns. F or t he p ur p oses of t his c urre nt st u d y, 
“st u d y  tr eat me nt”  is  d efi ne d  as gle m bat u m u ma b  ve d oti n   a n d/ or: varlil u ma b ,  ni v ol u ma b, 
pe m br oliz u ma b, or C D X- 3 0 1. 
F or all a d verse e ve nts, t he i n vesti gat or is res p o nsi ble f or o btai ni n g i nf or mati o n a de q uate t o 
deter mi ne  t he: 
•  a p pr o priate  d escri pti ve  t er m:  A d verse  e ve nts  s h o ul d  be  re p orte d  usi n g  c o ncise  me dical 
ter mi n ol o g y, prefer a bl y r eferri n g t o t he s y n dr o me/ dia g n osis rat her t ha n s y m pt o ms, w he n 
p ossi ble. 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 9 0  of 1 3 0  
•  se verit y of t he e v e nt : a d v erse e v e nt se verit y will b e pri maril y assesse d usi n g N CI 
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts v 4. 0. ( N CI -C T C A E), V ersi o n 4. 0, 
di visi o n of Ca ncer Tr eat me nt a n d Dia g n osis ( D C T D), Nati o nal Ca ncer I nstit ute ( R o bert, 
T h o mas et al. ), Nati o nal I nstit ute of H ealt h ( NI H), De part me nt of Healt h a n d H u ma n 
Ser vices ( D H H S) p u blis he d Ma y 2 9, 2 0 0 9 at 
htt ps://cte p.ca ncer. g o v/ pr ot oc ol de vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m  
•  o nset/res ol uti o n dates a n d o utc o me 
•  ca usalit y:  t he  rel ati o ns hi p  of  eac h  a d vers e  e ve nt  t o  st u d y  dr u g  will  be  defi ne d  as 
“ u nrelate d ” or “relat e d” t o st u d y treat me n t:  
o  U nrelate d :    T her e  is  little  or  n o  p ossi bilit y  t hat  t he  st u d y  dr u g  ca use d  t h e  re p orte d 
a d verse  e v e nt;  a n d  ot her  fact or(s)  i ncl u di n g  c o nc urre nt  ill nesses,  pr o gressi o n  a n d 
e x pressi o n  of  t he  disease  state,  c o nc urre nt  me di cati o ns,  or  a  reacti o n  t o  c o nc urre n t 
me dicati o ns a p pear t o e x plai n t he a d vers e e ve nt.  
o  Relate d :  t here e xists at least a reas o na ble p ossi bilit y t hat t he st u d y treat me nts ca use d 
or c o ntri b ute d t o t he a d v erse e ve nt; a n i na bilit y t o i de ntif y a n alter nate eti ol o g y f or a n 
a d verse e ve nt s h o ul d n ot , b y itself, j ustif y a “relate d” attri b uti o n. 
•  w het her  it  meets  t he  criteria  f or  classificati o n  as  a  seri o us  a d verse  e v e nt  (see Secti o n 
1 0. 2. 2. 2 ) 
T he f oll o wi n g st u d y -s pecific p oi nts of clarificati o n s h o ul d be n ote d w he n c o nsi deri n g a d v erse 
e ve nt re p orti n g a n d rec or di n g: 
•  Pr o gr essi o n  of  n e o plasia  s h o ul d  n ot  be  re p orte d  as  a n  a d verse  e ve nt  or  s eri o us  a d v erse 
e ve nt. Fi n di n gs t h at ar e clearl y c o nsiste nt wit h t h e e x pecte d pr o gressi o n of t he u n derl yi n g 
ca ncer  s h o ul d  n ot  be  r e p orte d  as  a n  a d verse  e ve nt,  a n d  h os pitalizati o ns  d ue  t o  t he 
pr o gressi o n of ca n cer d o n ot necess aril y q ualif y f or a s eri o us a d v erse e v e nt.  If t here is a n y 
u ncertai nt y  a b o ut  a  fi n di n g  or  e v e nt  bei n g  d ue  s olel y  t o  pr o gressi o n  of  ne o plasia,  t he 
fi n di n g  or  eve nt  s h o ul d  be  re p orte d  as  a n  a d v erse  e ve nt  or  s eri o us  a d verse  e ve nt  as 
a p pr o priate. Deat h d ue t o disease pr o gressi o n o cc urri n g wit hi n 2 8 da ys of st u d y treat me nt 
s h o ul d be re p orte d t o Cell de x wit hi n 2 4 h o urs of t he site’s a ware n ess of t he e ve nt; h o we ver, 
these e ve nts s h o ul d n ot b e d oc u me nte d as A Es or S A Es.  If t here is a n y u ncertai nt y a b o ut 
t he ca use of deat h, t he e v e nt s h o ul d be re p orte d as a seri o us a d v erse e ve nt. 
•  Wit h dra wal  d ue  t o  a n  a d verse  e v e nt  s h o ul d  be  disti n g uis he d  fr o m  wit h dra wal  d u e  t o 
i ns ufficient  res p o nse,  a n d  rec or de d  o n  t he  a p pr o priate  a d vers e  e ve nt  C R F  pa ge.  F or 
e x a m ple, if a n A E d ue t o rec urre nce/ pr o gressi o n of  disease  necessitates  disc o nti n uati o n 
fr o m  t he  st u d y,  t he  pri mar y  reas o n  f or  st u d y  disc o nti n uati o n  s h o ul d  be  rec or de d  as 
“ Rec urr e nce/ Pr o gressi o n of Disease” ( n ot A d vers e E ve nt).  
•  A b n or mal o bjecti ve test fi n di n gs s h o ul d be re p ort e d as a d verse e v e nts if t he fi n di n gs are 
ass ociate d  wit h  acc o m pa n yi n g  s y m pt o ms,  re q uire  a d diti o nal  di a g n ostic  testi n g  or 
me dical/s ur gical i nter v e nti o n, lea d t o d ose m o dificati o n/ disc o nti n uati o n of st u d y treat me nt 
a n d/ or ar e c o nsi der e d ot h er wise cli nicall y si g nifica nt.   
•  Dia g n ostic a n d t hera pe utic n o n -i n vasi ve a n d i n vasi ve pr oce d ures, s u c h as s ur ger y, s h o ul d 
n ot be re p orte d as a d vers e e ve nts.  H o w e ver, t he m e dical c o n diti o n f or w hic h t he pr oce d ure 
was  perf or m e d  s h o ul d  be  re p orte d  if  it  meets  t he  defi niti o n  of  a n  a d verse  e ve nt.  F or 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 9 1  of 1 3 0  
e x a m ple, a n ac ut e a p p e n dicitis t hat be gi ns d uri n g t he a d verse e ve nt re p orti n g p eri o d s h o ul d 
be re p orte d as t he a d verse e ve nt, a n d t he res ulti n g a p p e n dect o m y s h o ul d be rec or de d as 
treat me nt of t he a d vers e e ve nt. 
•  A n y A Es/ S A Es res ulti n g i n deat h s h o ul d be rec or de d wit h a n e n d date e q ual t o t he deat h 
date, w hile ot her e ve nts o n g oi n g at t he ti me of deat h s h o ul d be rec or de d wit h a n o utc o me 
of “c o nti n ui n g”. If re q u este d, a s u m mar y of a v aila ble a ut o ps y fi n di n gs s h o ul d be s u b mitte d 
as s o o n as p ossi ble t o Cell de x . 
1 0. 2. 2. 2.   Seri o us A d verse E ve nts ( S A Es): Defi niti o n  
A n S A E is a n y a d vers e e ve nt fr o m t his st u d y t hat res ults i n o ne of t he f oll o wi n g o utc o mes: 
•  Deat h (a n y A E t hat has a fatal o utc o me m ust be assi g ne d N CI -C T C A E Gra de 5)  
•  Re q uires i nitial or pr ol o n ge d i n patie nt h os pitalizati o n  e x cee di n g 2 4 h o urs.  As w ell, a n y 
e ve nt  occ urri n g  w hile  t he  patie nt  is  h os pitalize d  w hic h  w o ul d  ot her wise  re q uire 
h os pitalizati o n or  re q uires tra nsfer wit hi n t he h os pital t o a n ac ute/i nte nsi ve care u nit s h o ul d 
als o be re p orte d u n der t his criteri o n.  T his criteri o n w o ul d e x cl u de h os pitalizati o n i n t he 
a bse nce of a preci pitati n g a d v erse e ve nt, s u c h as a d missi o n f or treat me nt of a pree xist i n g 
c o n diti o n n ot ass ociate d  wit h a ne w/ w orse ni n g a d verse  e ve nt,  or  a d missi o n f or el ecti ve 
s ur ger y.  As  w ell,  a d missi o n  t o  re ha bilitati o n/ h os pice/ n ursi n g  facilities  a n d  o ut patie nt 
a d missi o n f or sa me -da y s ur geries are n ot c o nsi dere d “ h os pitalizati o ns” f or t he p ur p ose of 
t his criteri o n.) 
•  Is  life-t hr eate ni n g ( A n  A E  is  c o nsi dere d  "life-t hreate ni n g"  if,  i n  t he  vi e w  of  eit her  t he 
i n vesti gat or or s p o ns or, its occ urre n ce places t he patie nt at i m me diate ris k of deat h. It d oes 
n ot i ncl u de a n A E or s us p ecte d a d vers e reacti o n t hat, ha d it occ urre d i n a m ore se vere f or m, 
mi g ht ha ve ca use d d eat h.)  
•  Is a p ersiste nt or si g nifica nt disa bilit y/i n ca pacit y, or s u bsta ntial disr u pti o n of t he a bilit y t o 
c o n d uct n or mal life f u n cti o ns 
•  C o n ge nital a n o mal y/ birt h defect 
•  Ot her si g nifica nt me dical hazar d ( Me dical a n d s cie ntific j u d g me nt s h o ul d be e x ercise d i n 
deter mi ni n g w h et her a n e ve nt is a n i m p orta nt me dical e ve nt.  A n i m p orta nt me dical e ve nt 
ma y n ot be i m me diatel y life -t hreate ni n g a n d/ or res ult i n deat h or h os pitalizati o n. H o we ver, 
if it is deter mi ne d t hat t he e ve nt ma y je o par dize t he patie nt  a n d/ or ma y re q uire i nter ve nti o n 
t o pre ve nt o ne of t he ot her a d verse e v e nt o utc o mes, t he i m p orta nt me dical e ve nt s h o ul d be 
re p orte d as seri o us. E x a m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer ge nc y r o o m 
or at h o me f or aller gic br o nc h os pas m; bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n 
h os pitalizati o n; or de vel o p me nt of dr u g de pe n d e nc y or dr u g a b use.) 
T he f oll o wi n g st u d y -s pecific p oi nts of clarificati o n s h o ul d be n ote d w he n c o nsi deri n g seri o us 
a d verse e ve nt r e p orti n g a n d rec or di n g: 
•  Pr o gr essi o n  of  n e o plasia  s h o ul d  n ot  be  re p orte d  as  a n  a d verse  e ve nt  or  s eri o us  a d v erse 
e ve nt. Fi n di n gs t h at ar e clearl y c o nsiste nt wit h t h e e x pecte d pr o gressi o n of t he u n derl yi n g 
ca ncer  s h o ul d  n ot  be  r e p orte d  as  a n  a d verse  e ve nt,  a n d  h os pitalizati o ns  d ue  t o  t he 
pr o gressi o n of ca n cer d o n ot necess aril y q ualif y f or a s eri o us a d v erse e v e nt. If t here is a n y 
u ncertai nt y a b o ut a fi n di n g bei n g d ue s olel y t o pr o gressi o n of ne o plasia, t he fi n di n g s h o ul d 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 9 2  of 1 3 0  
be  re p ort e d  as a n  a d verse  e ve nt  or  seri o us  a d verse  e ve nt  as  a p pr o pri ate.  Deat h  d ue  t o 
disease  pr o gressi o n  o cc urri n g  wit hi n  2 8  d a ys  of  st u d y  treat me nt  s h o ul d  be  re p orte d  t o 
Cell de x wit hi n 2 4 h o urs of t he site’s a w are ness of t he e ve nt; h o we v er, t hes e e ve nts s h o ul d 
n ot be d oc u me nte d as A Es or S A Es.  If t here is a n y u ncertai nt y a b o ut t he ca use of d eat h, 
t he e ve nt s h o ul d be r e p orte d as a seri o us a d vers e e ve nt. 
1 0. 2. 2. 3.   A E/ S A E Re p orti n g  
T he i n vesti gat or is t o re p ort all directl y o bser v e d A Es  a n d all A Es  s p o nta n e o usl y re p orte d b y 
t he stu d y patie nt . I n a d diti o n, eac h st u d y patie nt  will be q uesti o ne d a b o ut A Es .  
A Es a n d S A Es s h o ul d be rec or d e d o n t he C R F fr o m t he ti me t he patie nt  has ta ke n at least o ne 
d ose of st u d y tre at me nt t hr o u g h ( w hic he ver occ urs first) eit her: a) 2 8 cale n dar d a ys aft er t he 
last a d mi nistrati o n of gle m bat u m u m a b ve d oti n or 7 0 cale n dar da ys aft er t he last a d mi nistrati o n 
of varlil u ma b (t he latter w hic he ver o cc urs lat er, C o h ort 2); 7 0 da ys after last d ose of t he P D- 1 
tar gete d c h ec k p oi nt i n hi bit or (t he latter w hic he ver occ urs later i n C o h orts 3 a n d 5); 2 8 cale n dar 
da ys a fter t he last a d mi nistrati o n of C D X -3 0 1 (t he latter w hic he ver occ urs later, C o h ort s 4 a n d 
5 ); or b ) i nitiati o n of alter nate a ntica ncer t hera p y.  
H o we ver:  
•  A n y  S A E  occ urri n g  a n y  ti me  after  t he  re p orti n g  peri o d  m ust  be  pr o m ptl y  re p orte d  if  a 
ca usal r elati o ns hi p t o st u d y treat me nt is s us pecte d  
•  F or A Es or S A Es wit h a ca usal relati o ns hi p t o t h e i n vesti gati o nal pr o d u ct, f oll o w -u p b y 
t he i n vesti gat or is r e q uire d u ntil t he e ve nt or its se q uelae res ol ve t o ≤ Gra d e 1, or sta bilize 
f or  at  least  t hree  m o nt hs  after  t he  last  a d mi nistrati o n  of  st u d y  treat me nt  ( w hic he ver  is 
s o o ner). 
All A Es  will be r e p orte d o n t he A E  p a ge(s) of t h e C R F, w hile S A Es will als o be re p orte d i n 
a n  e x pe dite d  fas hi o n  usi n g  t he S A E   Re p ort. T he  A E  C R Fs  a n d  S A E  Re p orts  m ust  be 
c o m plete d  i n  a  c o nsiste nt  ma n ner;  f or  e x a m ple,  t he  sa me A E  ter m,  ca us alit y,  s e verit y,  a n d 
o nset/res ol uti o n dates s h o ul d be use d o n b ot h f or ms.  
I n cas e of an S A E  (re gar dless of ca us alit y), an S A E  Re p ort m ust be c o m plete d a n d s u b mitte d 
t o Cell de x  wit hi n 2 4 h o urs of t he site’s n otificati o n of t he e ve nt, irres pecti ve of t he e xte nt of  
a vaila ble a d v erse e ve nt i nf or mati o n. T his ti mefra m e als o a p plies t o a d diti o nal ne w i nf or mati o n 
(f oll o w-u p)  o n  pre vi o usl y  f or war de d S A E  re p orts.  T he  i n vesti gat or  is  o bli gate d  t o  p urs ue 
a d diti o nal i nf or mati o n re q uire d f or t h or o u g h e v al uati o n of eac h S A E as m a y b e re q u este d b y 
Cell de x .  
Seri o us a d vers e e v e nt r e p orti n g t o re g ulat or y a ut h orities a n d all p artici pati n g i n vesti gat ors will 
be c o n d ucte d b y Cell de x i n acc or da n ce wit h 2 1 C F R 3 1 2. 3 2 a n d i nter nati o nal re g ulati o ns, as 
a p pr o priate. 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 9 3  of 1 3 0  
1 0. 2. 2. 4.   R a pi d  N otific ati o n of A d verse E ve nts of I nterest  
I n a d diti o n t o seri o us a d verse e ve nts, t he f oll o wi n g a d vers e e v e nts will be re p orte d wit hi n 2 4 
h o urs usi n g t he sa me ra pi d n otificati o n pr oce d ures t hat are use d f or seri o us a d verse e ve nts, 
e ve n if t he nat ure of t he a d verse e v e nt is n ot dee m e d seri o us: 
•  A n y p ote ntial tr eat me nt-li miti n g t o xicit y i n C o h orts 2- 5 ( See Secti o n  8. 7 ) 
•  Deat h d ue t o diseas e pr o gr essi o n, if occ urri n g wit hi n 2 8 da ys of st u d y treat me nt 
•  A n y  o v er d ose  ( defi n e d  as  t he  acci de ntal  or  i nte nti o nal  a d mi nistrati o n  of  a n y  d ose  of  a 
pr o d uct t hat is c o nsi dere d b ot h e x cessi ve a n d me dicall y i m p orta nt). 
•  If a fe male bec o m es, or is f o u n d t o be, pre g na nt wit hi n 6 m o nt hs of e x p os ure t o t he st u d y 
treat me nts ( mat er nal e x p os ure) or if a male has b ee n e x p ose d t o t he st u d y treat me nts wit hi n 
6 m o nt hs pri or t o c o nce pti o n ( pater nal e x p os ure).  A n y f oll o w -u p t o t he a b o ve -refere nce d 
e ve nts,  i ncl u di n g  o utc o me  of  pre g n a nc y.  F urt h er  f oll o w -u p  of  birt h  o utc o mes  will  be 
ha n dle d o n a case -b y -case basis.  I n t h e case of  pater nal  e x p os ure, t he i n vesti gat or m ust 
o btai n per missi o n fr o m t he patie nt’s part ner i n or der t o c o n d uct a n y f oll o w -u p or c ollect 
a n y i nf or mati o n.  
Gi ve n t he e x pecte d mec h a nis m of acti o n of v arlil u ma b, t he P D-1 tar get e d C PI , a n d C D X- 3 0 1, 
partic ular atte nti o n will be gi ve n t o a d vers e e ve nts i n C o h ort s 2- 5 t hat ma y b e sec o n d ar y t o 
acti vati o n  of  t he  i m m u ne  s yste m  a n d  ha ve  b ee n  o bser ve d  wit h  ot her  i m m u ne -sti m ulat or y 
a nti b o dies;  s uc h  e ve nts  i ncl u de  diarr hea/ c olitis,  ras h,  e n d ocri n o pat hies,  a n d  he p atitis  (see 
Secti o n 8. 8 ). 
1 0. 2. 2. 5.    L a b or at or y S af et y D at a 
T he f oll o wi n g cli nical la b orat or y tests will be perf or me d d uri n g t his st u d y t o asse ss safet y (s ee 
Ta ble 1  a n d T a ble 2  f or s pecific tests): 
•  He mat ol o g y  
•  Ser u m  C he mistries  
•  Uri nal ysis  
I n v esti gat ors m ust d oc u me nt t heir r e vie w of eac h la b orat or y re p ort b y si g ni n g or i nitiali n g a n d 
dati n g eac h re p ort, as w ell as a d dr essi n g t he cli nical si g nifica nce a n d ca us alit y (f or si g nifica nt 
a b n or malities). Secti o n  1 0. 2. 2. 1  pr o vi des  f urt her  g ui da nce  as  t o  w he n  a b n or mal  la b orat or y 
res ults are t o be re p ort e d as a d vers e e ve nts.  
1 0. 2. 2. 6.   Ot her S af et y D at a  
T he f oll o wi n g e val uati o ns will als o be perf or m e d d uri n g t he st u d y t o meas ure t he safet y a n d 
t olera bilit y of gle m bat u m u ma b ve d oti n as m o n ot hera p y a n d i n c o m bi nati o n wit h varlil u ma b : 
•  Vital si gn meas ur e me nts  
•  P h ysical  e x a mi nati o n  
•  E C Gs   
•  E C O G perf or ma nce stat us  (A p pe n di x 4 ) 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 9 4  of 1 3 0  
1 1.   S T A TI S TI C A L C O N SI D E R A TI O N S  
Detaile d met h o d ol o g y f or s u m mar y a n d statistical a nal ys es of t he data c ollecte d i n t his trial 
will be d oc u me nte d i n a Statistical A nal ysis Pla n ( S A P), w hic h will be dat e d a n d mai ntai ne d 
b y Cell de x.  
T his  d oc u me ntati o n  ma y  m o dif y  t he  pla ns  o utli ne d  i n  t he  pr ot oc ol;  h o we ver,  a n y  maj or 
m o dificati o ns of t he pri mar y e n d p oi nt d efi niti o n a n d/ or its a nal ysis will als o  be reflecte d i n a 
pr ot oc ol a me n d me nt. 
All  statistical  a nal ys es  will  be  perf or m e d  se paratel y  f or  t he fi ve treat me nt  c o h orts,  u nless 
s pecifie d  differe ntly.  Gi ve n  t he  ti mi n g  of  differe nt  c o h orts,  statistical  a nal ys es  will  be 
perf or me d f or eac h c o h ort w he n s ufficie nt dat a is a vaila ble u p o n c o m pleti o n of e nr oll me nt. 
1 1. 1.   A n al ysis E n d p oi nts  
Efficac y, Pri mar y  
•  O bjecti ve  res p o ns e rat e ( O R R) ( C o h orts 1- 3, 5) 
Efficac y, Sec o n dar y 
•  D urati o n of res p o ns e ( D O R)  
•  Pr o gr essi o n- fr ee s ur vi val ( P F S) 
•  O verall  s ur vi val ( O S) 
•  O R R ( C o h ort 4)  
Efficac y, E x pl orat or y 
•  I m m u ne-relat e d R E CI S T O R R a n d P F S ( C o h orts 2- 5) 
Safet y  
•  I nci de nce of a d v erse e ve nts 
•  Deat hs o n st u d y 
•  Disc o nti n uati o ns of st u d y dr u g d u e t o a d verse e v e nts 
•  C ha n ges i n vital si g n par a meters  
•  C ha n ges i n h e mat ol o g y, c he mistr y, a n d ot her l a b orat or y para meters  
•  E C G para meters  
•  E C O G perf or ma nce stat us  
C orrelati ve  
•  C o nce ntrati o n of A D C, T A , a n d fr ee M M A E  
•  P har mac o d y na mic  par a meters , i ncl u di n g g p N M B e x pressi o n le vels a n d ot h er bi o mar k ers  
i n  ser u m  a n d  b ot h  n or mal  a n d t u m or  tiss ue; l ocalizati o n  of  gle m bat u m u ma b  ve d oti n, 
C R 0 1 1, or  M M A E  at  t he  t u m or  site ;  e val uati o n  of  t u m or  i nfiltrati n g  a n d  peri p heral 
le u k oc yt es, circ ul ati n g t u m or cells, ot her i m m u ne res p o nse cells of i nterest , a n d t he effect 


Protocol CDX011-05 
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Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 95 of 130 
of CDX-301 on the tumor microenvironment, including the effect on intratumoral dendritic 
cell populations (Cohorts 4 and 5). Additional analysis may include immune response 
assessment to potentially relevant tumor antigens. 
11.2.  Sample Size and Power Calculation 
Five cohorts of patients will be studied. In Cohort 1, approximately 52 evaluable patients may 
be enrolled and treated with glembatumumab vedotin monotherapy with ORR as the primary 
endpoint. As patients who discontinue study prior to the first disease assessment for reasons 
unrelated to study treatment will be excluded from the response-evaluable population, it is 
anticipated that approximately 60 patients will be enrolled.  
For Cohort 1, the sample size was determined to estimate the ORR with one-sided significance 
level of 5% and power of 80%, using exact binomial test, to determine if the ORR exceeds a 
predefined minimum. A sample size of 52 evaluable patients will help test the null hypothesis 
of an ORR of 5% versus 15% under the alternative hypothesis. If the number of responses (CR 
or PR) is 6 or more, the null hypothesis will be rejected with the actual error rate of 0.045. If 
the number of responses is 5 or less, the alternative hypothesis will be rejected with an actual 
error rate of 0.188.  
For Cohorts 2, 3, and 5, approximately 30 patients per cohort, to achieve 25 evaluable, will be 
enrolled to have the maximum width of the 95% confidence interval (CI) of the estimated ORR 
to be no greater than 41%. If 7, 8, or 9 responses are observed (i.e., the estimated ORR is 28%, 
32%, 36%) among the 25 evaluable patients, then the lower limits of the two-sided 95% CIs 
of the estimated ORR are 12%, 15%, and 18% respectively. These calculations are based on 
the Clopper-Pearson method for exact confidence intervals. As a secondary consideration, 25 
evaluable patients can achieve 90% power for ORR of 25% comparing to 5% and 79% power 
comparing to 10% ORR with 1-sided type I error of 0.1 based on exact bionomial test. Cohort 
4 will enroll approximately 10-12 patients for safety and tolerability assessment of 
glembatumumab vedotin and CDX-301. Pre-study and on-treatment tumor biopsies will be 
analyzed for the effect of CDX-301 on the tumor microenvironment, including the effect on 
intratumoral dendritic cell populations. The anti-tumor activity will also be explored as a 
secondary endpoint. 
Patients in Cohorts 2-5 who experience an event determined to be a treatment-limiting toxicity 
will not be replaced and will be considered evaluable.  
11.3.  Interim Analysis 
No interim analysis is planned.  
11.4.  Analysis Populations 
11.4.1.  Efficacy Analysis 
The five treatment cohorts will be analyzed separately. For each cohort, the response-evaluable 
population will be the basis for the primary analysis of ORR in this study. Patients who 
discontinue study prior to the first disease assessment for reasons unrelated to study treatment 
(i.e., adverse events deemed unrelated to study treatment, withdrawal of consent, lost to follow-


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 96 of 130 
up, withdrawal due to administrative reasons, etc.) will be excluded from the response-
evaluable population and may be replaced. Patients who discontinue study prior to the first 
disease assessment due to treatment-related adverse events, symptomatic deterioration 
(adverse events due to progression), or death will be included in the response evaluable 
population. Every effort will be made to ascertain outcomes for all enrolled patients, 
irrespective of early discontinuation of protocol therapy. 
The Intention-to-Treat (ITT) population constitutes all treated patients and will be used for 
secondary analyses of ORR and all other endpoints.  
A supportive analysis using the per-protocol population may be performed for the efficacy 
analysis. The per-protocol population excludes patients that experienced important deviations 
from the protocol that may substantially affect the results of the primary analysis. In addition, 
a baseline measurement and at least one follow-up measurement obtained after at least one 
dose of study treatment may be required for inclusion in the analysis of a specific efficacy 
parameter. The final determination on protocol violations, and thereby the composition of the 
per-protocol population, will be made prior to locking the clinical database and will be 
documented in the statistical analysis plan. 
11.4.2.  Safety Analysis 
The safety population will include all patients who receive at least one dose of protocol 
treatment. A baseline measurement and at least one laboratory, vital sign, or other safety-
related measurement obtained after at least one dose of study treatment may be required for 
inclusion in the analysis of a specific safety parameter. 
11.5.  Statistical Methods 
For the analyses described below, the most recent tumor sample collected prior to study entry 
will be utilized to determine the tumor gpNMB expression level for each patient. Additional 
exploratory analyses may be performed to examine the distribution and intensity of gpNMB 
expression (i.e., staining intensity and percentage of positive tumor and stromal cells) relative 
to outcome, as well as comparison of Historic and Pre-Study or Pre-Study and On-Treatment 
samples to determine whether gpNMB expression changes over time and/or with specific prior 
therapies.   
All statistical analyses will be performed separately for the five treatment cohorts, unless 
specified differently. Given the timing of different cohorts, statistical analyses will be 
performed for each cohort when sufficient data is available upon completion of enrollment. 
11.5.1.  Efficacy Analysis 
Objective Response Rate 
ORR will be estimated as the proportion of patients who achieve best overall response of CR 
or PR per RECIST 1.1 that are confirmed at an interval of at least 28 days. Secondary analyses 
of ORR will include responses observed at a single-time point. The final analysis of ORR will 
be based on the investigator assessment of response. However, in the event of a positive study 
outcome, an additional assessment of ORR may be performed by an IRC. The estimate of the 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 9 7  of 1 3 0  
o bjecti ve  res p o nse  rate  will  be  acc o m pa ni e d  b y  o ne - a n d  t w o-si d e d  e x act 9 5 %  Cl o p per-
Pears o n c o nfi de nce i nter val  f or eac h c o h ort. I n a d diti o n, o ne-sa m ple e x act bi n o mial test will 
be use d t o test  t he n ull h y p ot heses  of O R R  (C o h ort 1: O R R < 5 %;  C o h orts 2 , 3, a n d 5: O R R 
< 5 %,  a n d  O R R < 1 0 %) wit h  o ne -si de d  si g nifica nce  le vel  of 0. 0 5  f or  C o h ort  1  a n d  0. 1  f or 
C o h orts  2,  3,   a n d  5. T he  pri mar y  O R R a nal ys es will  be base d  o n res pecti ve  e val ua bl e 
p o p ulati o n a n d t he sec o n dar y a n al ysis will be b ase d o n res pecti ve I T T p o p ulati o n. I n a d diti o n, 
s u p ple me ntar y  a nal yses  of  t u m or  res p o nse  a n d  pr o gressi o n  ma y  als o  be  perf or me d  usi n g 
ir R E CI S T criteria (i n w hic h ne w l esi o ns d o n ot c o nstit ute pr o gressi o n, b ut c o ntri b ute t o t he 
calc ulate d s u m of dia met er of all meas ura bl e disease).  E x pl orat or y a nal ysis will be perf or me d 
f or c o m pari n g t he t hr ee c o h orts o n effi cac y e n d p oi nts, a n d n o a dj ust me nt f or m ulti ple testi n g 
will be c o nsi dere d.  
Waterfall pl ots will be use d t o de pict gra p hi call y  t he ma xi m u m decrease fr o m baseli ne i n t he 
s u m  of  l o n gest  dia meters  of  tar get  l esi o ns.  Bas e d  o n  t he  ra n ge  of  g p N M B  e x pressi o n,  t he 
c orrel ati o n bet wee n g p N M B e x pressi o n  le vel a n d ma xi m u m decreas e fr o m  baseli ne i n t he s u m 
of l o n gest dia meters of tar get lesi o ns will be e val u ate d . F or t his a nal ysis all a vaila ble patie nts 
will be use d,  wit h g p N M B e x pressi o n meas ure d o n a c o nti n u o us scale ( perce nta ge of g p N M B -
p ositi ve t u m or cells).  
T o e x a mi ne t he pre dicti ve  p o wer of vari o us c ut -off val ues f or g p N M B e x pressi o n, a recei ver 
o perati n g  c ur ve  ( R O C)  a nal ysis  f or  r es p o nse  d ata (G ö ne n a n d S A S  I nstit ute. 2 0 0 7 ) will be 
perf or me d . 
D urati o n of Res p o nse 
D O R will be calc ulate d f or  t he I T T p o p ulati o n w h o ac hie ve C R or P R.  F or s uc h patie nts, D O R 
is  defi ne d  as  t he  n u m ber  of  da ys  fr o m  t he  start  date  of  P R  or  C R  ( w hic he ver  res p o nse  is 
ac hie ve d first) t o t he first date t h at rec urre nt or pr o gressi ve disease is o bj ecti vel y d o c u me nte d.  
I n s uc h cas es, r ec urre nt or pr o gr essi ve disease will be assess e d relati ve t o t he s mallest t u m or 
b ur de n meas ure me nts rec or de d si nce t he start of pr ot oc ol treat me nt. 
D O R will be s u m marize d descri pti vel y usi n g t he K a pla n-M eier met h o d.  D O R will be ri g ht -
ce ns ore d f or patie nts w h o ac hie ve C R or P R base d o n t he c o n ve nti o ns des cri be d f or P F S. 
Pr o gr essi o n-fr ee S ur vi val 
P F S is defi ne d as t he n u m ber of m o nt hs fr o m t he start date of pr ot oc ol treat me nt t o t he earlier 
of diseas e pr o gressi o n or deat h d ue t o a n y ca use.  Disease pr o gressi o n will be assesse d usi n g 
R E CI S T 1. 1  a n d ir R E CI S T f or c o h ort 2. P F S will be base d o n t he I T T pati e nt p o p ulati o n. 
P F S will be ri g ht -ce ns ore d f or patie nts w h o met o ne or m ore of t h e f oll o wi n g c o n diti o ns: 
•  Patie nts  wit h n o baseli ne or p ost -baseli ne disease assess me nts u nless deat h occ urre d pri or 
t o t he first pla n ne d assess me nt (i n w hic h cas e t he deat h will be c o nsi dere d a P F S e ve nt) 
•  Patie nts  w h o  i nitiate  s u bse q ue nt  a nti -ca n cer  t h era p y  i n  t he  a bse nce  of  d oc u me nte d  
pr o gressi o n 
•  Patie nts  w h o  die  or  ha ve  disease  pr o gressi o n  after  missi n g  t w o  or  m ore  c o nsec uti vel y 
sc he d ule d diseas e assess me nt visits 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 9 8  of 1 3 0  
•  Patie nts w h o are l ast k n o w n t o be ali ve a n d pr o gressi o n -free o n or bef ore t he data c ut-off 
date  
T he pr o gressi o n a n d ce ns ori n g d ates will be b ase d o n t he c o n ve nti o ns d escri be d i n t he Ma y 
2 0 0 7 F D A G ui da n ce f or I n d ustr y, ‘ Cli nic al Tri al E n d p oi nts f or t he A p pr ov al of C a ncer Dr u gs 
a n d Bi ol o gics ’. T he pri mar y a nal ysis of P F S will be base d o n P F S e ve nts deter mi ne d b y t he 
i n vesti gat or. I n a d diti o n, i n t he e ve nt of a p ositi ve st u d y o utc o me, a n a d diti o nal assess me nt of 
t u m or  res p o nse  a n d  pr o gr essi o n ma y  be  perf or me d  b y  a n  I R C  bli n de d  t o  i n vesti gat or 
assess me nts.   
P F S will be s u m marize d descri pti vel y usi n g t he Ka pla n -Mei er met h o d. Me dia n P F S a n d its 
c orres p o n di n g 9 5 % c o nfi de nce i nter v al will be re p orte d.  T he P F S rat e a n d its c orres p o n di n g 
9 5 % c o nfi de n ce i nter v al f or at vari o us la n d mar k ti me p oi nts will als o be esti mate d usi n g t he 
Ka pla n -Mei er met h o d.  Gree n w o o d’s f or m ula will be u s e d t o calc ulat e t he sta n dar d err ors of 
t he Ka pla n-Mei er esti mat e a n d u p per a n d l o w er li mits of t he 9 5 % c o nfi de nce i nter val.  Si milar 
a nal ys es ma y be p erf or me d f or a d diti o nal la n d mar ks.  
If feasi ble base d o n t he r a n ge of g p N M B e x pressi o n le vels, the ass ocia ti o n bet wee n g p N M B  
e x pressi o n  le vel a n d P F S will be e val uate d usi n g a C o x pr o p orti o nal hazar ds m o del.  F or t his 
a nal ysis,  p atie nts  wit h g p N M B e x pressi o n  meas ure d  o n  a  c o nti n u o us  scale  ( perce nta ge  of 
g p N M B -p ositi ve t u m or cells)  will be a n al yze d . W he n a fact o r is c o nti n u o us, t he hazar d rati o 
is i nter prete d as t he c ha n ge i n ris k f or eac h 1-u nit i ncreas e i n t he fact or.  F or e x a m ple, a hazar d 
rati o of 0. 9 9 i n dicates t h e hazar d f or t he e v e nt decreas es b y 1% f or eac h 1 % -u nit i ncrease i n 
g p N M B  e x pressi o n  le vel.  F or  C o h ort  1, if  a  tr ue  hazar d  rati o  of  0. 9 9  is  ass u me d  a n d  t he 
sta n dar d de viati o n f or g p N M B  e x pressi o n le vel is ± 3 5 %, 3 6 P F S e ve nts fr o m a m o n g t he 5 2 
e val ua ble patie nts  ( 7 0 %  e ve nt  r ate)  will  pr o vi de  a p pr o xi matel y 8 0 %  p o w er  wit h  o n e -si de d 
si g nifica n ce le v el of 1 0 % (Hsie h a n d La v ori 2 0 0 0 ). T he p re di cti ve p o w er of vari o us c ut-off 
val ues f or g p N M B  e x pressi o n will be e x pl ore d base d o n a  recei ver  o perati n g c ur ve  ( R O C) 
a nal ysis f or ce ns or e d d ata (G ö ne n a n d S A S I nstit ute. 2 0 0 7 ). Si milar a n al yses will be perf or me d 
f or C o h orts 2 a n d 3 se par atel y. 
O verall S ur vi val 
O S is defi ne d as t he n u m ber of m o nt hs ela pse d bet wee n t he start date of pr ot oc ol treat me nt 
a n d t he date of deat h ( w hate ver t he ca use).  O S will be base d o n t he I T T p o p ulati o n. Patie nts 
w h o are ali ve or l ost t o f oll o w -u p as of t he data a nal ysis c ut off date  will be ri g ht -ce ns ore d. T h e 
ce ns ori n g date will be det er mi ne d fr o m t he p atie nts’ date of last c o ntact or d ata a nal ysis c ut off 
date, w hic he ver e ve nt occ urs first.  T he d urati o n of O S will be s u m marize d descri pti vel y usi n g 
t he Ka pla n-Meier met h o d.  Me dia n O S a n d its c orres p o n di n g 9 5 % c o nfi de nce i nter val will be 
re p orte d. Me di a n f oll o w -u p f or O S will be esti mate d acc or di n g t o t he re verse Ka pla n-Meier 
esti mate of p ote ntial f oll o w - u p (Sc he m per a n d S mit h 1 9 9 6 ). 
1 1. 5. 2.   Pr ot oc ol T her a p y a n d C o nc o mit a nt Me dic ati o ns  
T he t otal n u m ber of d oses a n d t otal d ose a d mi nistere d will be ta b ulate d  b y c o h ort . T he pri mar y 
reas o n  f or  treat me nt  dela ys,  d ose  re d ucti o ns  a n d  per ma n e nt  disc o nti n uati o n  of  pr ot oc ol 
treat me nt will be ta b ulate d i n a si milar ma n ner. 


Protocol CDX011-05 
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Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 99 of 130 
Concomitant medications will be coded using WHO Drug Dictionary. All medication data will 
be listed individually and summarized by anatomical therapeutic class and preferred name. 
11.5.3.  Safety Analysis 
Safety and tolerability will be assessed by incidence, severity, and changes from baseline of 
all relevant parameters including AEs, vital signs, and laboratory values. 
AEs will be coded using the latest available version of the Medical Dictionary for Regulatory 
Activities (MedDRA). The number and percentage of patients experiencing one or more AEs 
will be summarized by relationship to study drug, and severity. Treatment-emergent AEs are 
defined as AEs that start on or after the first day study drug is administered. AEs will be 
summarized by the number and percentage of patients who experienced the event, according 
to system organ class and preferred term. A patient reporting multiple cases of the same AE 
will be counted once within each system organ class and similarly counted once within each 
preferred term. Unless specified otherwise, the denominator for these calculations will be 
based on the number of patients who receive at least one dose of study drug, irrespective of the 
total number of doses administered. AEs will also be summarized by NCI-CTCAE severity 
grade and by relationship to study drug. Additional summaries may also be provided for SAEs 
and events resulting in the permanent discontinuation of therapy. All AEs will be included in 
individual patient data listings. 
Vital sign and laboratory results will be summarized descriptively. The incidence of Grade 3 
and 4 hematological toxicities (including neutropenia, thrombocytopenia, and anemia) will be 
provided. The use of red blood cell and other blood component transfusions and/or growth 
factor support will be reported. Similar analyses will be done for selected chemistry tests 
(including liver and renal function tests). Data listings of all vital sign and laboratory data 
collected during the study will be presented. Laboratory values outside normal limits will be 
identified in data listings and will include flags for high and low values. 
12.  DATA HANDLING AND RECORD KEEPING 
12.1.  Data Quality Assurance 
Monitoring and auditing procedures defined by Celldex or designee will be followed, in order 
to comply with Good Clinical Practices (GCP) guidelines. Each center will be visited at regular 
intervals by a monitor to ensure compliance with the study protocol, GCP, and legal aspects. 
This will include on-site checking of the case report forms (CRF) for completeness and clarity, 
cross-checking with source documents, and clarification of administrative matters. 
To ensure the safety of participants in the study and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study. All the information 
required by the protocol should be provided; any omissions require explanation. 
Celldex will provide Case Report Forms (CRFs) for the recording and collection of data. The 
CRF will either be in paper or via an electronic data capture (EDC) system. Entries made in 
the CRF must be either verifiable against source documents, or have been directly entered into 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 100 of 130 
the CRF, in which case the entry in the CRF will be considered as the source data. The source 
data parameter to be verified and the identification of the source document must be 
documented. Corrections to CRFs and source data will be made only by authorized members 
of the study staff, clearly entered, initialed and dated. The investigator will sign the CRFs to 
indicate that, to his/her knowledge, they are complete and accurate. If further changes are made 
after this, the investigator will be made aware of the corrections and his/her approval will be 
documented by re-signing. In cases where an EDC system is utilized, an electronic audit trail 
is maintained with similar information collected. 
The investigator will permit Celldex direct access to source data/documents for trial-related 
monitoring, audits, review, and inspection(s). Through ongoing monitoring visits at the 
investigational sites, Celldex will periodically check the patient data recorded in the CRF’s 
against source documents, to ensure accuracy, completeness, and adherence to the protocol, 
regulatory compliance, and the maintenance of comprehensive clinical records.  
As well, the study may be audited by Celldex and/or regulatory agencies at any time. If 
requested, the investigator will provide Celldex, applicable regulatory agencies and/or 
applicable ethical review boards with direct access to original source documents. 
12.2.  Archiving of Study Documentation 
To enable evaluations and/or audits by regulatory authorities or Celldex, the investigator agrees 
to keep records, including the identity of all participating patients (sufficient information to 
link records, e.g., CRFs and hospital records); all original signed informed consent forms; 
copies of all CRFs; serious adverse event forms; source documents and detailed records of 
treatment disposition; and adequate documentation of relevant correspondence (e.g., letters, 
meeting minutes, telephone calls reports). The duration of record retention by the investigator 
should be according to ICH, local regulations, or as specified in the Clinical Study Agreement, 
whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Celldex should be prospectively notified. The 
study records must be transferred to a designee acceptable to Celldex, such as another 
investigator, another institution, or to an independent third party arranged by Celldex. The 
investigator must obtain Celldex’s written permission before disposing of any records, even if 
retention requirements have been met. 
13.  ETHICAL CONSIDERATIONS 
13.1.  Independent Ethics Committee or Institutional Review Board 
International Conference on Harmonization (ICH) GCP guidelines require that all 
investigational drug studies be conducted under the auspices of an Institution Review 
Board/Ethics Committee (IRB/EC). This committee, the makeup of which must conform to 
federal, state, and local guidelines regarding such, will approve all aspects of the study, 
including the protocol and informed consent to be used and any modifications made to the 
protocol or informed consent. The investigator will provide Celldex with a copy of the 
communication from the IRB/EC to the investigator indicating approval/favorable opinion of 


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the protocol and consent form. All changes to the protocol or consent form must be reviewed 
and approved prior to implementation, except where necessary to eliminate apparent 
immediate hazards to human patients. 
The investigator will provide Celldex with documentation of ethical review board approval of 
the protocol and the informed consent document before the study may begin at the investigative 
site(s). The investigator will also be responsible for obtaining periodic (IRB/EC) re-approval 
throughout the duration of the study. Copies of the investigator’s periodic report to the IRB/EC 
and copies of the IRB/EC’s continuance of approval must be retained in the site study files and 
furnished to Celldex. 
The IRB/ECs must supply to Celldex, upon request, a list of the IRB/EC members involved in 
the vote and a statement to confirm that the IRB/EC is organized and operates according to 
GCP and applicable laws and regulations.  
13.2.  Ethical Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that Celldex and the investigator abide by 
Good Clinical Practice Guidelines and under the guiding principles detailed in the Declaration 
of Helsinki. The study will also be carried out in keeping with applicable local law(s) and 
regulation(s). The investigator is responsible for complying with the protocol and all 
appropriate regulations and guidelines governing global clinical research. Additionally, he/she 
is responsible for ensuring that all participating staff members are adequately trained and 
competent to perform his/her assigned tasks.  
13.3.  Patient Information and Informed Consent 
A sample Informed Consent Form will be provided. Prior to the beginning of the study, the 
investigator must have the IRB/ECs written approval/favorable opinion of the written Informed 
Consent Form and any other written information to be provided to patients. The written 
approval of the EC/IRB together with the approved patient information/Informed Consent 
Forms must be filed in the study files. The Informed Consent Form must contain all elements 
required ICH Good Clinical Practices (GCP) Guidelines (E6) in addition to any other elements 
required by federal, state, local or institutional policy.  
The investigator will be responsible for obtaining an Informed Consent signed by each patient 
or his/her legally authorized representative, prior to his/her participation in the study, in 
accordance with ICH GCP guidelines. Informed Consent will be obtained from a patient or 
his/her legally authorized representative after a full explanation of the purpose of the study, the 
risks and discomforts involved, potential benefits, etc., have been provided by the investigator 
or designee, both verbally and in writing. The investigator is responsible to see that informed 
consent is obtained from each patient or legal representative and to obtain the appropriate 
signatures and dates on the informed consent document prior to the performance of any 
protocol procedures and prior to the administration of study drug. Participation in the study 
and date of informed consent given by the patient should be documented appropriately in the 
patient’s files. 


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The original or copy of the signed copy of the Informed Consent must be maintained in the 
institution’s records, and is subject to inspection by Celldex or regulatory agencies. The patient 
or his/her legally authorized representative will also be given a copy of the signed consent 
form. 
As used in this protocol, the term "informed consent" includes all consent and/or assent given 
by patients or their legal representatives. 
13.4.  Protocol Amendments 
Modifications to the study protocol will not be implemented by either Celldex or the 
investigator without agreement by each party and EC/IRB approval/favorable opinion. 
However, the investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to the trial patients without prior EC/IRB/Celldex 
approval/favorable opinion. The implemented deviation or change, the reasons for it, and if 
appropriate, the proposed protocol amendment, should be submitted to the EC/IRB and 
Celldex as soon as practical.  
Any deviations from the protocol must be fully explained and documented by the investigator. 
The circumstances, action taken and impact of the deviation on the trial must be communicated 
by the principal investigator to Celldex. Any subsequent actions will be assessed by the Celldex 
and documented.  
13.5.  Confidentiality 
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.  
Patient names will not be supplied to Celldex. Only the patient number and patient initials will 
be recorded in the case report form, and if the patient name appears on any other document 
(e.g., pathologist report), it must be obliterated before a copy of the document is supplied to 
Celldex. Study findings stored on a computer will be stored in accordance with local data 
protection laws. The patients will be informed in writing that representatives of Celldex, 
IEC/IRB, or Regulatory Authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws. 
If the results of the study are published, the patient’s identity will remain confidential.  
The investigator will maintain a list to enable patients’ records to be identified. 
14.  PUBLICATION POLICY 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of Celldex, who may utilize the data in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.  
Celldex supports publication of the results of this trial in appropriate scientific journals and 
meetings. In accord with standard editorial and ethical practice, Celldex encourages 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 0 3  of 1 3 0  
p u blica ti o n of m ultice nter trials o nl y i n t heir e ntiret y a n d n ot as i n di vi d ual ce nter d ata. A n y 
prese ntati o n or p u blicati o n of d ata c ollecte d fr o m t his st u d y will be ge n erate d i n acc or d a nce 
wit h t he f oll o wi n g pri nci ples: 
•  A ut h ors hi p  (i ncl u di n g  i d e ntificati o n  of  a  l ea d  a ut h or  a n d  c orres p o n di n g  a ut h or)  will  be 
deter mi ne d  b y  m ut ual  a gr ee me nt  i n  acc or d a nce  wit h  t he  I nt er nati o nal  C o m mittee  of 
Me dical J o ur nal E dit ors (I C MJ E) criteria f or a ut h ors hi p, acc or di n g t o o verall c o ntri b uti o n 
t o st u d y c o n d u ct, c hiefl y b y lea ders hi p i n st u d y d esi g n a n d decisi o n ma ki n g, a n d t he n b y 
c o ntri b uti o n. All mea ni n gf ul c o ntri b uti o ns will be ac k n o wle d ge d. 
•  A ut h ors will f oll o w G o o d P u blicati o n Practice ( G P P) a n d ot her rec o g nize d sta n dar ds a n d 
will w or k t o get her t o: dis c uss practical c o nsi derati o ns (e. g., c h oice of p ot e ntial j o ur nals or 
c o n gresses); a v oi d d u plicate p u blicati o n; e ns ure t hat p u blicati o ns are acc urate, bala n ce d, 
tra ns pare nt  a n d  pr o d uce d  i n  a  ti mel y  ma n n er;  ass u me  res p o nsi bilit y  f or  t he  c o nte nt, 
acc ur ac y a n d c o m plete n ess of t he p u blicati o n; esta blis h a pr ocess bas e d o n h o nest scie ntific 
de bate  t o  r es ol ve  differ e nces  i n  i nter pretati o n  of  data;  discl ose  all  p ote nti al  c o nflicts  of 
i nterest; discl ose f u n di n g s o urces i ncl u di n g Cell de x s u p p ort f or t he st u d y (f u n di n g a n d i n-
ki n d s u p p ort s uc h as me dical writi n g); a n d ass u me res p o nsi bilit y f or all fi nal decisi o ns o n 
p u blicati o n c o nte nt a n d f or fi nal a p pr o v al of t he v ersi o n f or s u b missi o n or prese ntati o n. 
•  Cell de x will pr o vi de a ut h ors wit h access t o all rele va nt st u d y d o c u me nts nee de d t o s u p p ort 
the p u blicati o n, i ncl u di n g pr ot oc ols, statistical a n al ysis pla ns, cli nical st u d y re p orts ( w he n 
a vaila ble), a n d data ta bles; descri be e dit orial a n d ot her s u p p ort t hat ma y be a vaila ble t o t he 
a ut h ors f or t he de v el o p me nt of a p u blicati o n a n d e ns ure t hat all a ut h ors a gree t o a n y s u p p ort 
t o be pr o vi de d; a n d pr o vi de a ti mel y re vie w of t he p u blicati o n or prese ntati o n.  
•  A d diti o nall y, a ut h ors a n d Cell de x will a v oi d pre mat ure release of st u d y i nf or mati o n t hat 
c o ul d je o par dize p u blicati o n a n d res pect e m bar g o es set b y j o ur nals a n d c o n gresses.  
 
 


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15.  REFERENCES  
Akinleye, A., M. Furqan, et al. (2013). "MEK and the inhibitors: from bench to bedside." 
Journal of hematology & oncology 6: 27. 
Alkhairy, O. K., R. Perez-Becker, et al. (2015). "Novel mutations in TNFRSF7/CD27: 
Clinical, immunologic, and genetic characterization of human CD27 deficiency." J Allergy 
Clin Immunol 136(3): 703-712 e710. 
Anandasabapathy, N., G. Breton, et al. (2015). "Efficacy and safety of CDX-301, recombinant 
human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human 
volunteers." Bone Marrow Transplant 50(7): 924-930. 
Anderson, C. M., A. C. Buzaid, et al. (1995). "Systemic treatments for advanced cutaneous 
melanoma." Oncology 9(11): 1149-1158; discussion 1163-1144, 1167-1148. 
Breton, G., J. Lee, et al. (2015). "Circulating precursors of human CD1c+ and CD141+ 
dendritic cells." J Exp Med 212(3): 401-413. 
Cancer Research UK "Skin Cancer Incidence Statistics [Internet]. 20012 Jun 29 [cited 2013 
Jul 
31]. 
 
Available 
from: 
http://www.cancerresearchuk.org/cancer-
info/cancerstats/types/skin/incidence/#source17." 
Chapman, P. B., L. H. Einhorn, et al. (1999). "Phase III multicenter randomized trial of the 
Dartmouth regimen versus dacarbazine in patients with metastatic melanoma." Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 17(9): 2745-
2751. 
Cortes, J., J. O'Shaughnessy, et al. (2011). "Eribulin monotherapy versus treatment of 
physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label 
randomised study." Lancet 377(9769): 914-923. 
Dong, H. Y., A. Shahsafaei, et al. (2002). "CD148 and CD27 are expressed in B cell 
lymphomas derived from both memory and naive B cells." Leuk Lymphoma 43(9): 1855-1858. 
Duan, F., Y. Lin, et al. (2009). "Immune rejection of mouse tumors expressing mutated self." 
Cancer Res 69(8): 3545-3553. 
Eisenhauer, E. A., P. Therasse, et al. (2009). "New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1)." Eur J Cancer 45(2): 228-247. 
Ferlay, J., H. R. Shin, et al. (2010). "Estimates of worldwide burden of cancer in 2008: 
GLOBOCAN 2008." International journal of cancer. Journal international du cancer 127(12): 
2893-2917. 
Flaherty, K. T., C. Robert, et al. (2012). "Improved survival with MEK inhibition in BRAF-
mutated melanoma." The New England journal of medicine 367(2): 107-114. 
Ginhoux, F., K. Liu, et al. (2009). "The origin and development of nonlymphoid tissue 
CD103+ DCs." J Exp Med 206(13): 3115-3130. 
Gönen, M. and SAS Institute. (2007). Analyzing receiver operating characteristic curves with 
SAS. Cary, NC, SAS Pub. 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
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Haniffa, M., A. Shin, et al. (2012). "Human tissues contain CD141hi cross-presenting dendritic 
cells with functional homology to mouse CD103+ nonlymphoid dendritic cells." Immunity 
37(1): 60-73. 
He, L. Z., N. Prostak, et al. (2013). "Agonist anti-human CD27 monoclonal antibody induces 
T cell activation and tumor immunity in human CD27-transgenic mice." J Immunol 191(8): 
4174-4183. 
Hirschhorn-Cymerman, D., G. A. Rizzuto, et al. (2009). "OX40 engagement and 
chemotherapy combination provides potent antitumor immunity with concomitant regulatory 
T cell apoptosis." J Exp Med 206(5): 1103-1116. 
Hodi, F. S., S. J. O'Day, et al. (2010). "Improved survival with ipilimumab in patients with 
metastatic melanoma." The New England journal of medicine 363(8): 711-723. 
Hsieh, F. Y. and P. W. Lavori (2000). "Sample-size calculations for the Cox proportional 
hazards regression model with nonbinary covariates." Controlled clinical trials 21(6): 552-560. 
International Agency for Research on Cancer "World Cancer Report 2008 [internet].  2008 
[cited 
2013 
Jul 
31]. 
Available 
at: 
http://www.iarc.fr/en/publications/pdfs-
online/wcr/2008/index.php  ". 
Jemal, A., R. C. Tiwari, et al. (2004). "Cancer statistics, 2004." CA: a cancer journal for 
clinicians 54(1): 8-29. 
Jilaveanu, L. B., J. Sznol, et al. (2012). "CD70 expression patterns in renal cell carcinoma." 
Hum Pathol 43(9): 1394-1399. 
Junker, K., W. Hindermann, et al. (2005). "CD70: a new tumor specific biomarker for renal 
cell carcinoma." J Urol 173(6): 2150-2153. 
Kris, M. G., P. J. Hesketh, et al. (2006). "American Society of Clinical Oncology guideline for 
antiemetics in oncology: update 2006." J Clin Oncol 24(18): 2932-2947. 
Kuan, C. T., K. Wakiya, et al. (2006). "Glycoprotein nonmetastatic melanoma protein B, a 
potential molecular therapeutic target in patients with glioblastoma multiforme." Clin Cancer 
Res 12(7 Pt 1): 1970-1982. 
Larkin, J., V. Chiarion-Sileni, et al. (2015). "Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma." N Engl J Med 373(1): 23-34. 
Larkin, J., F. S. Hodi, et al. (2015). "Combined Nivolumab and Ipilimumab or Monotherapy 
in Untreated Melanoma." N Engl J Med 373(13): 1270-1271. 
Lens, S. M., P. Drillenburg, et al. (1999). "Aberrant expression and reverse signalling of CD70 
on malignant B cells." Br J Haematol 106(2): 491-503. 
Little, E. G. and M. J. Eide (2012). "Update on the current state of melanoma incidence." 
Dermatologic clinics 30(3): 355-361. 
Lynch, D. H., A. Andreasen, et al. (1997). "Flt3 ligand induces tumor regression and antitumor 
immune responses in vivo." Nat Med 3(6): 625-631. 


Protocol CDX011-05 
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Maraskovsky, E., K. Brasel, et al. (1996). "Dramatic increase in the numbers of functionally 
mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations 
identified." J Exp Med 184(5): 1953-1962. 
Marron, T. U., M. Binder, et al. (2015). "In situ vaccine for low-grade lymphoma: Combination 
of intratumoral Flt3L and poly-ICLC with low-Dose radiotherapy." Journal of Clinical 
Oncology 33(15_suppl): TPS3105. 
Martin, K., P. Muller, et al. (2014). "The microtubule-depolymerizing agent ansamitocin P3 
programs dendritic cells toward enhanced anti-tumor immunity." Cancer Immunol 
Immunother 63(9): 925-938. 
Mays, S. R. and B. R. Nelson (1999). "Current therapy of cutaneous melanoma." Cutis 63(5): 
293-298. 
Medina, T., M. N. Amaria, et al. (2013). "Dabrafenib in the treatment of advanced melanoma." 
Drugs of today 49(6): 377-385. 
Middleton, M. R., J. J. Grob, et al. (2000). "Randomized phase III study of temozolomide 
versus dacarbazine in the treatment of patients with advanced metastatic malignant 
melanoma." Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 18(1): 158-166. 
Molica, S., G. Vitelli, et al. (1998). "CD27 in B-cell chronic lymphocytic leukemia. Cellular 
expression, serum release and correlation with other soluble molecules belonging to nerve 
growth factor receptors (NGFr) superfamily." Haematologica 83(5): 398-402. 
Morse, M. A., S. Nair, et al. (2000). "Preoperative mobilization of circulating dendritic cells 
by Flt3 ligand administration to patients with metastatic colon cancer." J Clin Oncol 18(23): 
3883-3893. 
Muller, P., M. Kreuzaler, et al. (2015). "Trastuzumab emtansine (T-DM1) renders HER2+ 
breast cancer highly susceptible to CTLA-4/PD-1 blockade." Sci Transl Med 7(315): 
315ra188. 
Muller, P., K. Martin, et al. (2014). "Microtubule-depolymerizing agents used in antibody-
drug conjugates induce antitumor immunity by stimulation of dendritic cells." Cancer Immunol 
Res 2(8): 741-755. 
Murase, S., M. Saio, et al. (1998). "Increased levels of CSF soluble CD27 in patients with 
primary central nervous system lymphoma." Cancer Lett 132(1-2): 181-186. 
Nishino, M., A. Giobbie-Hurder, et al. (2013). "Developing a common language for tumor 
response to immunotherapy: immune-related response criteria using unidimensional 
measurements." Clin Cancer Res 19(14): 3936-3943. 
Oken, M. M., R. H. Creech, et al. (1982). "Toxicity and response criteria of the Eastern 
Cooperative Oncology Group." Am J Clin Oncol 5(6): 649-655. 
Pardoll, D. M. (2012). "The blockade of immune checkpoints in cancer immunotherapy." 
Nature reviews. Cancer 12(4): 252-264. 


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Patel, P. M., S. Suciu, et al. (2011). "Extended schedule, escalated dose temozolomide versus 
dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 
18032)." European journal of cancer 47(10): 1476-1483. 
Perez, E. A., G. Lerzo, et al. (2007). "Efficacy and safety of ixabepilone (BMS-247550) in a 
phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, 
and capecitabine." J Clin Oncol 25(23): 3407-3414. 
Pollack, V. A., E. Alvarez, et al. (2007). "Treatment parameters modulating regression of 
human melanoma xenografts by an antibody-drug conjugate (CR011-vcMMAE) targeting 
GPNMB." Cancer Chemother Pharmacol 60(3): 423-435. 
Posnett, D. N., M. E. Engelhorn, et al. (2009). "Development of effective vaccines for old mice 
in a tumor model." Vaccine 27(7): 1093-1100. 
Qian, X., E. Mills, et al. (2008). "Pharmacologically enhanced expression of GPNMB 
increases the sensitivity of melanoma cells to the CR011-vcMMAE antibody-drug conjugate." 
Molecular oncology 2(1): 81-93. 
Ranheim, E. A., M. J. Cantwell, et al. (1995). "Expression of CD27 and its ligand, CD70, on 
chronic lymphocytic leukemia B cells." Blood 85(12): 3556-3565. 
Ripoll, V. M., K. M. Irvine, et al. (2007). "Gpnmb is induced in macrophages by IFN-gamma 
and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses." J 
Immunol 178(10): 6557-6566. 
Robert, C., A. Ribas, et al. (2014). "Anti-programmed-death-receptor-1 treatment with 
pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison 
cohort of a phase 1 trial." Lancet 384(9948): 1109-1117. 
Robert, C., J. Schachter, et al. (2015). "Pembrolizumab versus Ipilimumab in Advanced 
Melanoma." N Engl J Med 372(26): 2521-2532. 
Robert, C., L. Thomas, et al. (2011). "Ipilimumab plus dacarbazine for previously untreated 
metastatic melanoma." The New England journal of medicine 364(26): 2517-2526. 
Rose, A., Z. Dong, et al. (2009). "GPNMB is Novel Pro-Angiogenic Factor and Therapeutic 
Target in Breast Cancer." Poster Presented at MISAM (Montreal International Symposium on 
Angiogenesis and Metastasis); June. 
Rose, A. A., A. A. Grosset, et al. (2010). "Glycoprotein nonmetastatic B is an independent 
prognostic indicator of recurrence and a novel therapeutic target in breast cancer." Clin Cancer 
Res 16(7): 2147-2156. 
Rose, A. A., F. Pepin, et al. (2007). "Osteoactivin promotes breast cancer metastasis to bone." 
Mol Cancer Res 5(10): 1001-1014. 
Salmon, H., J. Idoyaga, et al. (2016). "Expansion and Activation of CD103(+) Dendritic Cell 
Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF 
Inhibition." Immunity 44(4): 924-938. 
Schemper, M. and T. L. Smith (1996). "A note on quantifying follow-up in studies of failure 
time." Controlled clinical trials 17(4): 343-346. 


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Selim, A. A. (2009). "Osteoactivin bioinformatic analysis: prediction of novel functions, 
structural features, and modes of action." Med Sci Monit 15(2): MT19-33. 
Selim, A. A., S. M. Abdelmagid, et al. (2003). "Anti-osteoactivin antibody inhibits osteoblast 
differentiation and function in vitro." Crit Rev Eukaryot Gene Expr 13(2-4): 265-275. 
Shao, H., C. M. Yuan, et al. (2010). "Minimal residual disease detection by flow cytometry in 
adult T-cell leukemia/lymphoma." Am J Clin Pathol 133(4): 592-601. 
Sharma, A., S. R. Shah, et al. (2012). "Vemurafenib: targeted inhibition of mutated BRAF for 
treatment of advanced melanoma and its potential in other malignancies." Drugs 72(17): 2207-
2222. 
Sheng, M. H., J. E. Wergedal, et al. (2008). "Osteoactivin is a novel osteoclastic protein and 
plays a key role in osteoclast differentiation and activity." FEBS Lett 582(10): 1451-1458. 
Shikano, S., M. Bonkobara, et al. (2001). "Molecular cloning of a dendritic cell-associated 
transmembrane protein, DC-HIL, that promotes RGD-dependent adhesion of endothelial cells 
through recognition of heparan sulfate proteoglycans." J Biol Chem 276(11): 8125-8134. 
Smith, T. J., J. Khatcheressian, et al. (2006). "2006 update of recommendations for the use of 
white blood cell growth factors: an evidence-based clinical practice guideline." J Clin Oncol 
24(19): 3187-3205. 
Sullivan, R. J., P. M. Lorusso, et al. (2013). "The intersection of immune-directed and 
molecularly targeted therapy in advanced melanoma: where we have been, are, and will be." 
Clinical cancer research : an official journal of the American Association for Cancer Research 
19(19): 5283-5291. 
Sutherland, M. S., R. J. Sanderson, et al. (2006). "Lysosomal trafficking and cysteine protease 
metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin 
conjugates." J Biol Chem 281(15): 10540-10547. 
Thomas, L. J., L. Z. He, et al. (2014). "Targeting human CD27 with an agonist antibody 
stimulates T-cell activation and antitumor immunity." Oncoimmunology 3(1): e27255. 
Tomihari, M., J. S. Chung, et al. (2010). "DC-HIL/glycoprotein Nmb promotes growth of 
melanoma in mice by inhibiting the activation of tumor-reactive T cells." Cancer Res 70(14): 
5778-5787. 
Topalian, S. L., F. S. Hodi, et al. (2012). "Safety, activity, and immune correlates of anti-PD-
1 antibody in cancer." The New England journal of medicine 366(26): 2443-2454. 
Trentin, L., R. Zambello, et al. (1997). "B lymphocytes from patients with chronic 
lymphoproliferative disorders are equipped with different costimulatory molecules." Cancer 
Res 57(21): 4940-4947. 
Tse, K. F., M. Jeffers, et al. (2006). "CR011, a fully human monoclonal antibody-auristatin E 
conjugate, for the treatment of melanoma." Clin Cancer Res 12(4): 1373-1382. 
U.S. Cancer Statistics Working Group (2007). "United States Cancer Statistics: 2004 Incidence 
and Mortality." Atlanta: U.S. Department of Health and Human Services, Centers for Disease 
Control and Prevention and National Cancer Institute. 


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van Montfrans, J. M., A. I. Hoepelman, et al. (2012). "CD27 deficiency is associated with 
combined immunodeficiency and persistent symptomatic EBV viremia." J Allergy Clin 
Immunol 129(3): 787-793 e786. 
van Oers, M. H., S. T. Pals, et al. (1993). "Expression and release of CD27 in human B-cell 
malignancies." Blood 82(11): 3430-3436. 
Vitale, L. A., L. Z. He, et al. (2012). "Development of a human monoclonal antibody for 
potential therapy of CD27-expressing lymphoma and leukemia." Clin Cancer Res 18(14): 
3812-3821. 
Wagner, J. D., M. S. Gordon, et al. (2000). "Current therapy of cutaneous melanoma." Plastic 
and reconstructive surgery 105(5): 1774-1799; quiz 1800-1771. 
Weber, J. S., S. P. D'Angelo, et al. (2015). "Nivolumab versus chemotherapy in patients with 
advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a 
randomised, controlled, open-label, phase 3 trial." Lancet Oncol 16(4): 375-384. 
Williams, M. D., B. Esmaeli, et al. (2010). "GPNMB expression in uveal melanoma: a potential 
for targeted therapy." Melanoma research 20(3): 184-190. 
Wischhusen, J., G. Jung, et al. (2002). "Identification of CD70-mediated apoptosis of immune 
effector cells as a novel immune escape pathway of human glioblastoma." Cancer Res 62(9): 
2592-2599. 
Wolchok, J. D., A. Hoos, et al. (2009). "Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria." Clin Cancer Res 15(23): 7412-
7420. 
Yardley, D. A., R. Weaver, et al. (2015). "EMERGE: A Randomized Phase II Study of the 
Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB-
Expressing Breast Cancer." J Clin Oncol 33(14): 1609-1619. 
Younes, A., N. L. Bartlett, et al. (2010). "Brentuximab vedotin (SGN-35) for relapsed CD30-
positive lymphomas." N Engl J Med 363(19): 1812-1821. 
 
 
 
 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 110 of 130 
 
Appendix 1: Approval Signature 
 
Approval Signature 
Protocol CDX011-05 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 111 of 130 
Appendix 2: Investigator Signature  
Investigator Signature 
Protocol CDX011-05 
I confirm that I have read this protocol, I understand it, and I will work according to this 
protocol, the applicable ICH guidelines for good clinical practices, and the applicable laws and 
regulations of the country of the study site for which I am responsible. I will accept the 
monitor's overseeing of the study. I will abide by the publication plan set forth in the protocol 
and my agreement with Celldex Therapeutics, Inc. I will promptly submit the protocol to 
applicable ethical review board(s) and will not begin the study until regulatory approval has 
been obtained. 
Instructions to the Investigator: Please SIGN and DATE this signature page and PRINT your name. Return the original, 
completed and signed page to Celldex Therapeutics, Inc., and retain a photocopy with this protocol. 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
 
 
 
 
Investigator Name (Please Print) 
 
Investigator Title 
 
 
 
 
 
 
 
 
Name of Facility 
 
Location of Facility 
 
 
[City, State (if applicable), Country] 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 1 2  of 1 3 0  
A p pe n di x 3: R E CI S T 1. 1 Crite ri a  
T o assess o bj ecti ve res p o nse or f ut ure pr o gressi o n, it is necessar y t o esti mate t he o verall t u m or b ur de n 
at baseli ne a n d use t his as a c o m parat or f or s u bse q ue nt meas ure me nts. All baseli ne e val uati o ns s h o ul d 
be  perf or me d  as  cl ose  as  p ossi ble  t o  t he  treat me nt  start  a n d  ne ver  m ore  t ha n  4  wee ks  bef ore  t he 
be gi n ni n g of t he treat me nt. T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o 
c haracterize  eac h  i de ntifie d  a n d  re p orte d  lesi o n  at  baseli ne  a n d  d uri n g  f oll o w -u p.  I ma gi n g  base d 
e val uati o n s h o ul d al wa ys be d o ne rat her t ha n cli nical e xa mi nati o n, u nless t he lesi o n(s) bei n g f oll o we d 
ca n n ot  be  i ma ge d  b ut  are assessa ble  b y  cli nical e xa m.  ( See  “ Met h o ds  of  Lesi o n  Meas ure me nt”  f or 
f urt her g ui da nce.) 
O nl y  patie nts  wit h  meas ura ble  disease  o n  baseli ne  e val uati o ns  s h o ul d  be  i ncl u de d  i n  Pr ot oc ol 
C D X 0 1 1- 0 5. Meas ura ble  disease  is  defi ne d  b y  t he  prese nce  of  at  least  o ne  meas ura ble  lesi o n   (see 
“ Meas ura bilit y  of  T u m or  at  Baseli ne”  bel o w ). At  baseli ne,  lesi o ns  s h o ul d  be  i de ntifie d  as  eit her 
“ Tar get” or “ N o n -T ar get” as f oll o ws:  
T ar get Lesi o ns :  
•  
U p t o a ma xi m u m of fi ve meas ura ble tar get lesi o ns t otal ( wit h a ma xi m u m of t w o tar get lesi o ns per 
or ga n) s h o ul d be i de ntifie d as tar get lesi o ns a n d will be rec or de d a n d meas ure d at baseli ne. ( T his 
mea ns i n i nsta nces w here patie nts ha ve o nl y o ne or  t w o or ga n sites i n v ol ve d a ma xi m u m of t w o 
a n d f o ur lesi o ns , res pecti vel y, will be rec or de d.)  
•  
T ar get lesi o ns s h o ul d be selecte d o n t he basis of t heir size (lesi o ns  wit h t he l o n gest dia meter), be 
re prese ntati ve  of  all  i n v ol ve d  or ga ns a n d  s h o ul d  be  t h ose  t ha t  le n d  t he msel ves  t o  re pr o d uci ble 
re peate d meas ure me nts. It ma y be t he case t hat, o n occasi o n, t he lar gest lesi o n d oes n ot le n d itself 
t o re pr o d uci ble meas ure me nt, i n w hic h circ u msta nce t he ne xt lar gest lesi on t hat  ca n be meas ure d 
re pr o d uci bl y s h o ul d be selecte d.  
•  
All tar get lesi o n meas ure me nts s h o ul d be rec or de d i n metric n otati o n, usi n g cali pers if cli nicall y 
assesse d.  
•  
A s u m of t he dia meters (l o n gest f or n o n -n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all tar get 
lesi o ns will be calc ulate d a n d re p orte d as t he baseli ne s u m dia meters. T he baseli ne s u m dia meters 
will be use d as refere nce t o f urt her c haracterize a n y o bjecti ve t u m or re gressi o n i n t he meas ura ble 
di me nsi o n of t he disease. See “ T u m or res p o nse e val uati o n” . 
N o n -T ar get Lesi o ns : 
•  
All ot her meas ura ble/ n o n- meas ur a ble lesi o ns ( or sites of disease) , i ncl u di n g pat h ol o gical l y m p h 
n o des , s h o ul d  be  i de ntifie d  as  n o n-tar get  lesi o ns  a n d  s h o ul d  als o  be  rec or de d  at  baseli ne.  It  is 
acce pta ble t o rec or d m ulti ple n o n -tar get lesi o ns i n v ol vi n g t he sa me or ga n as a si n gle ite m o n t he 
case re p ort f or m (e. g. ‘ m ulti ple e nlar ge d pel vic l y m p h n o des’ or ‘ m ulti ple li ver metastases’).  
•  
N o n -tar get  lesi o ns  s h o ul d  be  f oll o we d  as  ‘ prese nt’,  ‘a bse nt’,  or  i n  rare  cases  ‘ u ne q ui v ocal 
pr o gressi o n’ ( See “ T u m or res p o nse e val uati o n”). W hile s o me n o n-tar get lesi o ns ma y act uall y be 
meas ura ble, t he y nee d n ot be meas ure d a n d i nstea d s h o ul d be assesse d o nl y q ualitati vel y.  


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 1 3  of 1 3 0  
M E A S U R A BI LI T Y O F T U M O R A T B A S E LI N E  
•  
Meas ura ble :  T u m or  lesi o ns  m ust  be  acc uratel y  meas ure d  i n  at  least  o ne  di me nsi o n  (l o n gest 
dia meter i n t he pla ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m size of:  
o  1 0 m m b y C T sca n ( C T sca n slice t hic k ness n o greater t ha n 5 m m).  
o  1 0 m m cali per meas ure me nt b y cli nical e xa m (lesi o ns w hic h ca n n ot be acc uratel y meas ure d 
wit h cali pers s h o ul d b e rec or de d as n o n -meas ura ble).  
o  2 0 m m b y c hest X- ra y. 
N ote: T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, a l y m p h n o de m ust be ≥1 5 m m i n 
s h ort  a xis  w he n  assesse d  b y  C T  sca n  (f or  l y m p h  n o des,  o nl y  t he  s h ort  a xis  is  meas ure d  a n d 
f oll o we d). 
•  
N o n -meas ur a ble: N o n -meas ura ble  lesi o ns  e nc o m pass  a ll  ot her  lesi o ns,  i ncl u di n g  s mall  lesi o ns 
(l o n gest dia meter  < 1 0 m m or pat h ol o gical l y m p h n o des wit h ≥1 0 t o < 1 5 m m s h ort a xis) , as well as 
tr ul y  n o n-meas ura ble  lesi o ns.  Lesi o ns  c o nsi dere d  tr ul y  n o n -meas ura ble i ncl u de:   le pt o me ni n geal 
disease ; ascites; ple ural  or  pericar dial  eff usi o ns;  i nfla m mat or y  breast  disease; l y m p ha n gitic 
i n v ol ve me nt  of  s ki n  or  l u n g; a n d  a b d o mi nal  masses/a b d o mi nal  or ga n o me gal y  i de ntifie d  b y 
p h ysical e xa m t hat is n ot meas ura ble b y re pr o d uci ble i ma gi n g tec h ni q ues.  
S pecial c o nsi derati o ns re gar di n g lesi o n meas ura bilit y:  
•  
Mali g na nt  l y m p h  n o des : L y m p h  n o des  merit  s pecial  me nti o n  si nce  t he y  are  n or mal  a nat o mical 
str uct ures w hic h ma y be visi ble b y i ma gi n g e ve n if n ot i n v ol ve d b y t u m or. N o dal size is n or mall y 
rep orte d as t w o di me nsi o ns i n t he pla ne i n w hic h t he i ma ge is o btai ne d (f or C T sca n t his is al m ost 
al wa ys t he a xial pla ne; f or M RI t he pla ne of ac q uisiti o n ma y be a xial, sa gi ttal or c or o nal). T he 
s maller of t hese meas ures is t he s h ort a xis. At baseli ne a n d in f oll o w -u p, o nl y t he s h ort a xis will be 
meas ure d a n d f oll o we d. T o be c o nsi dere d pat h ol o gicall y  e nlar ge d a n d meas ura ble, a l y m p h n o de 
m ust be ≥1 5 m m i n s h ort a xis w he n assesse d b y C T sca n ( C T sca n slice t hic k ness rec o m me n de d t o 
be n o greater t ha n 5 m m). All  ot her pat h ol o gical n o des (t h ose wit h s h ort a xis ≥1 0 m m b ut < 1 5 m m) 
s h o ul d be c o nsi dere d n o n-tar get lesi o ns. N o des t hat ha ve a s h ort a xis < 1 0 m m are c o nsi dere d n o n-
pat h ol o gical a n d s h o ul d n ot be rec or de d or f oll o we d. 
•  
B o ne lesi o ns : B o ne sca n, P E T sca n or plain fil ms are n ot c o nsi dere d a de q uate i ma gi n g tec h ni q ues 
t o  meas ure  b o ne  lesi o ns.  H o we ver,  t hese  tec h ni q ues  ca n  be  use d  t o  c o nfir m  t he  prese nce  or 
disa p peara nce of b o ne lesi o ns. L ytic b o ne lesi o ns or mi xe d l ytic -blastic lesi o ns, wit h i de ntifia ble 
s oft tiss ue c o m p o ne nts, t hat ca n be e val uate d b y cr oss secti o nal i ma gi n g tec h ni q ues s uc h as C T or 
M RI ca n be c o nsi dere d as meas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt meets t he defi niti o n of 
meas ura bilit y , descri be d a b o ve. Blastic b o ne lesi o ns are n o n -meas ura ble.  
•  
C ystic lesi o ns: Lesi o ns t hat meet t he criteria f or ra di o gra p hicall y -defi ne d si m ple c ysts s h o ul d n ot 
be  c o nsi dere d  as  mali g na nt  lesi o ns  ( neit her  meas ura ble  n or  n o n -meas ura ble)  si nce  t he y  are,  b y 
defi niti o n, si m ple c ysts. ‘ C ystic lesi o ns’ t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d 
as meas ura ble lesi o ns, if t he y meet t he defi niti o n of meas ura bilit y , descri be d a b o ve. H o we ver, if 
n o n- c ystic lesi o ns are prese nt i n t he sa me patie nt, t hese are preferre d f or selecti o n as tar get lesi o ns.  
•  
Lesi o ns wit h p ri or l ocal treat me nt: T u m or lesi o ns sit uate d i n a pre vi o usl y irra diate d area, or i n a n 
area s u bjecte d t o ot her l oc o -re gi o nal t hera p y, are us uall y n ot c o nsi dere d meas ura ble u nless t here 
has bee n de m o nstrate d pr o gressi o n i n t he lesi o n.  


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 1 4  of 1 3 0  
M E T H O D S O F L E SI O N M E A S U R E M E N T  
•  
Cli nical e xa m : Cli nical lesi o ns will o nl y be c o nsi dere d meas ura ble w he n t he y are s u perficial a n d 
≥1 0 m m dia meter  as  assesse d  usi n g  cali pers  (e. g.  s ki n  n o d ules).  F or  t he  case  of  s ki n  lesi o ns, 
d oc u me ntati o n b y c ol or p h ot o gra p h y i ncl u di n g a r uler t o  esti mate t he size of t he lesi o n is s u g geste d. 
As  n ote d  a b o ve,  w he n  lesi o ns  ca n  be  e val uate d  b y  b ot h  cli nical  e xa m  a n d  i ma gi n g,  i ma gi n g 
e val uati o n s h o ul d be u n derta ke n si nce it is m ore o bjecti ve a n d ma y als o be re vie we d at t he e n d of 
t he st u d y. 
•  
C hest X -ra y: C hest C T is preferre d o ver c hest X-ra y, partic ularl y w he n pr o gressi o n is a n i m p orta nt 
e n d p oi nt, si nce C T is m ore se nsiti ve t ha n X-ra y, partic ularl y i n i de ntif yi n g ne w lesi o ns. H o we ver, 
lesi o ns o n c hest X-ra y ma y be c o nsi dere d meas ura ble if t he y are clearl y defi ne d a n d s urr o u n de d b y 
aerate d l u n g.  
•  
C T, M RI : C T is t he best c urre ntl y a vaila ble a n d re pr o d uci ble met h o d t o meas ure lesi o ns selecte d 
f or res p o nse assess me nt. T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T sca n base d o n 
t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. W he n C T sca ns ha ve slice t hic k ness greater 
t ha n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice t he slice t hic k ness. M RI is 
als o  acce pta ble  i n  certai n  sit uati o ns  (e. g.  f or  b o d y  sca ns).  If  t here  is  c o ncer n a b o ut  ra diati o n 
e x p os ure at C T, M RI ma y be use d i nstea d of C T i n selecte d i nsta nces.  
•  
F D G -P E T :  W hile  F D G-P E T  res p o nse  assess me nts  nee d  a d diti o nal  st u d y,  it  is  s o meti mes 
reas o na ble t o i nc or p orate t he use of F D G-P E T sca n ni n g t o c o m ple me nt C T sca n ni n g i n asses s me nt 
of pr o gressi o n. ( See “ T u m or Res p o nse E val uati o n”.) 
•  
Ultras o u n d : Ultras o u n d is n ot usef ul i n assess me nt of lesi o n size a n d s h o ul d n ot be use d as a met h o d 
of meas ure me nt. Ultras o u n d e xa mi nati o ns ca n n ot be re pr o d uce d i n t heir e ntiret y f or i n de pe n de nt 
re vie w at a later date a n d, beca use t he y are o perat or de pe n de nt, it ca n n ot be g uara ntee d t hat t he 
sa me tec h ni q ue a n d meas ure me nts will be ta ke n fr o m o ne assess me nt t o t he ne xt. If ne w lesi o ns 
are i de ntifie d b y ultras o u n d i n t he c o urse of t he st u d y, c o nfir mati o n b y C T or M RI is a d vise d.  
•  
E n d osc o p y, la par osc o p y : T he utilizati o n of t hese tec h ni q ues f or o bj ecti ve t u m or e val uati o n is n ot 
a d vise d. H o we ver, t he y ca n be usef ul t o c o nfir m c o m plete pat h ol o gical res p o nse w he n bi o psies are 
o btai ne d or t o deter mi ne rela pse  i n trials w here rec urre nce f oll o wi n g c o m plete res p o nse or s ur gical 
resecti o n is a n e n d p oi nt. 
•  
T u m or  mar kers :  T u m or  mar kers  al o ne  ca n n ot  be  use d  t o  assess  o bjecti ve  t u m or  res p o nse.  If 
mar kers are i nitiall y a b o ve t he u p per n or mal li mit, h o we ver, t he y m ust n or malize f or a patie nt t o 
be c o nsi dere d i n c o m plete res p o nse.  
•  
C yt ol o g y, hist ol o g y : T hese tec h ni q ues ca n be use d t o differe ntiate bet wee n P R a n d C R i n rare cases 
if  re q uire d  b y  pr ot oc ol  (f or  e xa m ple,  resi d ual  lesi o ns  i n  t u m or  t y pes  s uc h  as  ger m  cell  t u m ors, 
w here  k n o w n  resi d ual be ni g n  t u m ors  ca n  re mai n).  W he n  eff usi o ns  are  k n o w n  t o  be  a  p ote ntial 
a d verse effect of treat me nt (e. g. wit h certai n ta xa ne c o m p o u n ds or a n gi o ge nesis i n hi bit ors), t he 
c yt ol o gical c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n t hat a p pears or w orse ns d uri n g 
treat me nt ca n be c o nsi dere d if t he meas ura ble t u m or has met criteria f or res p o nse or sta ble disease 
i n or der t o differe ntiate bet wee n res p o nse ( or sta ble disease) a n d pr o gressi ve disease. 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 1 5  of 1 3 0  
T U M O R R E S P O N S E E V A L U A TI O N  
E v al u ati o n of t ar get lesi o ns:  
T ar get lesi o ns will be assi g ne d a n o verall res p o nse assess me nt at eac h e val uati o n ti me p oi nt acc or di n g 
t o t he f oll o wi n g defi niti o ns:  
•  
C o m plete  Res p o nse  ( C R):  Disa p peara nce  of  all  tar get  lesi o ns.  A n y  pat h ol o gical  l y m p h  n o des 
( w het her target or n o n -tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m. 
•  
P arti al Res p o nse ( P R):  At least a 3 0 % decrease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g as 
refere nce t he baseli ne s u m dia meters. 
•  
Pr o gressi ve  Dise ase ( P D):  At least a 2 0 % i ncrease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g 
as refere nce t he s mallest s u m o n st u d y (t his i ncl u des t he baseli ne s u m if t hat is t he s mallest o n 
st u d y).  I n  a d diti o n  t o  t he  relati ve  i ncrease  of  2 0 %,  t he  s u m  m ust  als o  de m o nstrate  a n  a bs ol ute 
i ncrease of at least 5 m m. ( N ote: t he a p peara nce of o ne or m ore ne w lesi o ns is als o c o nsi dere d 
pr o gressi o n). 
•  
St a ble  Dise ase  ( S D):  Neit her  s ufficie nt  s hri n ka ge  t o  q ualif y  f or  P R, n or  s ufficie nt  i ncrease  t o 
q ualif y f or P D, ta ki n g as refere nce t he s mallest s u m dia meters w hile  o n st u d y. 
S pecial n otes o n t he assess me nt of tar get lesi o ns  
•  
L y m p h n o des:  L y m p h n o d es i de ntifie d as tar get lesi o ns s h o ul d al wa ys ha ve t he act ual s h ort a xis 
meas ure me nt rec or de d ( meas ure d i n t he sa me a nat o mical pla ne as t he baseli ne e xa mi nati o n), e ve n 
if t he n o des re gress t o bel o w 1 0 m m o n st u d y. T his mea ns t hat w he n l y m p h n o des are i ncl u de d as 
tar get lesi o ns, t he ‘s u m’ of lesi o ns ma y n ot be zer o e ve n if c o m plete res p o nse criteria are met, si nce 
a n or mal l y m p h n o de is defi ne d as ha vi n g a s h ort a xis of < 1 0 m m. F or P R, S D a n d P D, t he act ual 
s h ort a xis meas ure me nt of t he n o des is t o be i ncl u de d i n t he s u m of tar get lesi o ns. 
•  
T ar get lesi o ns t hat  bec o me  ‘t o o s mall t o  meas ure’:  W hile  o n st u d y,  all lesi o ns  ( n o dal  a n d  n o n -
n o dal) rec or de d at baseli ne s h o ul d ha ve t heir ac t ual meas ure me nts rec or de d at eac h s u bse q ue nt 
e val uati o n, e ve n w he n ver y s mall (e. g. 2 m m). H o we ver, s o meti mes lesi o ns or l y m p h n o des t hat are 
rec or de d as tar get lesi o ns at baseli ne bec o me s o fai nt o n C T sca n t hat t he ra di ol o gist ma y n ot feel 
c o mf orta ble  assi g ni n g  a n  e xact  meas ure  a n d  ma y  re p ort  t he m  as  bei n g  ‘t o o  s mall  t o  meas ure’. 
W he n t his occ urs it is i m p orta nt t hat a val ue be rec or de d o n t he case re p ort f or m. If it is t he o pi ni o n 
of t he ra di ol o gist t hat t he lesi o n has li kel y disa p peare d, t he meas ure me nt  s h o ul d be rec or de d as 
0 m m. If t he lesi o n is belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ult 
val ue of 5 m m s h o ul d be assi g ne d.  ( N ote: It is less li kel y t hat t his r ule will be use d f or l y m p h n o des 
si nce t he y us uall y ha ve a defina ble size w he n n or mal a n d are fre q ue ntl y s urr o u n de d b y fat s uc h as 
i n t he retr o perit o ne u m; h o we ver, if a l y m p h n o de is belie ve d t o be prese nt a n d is fai ntl y see n b ut 
t o o s mall t o meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d i n t his circ u msta nce as well). T his 
defa ult val ue is deri ve d fr o m t he 5 m m C T slice t hic k ness ( b ut s h o ul d n ot be c ha n ge d wit h var yi n g 
C T slice t hic k ness). T he meas ure me nt of t hese lesi o ns is p ote ntiall y n o n -re pr o d uci ble, t heref ore 
pr o vi di n g t his defa ult val ue will pre ve nt false res p o nses or pr o gressi o ns base d u p o n meas ure me nt 
err or. T o reiterate, h o we ver, if t he ra di ol o gist is a ble t o pr o vi de a n act ual meas ure, t hat s h o ul d be 
rec or de d, e ve n if it is bel o w 5 m m. 
•  
Lesi o ns  t hat  s plit  or  c oalesce  o n  treat me nt .  W he n  n o n-n o dal  lesi o ns  ‘fra g me nt’,  t he  l o n gest 
dia meters of t he fra g me nte d p orti o ns s h o ul d be a d de d t o get her t o calc ulate t he tar get lesi o n s u m. 
Si milarl y, as lesi o ns c oalesce, a pla ne bet wee n t he m ma y be mai ntai ne d t hat w o ul d ai d i n o btai ni n g 
ma xi mal dia meter meas ure me nts of eac h i n di vi d ual lesi o n. If t he lesi o ns ha ve tr ul y c oalesce d s uc h 
t hat t he y are n o l o n ger se para ble, t he vect or of t he l o n gest dia meter i n t his i nsta nce s h o ul d be t he 
ma xi mal l o n gest dia meter f or t he ‘c oalesce d lesi o n’.  


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 1 6  of 1 3 0  
E v al u ati o n of n o n- t ar get lesi o ns: 
N o n -tar get lesi o ns  will  be  assi g ne d  a n  o verall  res p o nse  assess me nt  at  eac h  e val uati o n  ti me  p oi nt 
acc or di n g t o t he f oll o wi n g defi niti o ns: 
•  
C o m plete  Res p o nse  ( C R):  Disa p peara nce  of  all  n o n -tar get  lesi o ns  a n d  n or malizati o n  of  t u m or 
mar ker le vel. All l y m p h n o des m ust be n o n - pat h ol o gical i n size ( < 1 0 m m s h ort a xis). 
•  
N o n -C R/ N o n -P D:  Persiste nce  of  o ne  or  m ore  n o n -tar get  lesi o n(s)  a n d/ or  mai nte na nce  of  t u m or 
mar ker le vel a b o ve t he n or mal li mits.  
•  
Pr o gressive Dise ase ( P D):  U ne q ui v ocal pr o gressi o n (see c o m me nts bel o w) of e xisti n g n o n -tar get 
lesi o ns. ( N ote: t he a p peara nce of o ne or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n). 
S pecial n otes o n assess me nt of pr o gressi o n of n o n -tar get disease: 
•  
W he n t he patie nt als o has meas ura ble disease: I n t his setti n g, t o ac hie ve ‘ u ne q ui v ocal  pr o gressi o n’ 
o n t he basis of t he n o n -tar get disease, t here m ust be a n o verall le vel of s u bsta ntial w orse ni n g i n 
n o n- tar get  disease s uc h t hat,  e ve n  i n  prese nce  of  S D  or  P R  i n  tar get  disease, t he  o verall  t u m or 
b ur de n has i ncrease d s ufficie ntl y t o merit disc o nti n uati o n of t hera p y (see f urt her details bel o w). A 
m o dest ‘i ncrease’ i n t he size of o ne or m ore n o n -tar get lesi o ns is us uall y n ot s ufficie nt t o q ualit y 
f or u ne q ui v ocal pr o gressi o n stat us. T he desi g nati o n of o verall pr o gressi o n s olel y o n t he basis of 
c han ge i n n o n -tar get disease i n t he face of S D or P R of tar get disease will t heref ore be e xtre mel y 
rare. 
•  
W he n t he patie nt has o nl y n o n -meas ura ble disease:  T he sa me ge neral c o nce pts a p pl y here as n ote d 
a b o ve,  h o we ver,  i n  t his  i nsta nce  t here  is  n o  meas ura ble  disease  assess me nt  t o  fact or  i nt o  t he 
i nter pretati o n of a n i ncrease i n n o n-meas ura ble disease b ur de n. Beca use w orse ni n g i n n o n -tar get 
disease ca n n ot be easil y q ua ntifie d ( b y defi niti o n: if all lesi o ns are tr ul y n o n -meas ura ble) a usef ul 
test t hat ca n be a p plie d w he n assessi n g patie nts f or u ne q ui v ocal pr o gressi o n is t o c o nsi der if t he 
i ncrease i n o verall disease b ur de n base d o n t he c ha n ge i n n o n-meas ura ble disease is c o m para ble i n 
ma g nit u de t o t he i ncrease t hat w o ul d be re q uire d t o declare P D f or meas ura ble dis ease:  i.e.,  a n 
i ncrease i n t u m or b ur de n re prese nti n g a n a d diti o nal 7 3 % i ncrease i n ‘ v ol u me’ ( w hic h is e q ui vale nt 
t o  a  2 0 %  i ncrease  dia meter  i n  a  meas ura ble  lesi o n).  E xa m ples  i ncl u de  a n  i ncrease  i n  a  ple ural 
eff usi o n fr o m ‘trace’ t o ‘lar ge’, a n i ncrease i n l y m p ha n gitic disease fr o m l ocalize d t o wi des prea d, 
or  ma y  be  descri be d  i n  pr ot oc ols as ‘s ufficie nt  t o  re q uire  a c ha n ge  i n  t hera p y’.  If  ‘ u ne q ui v ocal 
pr o gressi o n’ is see n, t he patie nt s h o ul d be c o nsi dere d t o ha ve ha d o verall P D at t hat p oi nt. W hile it 
w o ul d be i deal t o ha ve o bjecti ve criteria t o a p pl y t o n o n -meas ura ble disease, t he ver y nat ure of t hat 
disease ma kes it i m p ossi ble t o d o s o, t heref ore t he i ncrease m ust be s u bsta ntial.  
Ne w lesi o ns:  
T he a p peara nce of ne w mali g na nt lesi o ns de n otes disease pr o gressi o n; t heref ore, s o me c o m me nts o n 
detecti o n of ne w lesi o ns are i m p orta nt.  
•  
T here are n o s pecific criteria f or t he i de ntificati o n of ne w ra di o gra p hic lesi o ns; h o we ver, t he fi n di n g 
of a ne w lesi o n s h o ul d be u ne q ui v ocal: i.e. n ot attri b uta ble t o differe nces i n sca n ni n g tec h ni q ue, 
c ha n ge  i n  i ma gi n g  m o dalit y  or  fi n di n gs  t h o u g ht  t o  re prese nt  s o met hi n g  ot her  t ha n  t u m or  (f or 
e xa m ple, s o me ‘ ne w’ b o ne lesi o ns ma y be si m pl y heali n g or flare of pre -e xisti n g lesi o ns). T his is 
partic ularl y i m p orta nt w he n t he patie nt’s base li ne lesi o ns s h o w partial or c o m plete res p o nse. F or 
e xa m ple, necr osis of a li ver lesi o n ma y be re p orte d o n a C T sca n re p ort as a ‘ ne w’ c ystic lesi o n, 
w hic h it i s n ot. 
•  
A lesi o n i de ntifie d o n a f oll o w -u p st u d y i n a n a nat o mical l ocati o n t hat was n ot sca n ne d a t baseli ne 
is c o nsi dere d a ne w lesi o n a n d will i n dicate disease pr o gressi o n. A n e xa m ple of t his is t he patie nt 
w h o has visceral disease at baseli ne a n d w hile o n st u d y has a C T or M RI brai n or dere d t hat re veals 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 1 7  of 1 3 0  
metastases. T he patie nt’s brai n metastases are  c o nsi dere d t o be e vi de nce of P D e ve n if he/s he di d 
n ot ha ve brai n i ma gi n g at baseli ne.  
•  
If a ne w lesi o n is e q ui v ocal, f or e xa m ple beca use of its s mall size, c o nti n ue d t hera p y a n d f oll o w-
u p e val uati o n will clarif y if it re prese nts tr ul y ne w disease. If re peat sca ns c o nfir m t here is defi nitel y 
a ne w lesi o n, t he n pr o gressi o n s h o ul d be declare d usi n g t he date of t he i nitial sca n. 
•  
W hile  F D G -P E T  res p o nse  assess me nts  nee d  a d diti o nal  st u d y,  it  is  s o meti mes  reas o na ble  t o 
i nc or p orate  t he  use  of  F D G-P E T  sca n ni n g  t o  c o m ple me nt  C T  sca n ni n g  i n  assess me nt  of 
pr o gressi o n ( partic ularl y p ossi ble ‘ ne w’ disease). Ne w lesi o ns o n t he basis of F D G -P E T i ma gi n g 
ca n be i de ntifie d acc or di n g t o t he f oll o wi n g al g orit h m:  
a. Ne gati ve F D G -P E T at baseli ne, wit h a p ositi ve F D G -P E T at f oll o w- u p is a si g n of P D base d 
o n a ne w lesi o n. ( A ‘ p ositi ve’ F D G -P E T sca n lesi o n mea ns o ne w hic h is F D G a vi d wit h a n 
u pta ke greater t ha n t wice t hat of t he s urr o u n di n g tiss ue o n t he atte n uati o n c orrecte d i ma ge.)  
b.  N o F D G -P E T at baseli ne a n d a p ositi ve F D G -P E T at f oll o w -u p: If t he p ositi ve F D G -P E T at 
f oll o w-u p c orres p o n ds t o a ne w site of disease c o nfir me d b y C T, t his is P D. If t he p ositi ve 
F D G -P E T at f oll o w -u p is n ot c o nfir me d as a ne w site of disease o n C T, a d diti o nal f oll o w - u p 
C T sca ns are nee de d t o deter mi ne if t here is tr ul y pr o gressi o n occ urri n g at t hat site (if s o, t he 
date of P D will be t he date of t he i nitial a b n or mal F D G -P E T sca n). If t he p ositi ve F D G -P E T 
at f oll o w-u p c orres p o n ds t o a pre -e xisti n g site of disease o n C T t hat is n ot pr o gressi n g o n t he 
b asis of t he a nat o mic i ma ges, t his is n ot P D.  
E v al u ati o n of o ver all res p o nse: 
It is ass u me d t hat at eac h pr ot oc ol s pecifie d ti me p oi nt, a n o verall res p o nse assess me nt occ urs. T he 
patie nt’s o verall res p o nse assi g n me nt will de pe n d o n t he fi n di n gs of b ot h tar get a n d n o n -tar get disease 
a n d will als o ta ke i nt o c o nsi derati o n t he a p peara nce of ne w lesi o ns.  
A p pe n di x  3  T a ble  1 . Sc he d ule  of  Assess me nts  pr o vi des  a  s u m mar y  of  t he  o verall  res p o nse  stat us 
calc ulati o n at eac h ti me p oi nt f o r patie nts w h o ha ve meas ura ble disease at baseli ne. W he n patie nts ha ve 
n o n- meas ura ble (t heref ore, n o n -tar get) disease o nl y, A p pe n di x 3 T a ble 2 . O utc o mes f or Metastatic or 
L ocall y A d va nce d Mela n o ma Patie nts Treate d wit h A p pr o ve d T ar gete d T hera pies is t o be use d.  
S pecial n otes o n e val uati o n of o verall res p o nse:  
•  
Missi n g assess me nts a n d i ne val ua ble desi g nati o n:  
o  W he n  n o  i ma gi n g/ meas ure me nt  is  d o ne  at  all  at  a  partic ular  ti me  p oi nt,  t he  patie nt  is  n ot 
e val ua ble ( N E) at t hat ti me  p oi nt. 
o  If o nl y a s u bset of lesi o n meas ure me nts are ma de at a n assess me nt, us uall y t he case is als o 
c o nsi dere d  N E  at  t hat  ti me  p oi nt,  u nless  a  c o n vi nci n g  ar g u me nt  ca n  be  ma de  t hat  t he 
c o ntri b uti o n  of  t he  i n di vi d ual  missi n g  lesi o n(s)  w o ul d  n ot  c ha n ge  t he  as si g ne d  ti me  p oi nt 
res p o nse. T his w o ul d be m ost li kel y t o ha p pe n i n t he case of P D. F or e xa m ple, if a patie nt ha d 
a baseli ne s u m of 5 0 m m wit h t hree meas ure d lesi o ns a n d at f oll o w -u p o nl y t w o lesi o ns were 
assesse d, b ut t h ose ga ve a s u m of 8 0 m m, t he patie nt will ha ve ac hie ve d P D stat us, re gar dless 
of t he c o ntri b uti o n of t he missi n g lesi o n. 
•  
‘ S y m pt o matic  deteri orati o n’:  Patie nts  wit h  a  gl o bal  deteri orati o n  of  healt h  stat us  re q uiri n g 
disc o nti n uati o n of treat me nt wit h o ut o bjecti ve e vi de nce of disease pr o gressi o n at t hat ti me s h o ul d 
be re p orte d as ‘s y m pt o matic deteri orati o n’. E ver y eff ort s h o ul d be ma de t o d oc u me nt o bj ecti ve 
pr o gressi o n e ve n after disc o nti n uati o n of treat me nt. S y m pt o matic deteri orati o n is n ot a descri pt or 
of a n o bjecti ve res p o nse: it is a reas o n f o r st o p pi n g st u d y t hera p y. T he o bjecti ve res p o nse stat us of 
s uc h  patie nts  is  t o  be  deter mi ne d  b y  e val uati o n  of  tar get  a n d  n o n-tar get  disease  as  s h o w n  i n 
A p pe n di x 3 T a ble 1  a n d A p pe n di x 3 T a ble  2. 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 1 8  of 1 3 0  
•  
I n s o me circ u msta nces it ma y be diffic ult t o disti n g uis h resi d ual disease fr o m n or mal tiss ue. W he n 
t he e val uati o n of c o m plete res p o nse de pe n ds u p o n t his deter mi nati o n, it is rec o m me n de d t hat t he 
resi d ual lesi o n be i n vesti gate d (fi ne nee dle as pirate/ bio ps y) bef ore assi g ni n g a stat us of c o m plete 
res p o nse. F D G- P E T ma y b e use d t o u p gra de a res p o nse t o a C R i n a ma n ner si milar t o a bi o ps y i n 
cases w here a resi d ual ra di o gra p hic a b n or malit y  is t h o u g ht t o re prese nt fi br osis or scarri n g. 
•  
F or e q ui v ocal fi n di n gs of pr o gressi o n (e. g. ver y s mall a n d u ncertai n ne w lesi o ns; c ystic c ha n ges or 
necr osis i n e xisti n g lesi o ns), treat me nt ma y c o nti n ue u ntil t he ne xt sc he d ule d assess me nt. If at t he 
ne xt sc he d ule d assess me nt, pr o gressi o n is c o nfir me d, t he date of pr o gressi o n s h o ul d be t he earlier 
date w he n pr o gressi o n was s us pecte d.  
•  
C o nfir mati o n of res p o nse: I n t he e ve nt of c o m plete or partial res p o nses, eff orts s h o ul d be ma de t o 
o btai n a c o nfir mat or y sca n ( n o s o o ner t ha n 2 8 da ys later). 
 
A p pe n di x 3 T a ble 1: O ver all res p o nse: p atie nts wit h t ar get +/ – n o n -t ar get dise ase. 
T ar get lesi o ns   
N o n -tar get lesi o ns  
Ne w lesi o ns  
O verall res p o nse  
C R  
C R  
N o  
C R  
C R  
N o n -C R/ n o n -P D  
N o  
P R  
C R  
N ot e val uate d  
N o  
P R  
P R  
N o n -P D or n ot all e val uate d  
N o  
P R  
S D  
N o n -P D or n ot all e val uate d  
N o  
S D  
N ot all e val uate d  
N o n -P D  
N o  
N E  
P D  
A n y  
Yes or N o  
P D  
A n y  
P D  
Yes or N o  
P D  
A n y  
A n y  
Yes  
P D  
C R = c o m plete res p o nse, P R = p artial res p o nse, S D = sta ble disease, P D = pr o gressi ve diseas e, a n d N E = 
i ne val ua ble. 
 
A p pe n di x 3 T a ble 2 : O ver all res po nse: p atie nts wit h n o n -t ar get dise ase o nl y. 
N o n -tar get lesi o ns  
Ne w lesi o ns  
O verall res p o nse  
C R  
N o  
C R  
N o n -C R/ n o n -P D  
N o  
N o n -C R/ n o n -P D a 
N ot all e val uate d  
N o  
N E  
U ne q ui v ocal P D  
Yes or N o  
P D  
A n y  
Yes  
P D  
C R = c o m plete res p o nse, P D = pr o gressi ve  diseas e, a n d N E = i ne val u a ble 
a ‘ N o n- C R/ n o n-P D’ is preferre d o ver ‘sta ble disease’ f or n o n -tar get disease si n ce S D is i n creasi n gl y use d as 
e n d p oi nt f or assess me nt of effica c y i n s o me trials s o t o assi g n t his cate g or y w h e n n o lesi o ns ca n b e meas ure d is n ot  
a d vise d. 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 119 of 130 
FREQUENTLY ASKED QUESTIONS 
What should be done if several unique lesions at baseline become confluent at a follow-up 
evaluation? 
Measure the longest diameter of the confluent mass and record to add into the sum of the longest 
diameters. 
How large does a new lesion have to be to count as progression? Does any small sub-centimeter 
lesion qualify, or should the lesion be at least measurable? 
New lesions do not need to meet ‘measurability criteria’ to be considered valid. If it is clear on previous 
images (with the same technique) that a lesion was absent then its definitive appearance implies 
progression. If there is any doubt (because of the techniques or conditions) then it is suggested that 
treatment continue until next scheduled assessment when, generally, all should be clear. Either it gets 
bigger and the date of progression is the date of the first suspicion, or it disappears and one may then 
consider it an artifact with the support of the radiologists. 
How should one lesion be measured if on subsequent exams it is split into two? 
Measure the longest diameter of each lesion and add this into the sum.  
Does the definition of progression depend on the status of all target lesions or only one? 
As per the RECIST 1.1 guideline, progression requires a 20% increase in the sum of diameters of all 
target lesions AND a minimum absolute increase of 5 mm in the sum.  
What is the criterion for a measurable lesion if the CT slice thickness is >5 mm? 
RECIST 1.1 recommends that CT scans have a maximum slice thickness of 5 mm and the minimum 
size for a measurable lesion is twice that: 10 mm (even if slice thickness is <5 mm). If scanners with 
slice thickness >5 mm are used, the minimum lesion size must have a longest diameter twice the actual 
slice thickness. 
What should we record when target lesions become so small they are below the 10 mm 
‘measurable’ size? 
Target lesion measurability is defined at baseline. Thereafter, actual measurements, even if <10 mm, 
should be recorded. If lesions become very small, some radiologists indicate they are ‘too small to 
measure’. This guideline advises that when this occurs, if the lesion is actually still present, a default 
measurement of 5 mm should be applied. If in fact the radiologist believes the lesion has gone, a default 
measurement of 0 mm should be recorded. 
If a patient has several lesions which have decreased in size to meet PR criteria and one has 
actually disappeared, does that patient have PD if the ‘disappeared’ lesion reappears? 
Unless the sum meets the PD criteria, the reappearance of a lesion in the setting of PR (or SD) is not 
PD. The lesion should simply be added into the sum. If the patients had had a CR, clearly reappearance 
of an absent lesion would qualify for PD. 
When measuring the longest diameter of target lesions in response to treatment, is the same axis 
that was used initially used subsequently, even if there is a shape change to the lesion that may 
have produced a new longest diameter? 
The longest diameter of the lesion should always be measured even if the actual axis is different from 
the one used to measure the lesion initially (or at different time point during follow-up). The only 
exception to this is lymph nodes: as per RECIST 1.1 the short axis should always be followed and as 
in the case of target lesions, the vector of the short axis may change on follow-up. 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 120 of 130 
Target lesions have been selected at baseline and followed but then one of these target lesions 
then becomes non-evaluable (i.e. different technique used). What is the effect this has on the other 
target lesions and the overall response? 
What may be done in such cases is one of the following:  
(a) If the patient is still being treated, call the center to be sure that future evaluations are done with the 
baseline technique so at least SOME courses are fully evaluable 
(b) If that is not possible, check if there IS a baseline exam by the same technique which was used to 
follow patients, in which case if you retrieve the baseline measures from that technique you will also 
retrieve the lesion’s ability to be evaluated.  
(c) If neither (a) nor (b) is possible then it is a judgment call about whether you delete the lesion from 
all forms or consider the impact of the lesion overall is so important that its status of being non-
evaluable makes the overall response interpretation in-evaluable without it. Such a decision should be 
discussed in a review panel.  
It is NOT recommended that the lesion be included in baseline sums and then excluded from follow-
up sums since this biases in favor of a response. 
What if a single non-target lesion cannot be reviewed, for whatever reason; does this negate the 
overall assessment? 
Sometimes the major contribution of a single non-target lesion may be in the setting of CR having 
otherwise been achieved: failure to examine one non-target in that setting will leave you unable to claim 
CR. It is also possible that the non-target lesion has undergone such substantial progression that it would 
override the target disease and render patient PD. However, this is very unlikely, especially if the rest 
of the measurable disease is stable or responding. 
A patient has a 32% decrease in sum cycle 2, a 28% decrease cycle 4 and a 33% decrease cycle 6. 
Does confirmation of PR have to take place in sequential scans or is a case like this confirmed 
PR? 
It is not infrequent that tumor shrinkage hovers around the 30% mark. In this case, most would consider 
PR to have been confirmed looking at this overall case. Had there been two or three non-PR 
observations between the two time point PR responses, the most conservative approach would be to 
consider this case SD. 
A patient has a lesion measurable by clinical exam and by CT scan. Which should be followed? 
CT scan. Always follow by imaging if that option exists since it can be reviewed and verified. 
A lesion which was solid at baseline has become necrotic in the center. How should this be 
measured? 
The longest diameter of the entire lesion should be followed. Eventually, necrotic lesions which are 
responding to treatment decrease in size. In reporting the results of trials, you may wish to report on 
this phenomenon if it is seen frequently since some agents (e.g. angiogenesis inhibitors) may produce 
this effect.  
If I am going to use MRI to follow disease, what is minimum size for measurability? 
MRI may be substituted for contrast enhanced CT for some sites, but not lung. The minimum size for 
measurability is the same as for CT (10 mm) as long as the scans are performed with slice thickness of 
5mm and no gap. In the event the MRI is performed with thicker slices, the size of a measurable lesion 
at baseline should be two times the slice thickness. In the event there are inter-slice gaps, this also needs 
to be considered in determining the size of measurable lesions at baseline. 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 121 of 130 
 
Can PET–CT be used with RECIST?  
At present, the low dose or attenuation correction CT portion of a combined PET–CT is not always of 
optimal diagnostic CT quality for use with RECIST measurements. However, if your site has 
documented that the CT performed as part of a PET–CT is of the same diagnostic quality as a diagnostic 
CT (with IV and oral contrast) then the PET–CT can be used for RECIST measurements. Note, 
however, that the PET portion of the CT introduces additional data which may bias an investigator if it 
is not routinely or serially performed. 
 
Adapted from Eisenhower 2009 (Eisenhauer, Therasse et al. 2009) 
 
 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 122 of 130 
Appendix 4: ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair. 
5 
Dead 
* As published in Am. J. Clin. Oncol (Oken, Creech et al. 1982)  
 
 
 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 123 of 130 
Appendix 5: Cockroft and Gault Equation 
 
(140 - age [yrs]) (body wt [kg]) 
Creatinine clearance for males =  
————————————— 
(72) (serum creatinine [mg/dL]) 
 
Creatinine clearance for females = 0.85 x male value 
 
 
 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 124 of 130 
 
Appendix 6: Approved and/or Investigational Immune-Directed 
and Molecularly Targeted Drugs used with Advanced Melanoma 
Product Name 
Mechanism of Action 
Molecular Target 
Approved Products 
IPILIMUMAB 
(Yervoy) 
 
Checkpoint inhibitor 
 
CTLA-4 
NIVOLUMAB  
(Opdivo) 
Checkpoint inhibitor 
PD-1 
PEMBROLIZUMAB  
(Keytruda) 
Checkpoint inhibitor 
PD-1 
VEMURAFENIB (Zelboraf) 
 
Kinase inhibitor 
BRAF oncogene 
(V600E mutation) 
DABRAFENIB (Tafinlar) 
 
Kinase inhibitor 
BRAF oncogene 
 
TRAMETINIB (Mekinist) 
 
Kinase inhibitor 
MEK 1/2 (MAP-ERK signaling 
pathway) 
SORAFENIB 
(Nexavar) 
Kinase inhibitor 
Multiple pathways including 
BRAF/MEK/ERK 
Investigational Products 
ATEZOLIZUMAB 
(MPDL3280A) 
Checkpoint inhibitor 
PD-L1  
(PD-1 ligand) 
MDX-1105 
Checkpoint inhibitor 
PD-L1 
(PD-1 ligand) 
AMPLIMMUNE 
(AMP-224) 
Checkpoint inhibitor 
PD-1 
LCX818 
Kinase inhibitor 
BRAF oncogene 
MEK162 
Kinase inhibitor 
MEK 1/2 (MAP-ERK signaling 
pathway) 
SELUMETINIB  
(AZD6244) 
Kinase inhibitor 
MEK 1/2 (MAP-ERK signaling 
pathway) 
PIMASERTIB 
(MSC1936369B) 
Kinase inhibitor 
MEK 1/2 (MAP-ERK signaling 
pathway) 
 
NB: Several additional investigational drugs are in early clinical development and are not listed here. Please  
check with the medical monitor and clinicaltrials.gov for further information on the mechanism of action of 
other investigative agents relevant for patients with advanced melanoma.  
 
 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 2 5  of 1 3 0  
A p pe n di x 7: S u m m ar y of C h a n ges  
T he f oll o wi n g c ha n ges ha ve bee n ma de t o Pr ot oc ol C D X 0 1 1- 0 5 as A me n d me nt 4: 
S E C TI O N( S)  
C H A N G E/ R A TI O N A L E  
2 Gl ossar y of A b bre viati o ns  
3 S y n o psis  
4 Sc he d ule of Assess me nts  
5. 5 C D X -3 0 1  
5. 6 St u d y Rati o nale  
6 St u d y O bj ec ti ves 
7 I n vesti gati o nal Pla n  
7. 1 O verall Desi g n a n d Pla n of t he St u d y  
7. 2 N u m ber of P atie nts  
7. 2. 2. 1 I ncl usi o n Criteria  
7. 2. 2. 2 E xcl usi o n Criteria  
7. 2. 4 Wit h dra wals a n d Re plac e me nt of P atie nts  
7. 2. 5 C o m pleti o n of St u d y  
8 St u d y Treat me nt  
8. 5 C D X -3 0 1  
8. 6 D os e M o dificati o ns  
8. 6. 4 C D X -3 0 1  
8. 7 Treat me nt -Li miti n g T o xicit y  
8. 8 P ote ntial T o xicit y a n d Ma na ge me nt of T o xicit y  
8. 9 Acc o u nta bilit y  
8. 1 0 C o m plia nce  
9 C o nc o mita nt T hera p y  
9. 4 C D X -3 0 1  
1 0 St u d y Pr oce d ures  
1 0. 1. 2 St u d y E nr oll me nt  
1 0. 2. 1. 2 I m m u n o ge nicit y  
1 0. 2. 1. 3 P har mac o ki netic E val uati o ns  
1 0. 2. 1. 4 P har mac o d y na mics  
1 0. 2. 2. 3 A E/ S A E Re p orti n g  
1 0. 2. 2. 4 Ra pi d N otificati o n of A d verse E ve nts of 
I nterest 
1 1 Statistical C o nsi derati o ns  
1 1. 1 A nal ysis E n d p oi nts  
1 1. 2 Sa m ple Size a n d P o wer Calc ulati o n  
1 1. 4. 1 a n d 1 1. 5. 1 Efficac y A nal ysis  
1 5 Refere nces  
A d de d C o h orts 4 a n d 5 f or t he c o m bi nati o n of 
gle m bat u m u ma b ve d oti n a n d C D X -3 0 1 +/ - P D -1 
tar gete d C PI base d o n t he rati o nale t hat c o m bi ni n g 
c yt ot o xic t hera p y wit h i m m u n ot hera p y ma y i n d uce 
a n i m m u ne res p o nse a n d i m pr o ve a nti -t u m or 
acti vit y. T hese ne w c o h orts res ult i n t he f oll o wi n g 
c ha n ges:  
•  
I ncl u de d C D X-3 0 1 as a d diti o nal t hera p y  
•  
I ncrease d t he n u m ber of patie nts i n st u d y o verall 
•  
I ncl u de d C D X-3 0 1 +/ - C PI i n st u d y o bj ecti ves  
•  
O ver vie w of st u d y desi g n  
•  
A d de d t o T L T criteria 
•  
Re vise d eli gi bilit y criteria i ncl u di n g:  
o  
I ncl usi o n # 5c, a d de d t hat all patie nts i n 
c o h orts 4 a n d 5 m ust s u b mit a ma n dat or y 
pre -e ntr y a n d o n-treat me nt bi o ps y u ntil 
f urt her data is n ot nee de d  
o  
E xcl usi o n # 2 4, a d de d wi n d o w f or 
vacci nati o ns pri or t o st u d y e ntr y f or 
c o h orts 4 a n d 5  
•  
Criteria  f or  e val uati o n  i ncl u des  C D X -3 0 1, 
C o h orts 4 a n d 5  
•  
Statistical met h o ds  
•  
Secti o n  4:  ne w  T a ble  2  o n  sc he d ule  of  st u d y 
pr oce d ures f or C o h orts 4 a n d 5  
•  
Secti o n 5. 5: ne w secti o n o n C D X -3 0 1  
•  
Secti o n  7. 2. 5:  st u d y  c o m pleti o n  re vise d  t o  5 4 
m o nt hs  
•  
Secti o n  8. 5:  ne w  secti o n  o n  C D X -3 0 1  dr u g 
pr o d uct, st ora ge, pre parati o n a n d a d mi nistrati o n  
•  
Secti o n  8. 6. 4:  ne w  secti o n  o n  C D X -3 0 1  d ose 
m o dificati o ns  
•  
Secti o n  9. 4:  ne w  secti o n  o n  
C D X -3 0 1 
c o nc o mita nt t hera p y  
3 S y n o psis  
7. 1 O verall Desi g n a n d Pla n of t he St u d y  
7. 2. 4 Wit h dra wals a n d Re plac e me nt of P atie nts  
1 1. 4. 1 Efficac y A nal ysis  
Defi ne d res p o nse -e val ua ble p o p ulati o n f or 
clarificati o n  
4 Sc he d ule of Assess me nts, T a bles 1 a n d 2, f o ot n ote 2 3  
8. 6. 3 P D -1 T ar gete d C hec k p oi nt I n hi bit or  
All o we d f or u p t o  2 -3 d oses of misse d C PI pri or t o 
st u d y e ntr y t o e n ha nce e nr olle d 
5. 2. 3 Gle m bat u m u ma b Ve d oti n: Cli nical S u m mar y  
U p date d n u m ber of patie nts tr eate d  
8. 1. 1 Descri pti o n, P ac ka gi n g, a n d La beli n g  
A d de d descri pti o n of t he dr u g pr o d uct f or refere nce  
8. 3 Ni v ol u m a b a n d 8. 4 P e m br oliz u ma b  
U p date d dates of t he m ost rec e nt pac ka ge i nserts  
1 4 P u blicati o n P olic y  
Re vise d t o i ncl u de I C MJ E criteria a n d G P P 
pri nci ples  
A p pe n di x 1 A p pr o val Si g nat ure  
A p pr o ver c ha n ge d d ue t o de part ure of C M O  
T hr o u g h o ut  
T y p o gra p hical c orrecti o ns a n d f or matti n g 
a dj ust me nts  


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 2 6  of 1 3 0  
T he f oll o wi n g c ha n ges ha ve bee n ma de t o Pr ot oc ol C D X 0 1 1- 0 5 as A me n d me nt 3: 
S E C TI O N( S)  
C H A N G E/ R A TI O N A L E  
C o ver pa ge  
3 S y n o psis  
5 B ac k gr o u n d/ Rati o nale  
5. 4 P D -1 T ar gete d C hec k p oi nt 
I n hi bit or 
5. 5. 3 Rati o nale f or P er mitti n g 
C o nti n ue d Treat me nt i n Cases of 
A p pare nt Pr o gressi ve Disease  
6 St u d y O bj ecti ves  
7 I n vesti gati o nal Pla n  
7. 1 O verall Desi g n a n d  Pla n of t he 
St u d y  
7. 2 N u m ber of P atie nts  
7. 2. 2 . 1 I ncl usi o n Criteria 
7. 2. 2. 2 E xcl usi o n Criteria  
7. 2. 4 Wit h dra wals a n d Re plac e me nt 
of P at ie nts 
7. 2. 5 C o m pleti o n of St u d y  
8 St u d y Treat me nt  
8. 5. 3 P D -1 T ar gete d C PI  
8. 7 P ote ntial T o xicit y a n d 
Ma na ge me nt of T o xicit y  
8. 8 Acc o u nta bilit y  
1 0. 2. 2. 3 A E/ S A E Re p orti n g  
1 0. 2. 2. 4 Ra pi d N otificati o n of 
A d verse E ve nts  
A d de d C o h ort 3 f or t he c o m bi nati o n  of gle m bat u m u ma b ve d ot i n a n d 
P D -1 tar gete d c hec k p oi nt i n hi bit or ( C PI) base d o n t he rati o nale t hat 
c o m bi ni n g c yt ot o xic t hera p y wit h i m m u n ot hera p y ma y i n d uce  a n 
i m m u ne res p o nse a n d i m pr o ve d a nti-t u m or acti vit y. T his ne w c o h ort 
res ults i n t he f oll o wi n g c ha n ges 
•  
St u d y title  
•  
I ncl u de d  ni v ol u ma b  a n d  pe m br oliz u ma b  as  a d diti o nal 
t hera pies 
•  
I ncrease d t he n u m ber of patie nts i n st u d y o verall 
•  
I ncl u de d P D-1 tar gete d t hera p y i n st u d y o bj ecti ves  
•  
A d de d treat me nt -li miti n g t o xi cit y r ule 
•  
Re vise d eli gi bilit y criteria:  
o  
I ncl usi o n  # 3,  a d de d 
“ F or  C o h ort  3,  pr o gressi o n 
(c onfir me d  fr o m  t w o  sc a ns  at  le ast  4  weeks  a p art) m ust 
h ave  occ urre d  d uri n g t he P D -1  t ar gete d  C PI  tre at me nt 
a n d t he i nvesti g at or h as dee me d it a p pr o pri ate t o c o nti n ue 
t o tre at bey o n d c o nfir me d dise ase pr o gressi o n. ”  
o  
I ncl usi o n  #4,  a d de d “ F or  C o h ort  3,  pri or  tre at me nt 
receive d m ust i ncl u de P D-1 t ar gete d C PI  (i.e., niv ol u m a b 
or  pe m br oliz u m a b)  a d mi nistere d  d uri n g  t he  m ost  rece nt 
dise ase  pr o gressi o n  a n d  f or  p atie nts  wit h  a  B R A F 
m ut ati o n,  at  le ast  o ne  B R A F - or  M E K -t ar gete d  t her a py 
w he n a p pr o pri ate. ”  
o  
I ncl usi o n # 5, i ncl u de d s ki nf ol d bi o ps y f or t his c o h ort; f or 
b ot h c o h orts 2 a n d 3 wit h t he i m m u n ot hera p y c o m bi nati o n 
n ote d t hat t he bi o ps y will be c ollecte d u ntil f urt her data is 
n ot nee de d t o re d uce patie nt b ur de n  
o  
I ncl usi o ns # 1 9-2 1, a d de d ne w c o h ort 3  
o  
E xcl usi o n  # 3,  n ote d  t hat  was h o ut  peri o d  f or  pri or 
m o n ocl o nal a nti b o dies d oes n ot a p pl y si nce treat me nt wit h 
pri or P D -1 tar gete d t hera p y s h o ul d be c o nti n u o us  
o  
E xcl usi o ns  # 2 2  a n d  # 2 3  a d de d  t o  e xcl u de  patie nts  wit h 
i nterstitial l u n g disease a n d act i ve di vertic ulitis f or safet y  
•  
Statistical met h o ds  
•  
Secti o n 5. 4. 1: ne w secti o n of P D -1 pat h wa y a n d i n hi bit ors  
•  
Secti o n 7. 2. 5: st u d y c o m pleti o n u p date d t o 3 6 m o nt hs  
•  
S ecti o ns  8. 3  a n d  8. 4: ne w  secti o ns  o n ni v ol u ma b  a n d 
pe m br oliz u ma b  dr u g  pr o d ucts,  st ora ge,  pre p arati o n  a n d 
a d mi nistrati o n  
•  
Secti o n  8. 5. 3:  ne w  secti o n  o n  d ose  m o dificati o n  f or  P D -1 
C PI  
2 Gl ossar y of A b bre viati o ns  
1 5 Refere nces  
I ncl u de d ter ms a n d refere nces rele va nt t o P D-1 C PI  
3. Sc he d ule of Assess me nt s 
F o ot n ote 5: clarifie d t hat t he s c he d uli n g of d isease assess me nt visits 
is base d o n first d ose of gle m b at u m u ma b ve d oti n at C 1 D 1 
F o ot n ote 1 8: n ote d t hat P B M C will be c ollecte d u ntil s ufficie nt data 
has bee n ge nerate d  t o mi ni miz e patie nt b ur de n 
Wit h a d diti o n of C o h ort 3:  
•  
T a ble 1: i ncl u de d C o h ort 3 i n  P B M C a n d P K c ollecti o n 
•  
F o ot n ote 3: i ncl u de d treat me nt of P D -1 C PI  


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 2 7  of 1 3 0  
•  
F o ot n ote  1 3:  assess me nt  of  vital  si g ns  w he n  P D -1  C PI  is 
d ose d  
•  
F o ot n ote 1 9: P K a nal ysis a d de d w hic h ma y be perf or me d f or 
eac h  i m m u n o ge nicit y  sa m pl e  t o  i nter pret  a n y  ne gati ve 
i m m u n o ge nicit y res ults 
•  
F o ot n ote  2 1:  s pecifie d  P D -1  C PI  treat me nt,  cli nical  visits 
a n d m o nit ori n g  
5. 2. 3 Gle m bat u m u ma b ve d oti n: 
Cli nical S u m mar y  
A d de d i nteri m s u m mar y of res ults fr o m C o h ort 1 fr o m E S M O 2 0 1 6 
C o n gress prese ntati o n  
1 0. 2. 2. 2 Seri o us A d verse E ve nts 
( S A Es): Defi niti o n 
S A E defi niti o n u p date d t o reflect Cell de x c ore safet y la n g ua ge f or 
pr ot oc ols base d o n F D A g ui da nce  
S y n o psis, Statistical Met h o ds  
1 1 Statistical C o nsi derati o ns  
I ncl u de d a nal yses a n d met h o ds f or C o h ort 3; n u m ber of pati e nts 
T hr o u g h o ut  
F or matti n g m o difi cati o ns a n d t y p o gra p hical c orrecti o ns  
 
T he f oll o wi n g c ha n ges ha ve bee n ma de t o Pr ot oc ol C D X 0 1 1- 0 5 as A me n d me nt 2: 
S E C TI O N( S)  
C H A N G E/ R A TI O N A L E  
C o ver pa ge  
3 S y n o psis  
5 B ac k gr o u n d/ Rati o nale  
6 St u d y O bj ecti ves  
7 I n vesti gati o nal Pla n 
7. 1 O verall Desi g n a n d Pl a n of t he 
St u d y  
7. 2 N u m ber of P atie nts  
7. 2. 2. 1 I ncl usi o n Criteria  
7. 2. 2. 2 E xcl usi o n Criteria  
7. 2. 4. 1 Rati o nale f or C o nti n ue d 
Treat me nt  
7. 2. 4. 2 Disc o nti n uati o n of St u d y 
Treat me nt  
8 St u d y Treat me nt  
8. 6 Acc o u nta bilit y  
 
A d de d C o h ort 2  f or t he c o m bi nati o n of gle m bat u m u ma b ve d oti n a n d 
varlil u ma b base d  o n  t he  rati o nale  t hat  c o m bi ni n g  c yt ot o xic  t hera p y 
wit h i m m u n ot hera p y ca n res ult i n s y ner gistic acti vit y; t his  ne w c o h ort 
res ulte d i n t he f oll o wi n g c ha n ges: 
•  
St u d y title  
•  
I ncl u de d varlil u ma b as i n vesti gati o nal treat ment  
•  
I ncrease d t he n u m ber of patie nts i n st u d y o verall  
•  
I ncl u de d c o m bi nati o n treat me nt i n st u d y o bj ecti ves 
•  
I m m u ne-me diate d  R E CI S T 
(ir R E CI S T) as s u p ple me ntar y, 
retr os pecti ve assess me nt  
•  
A d de d treat me nt-li miti n g t o xi cit y r ules a n d d ose m o dificati o ns  
•  
Re vise d eli g i bilit y criteria:  
o  
I ncl usi o n  # 5, s u b missi o n  of  visceral t u m or lesi o ns f or 
patie nts  wit h  n o n -c uta ne o us  disease ; ne w re q uire me nt  of 
s ki n f ol d bi o ps y f or bi o mar ker a nal ysis  
o  
deleti o n  of  e xcl usi o n  # 1 0, “ Syste mic  r a di ati o n  t her a py 
wit hi n 4 weeks, pri or f oc al r a di ot her a py wit hi n 2 weeks, or 
r a di o p h ar m ace utic als (str o nti u m, s a m ari u m) wit hi n 8 weeks 
pri or  t o  t he  first  d ose  of  st u dy  tre at me nt ”  a n d  re visi o n  of 
i ncl usi o n # 5 t o e nc o m pass t he safet y i nte nt, “ Res ol uti o n of 
t oxicities rel ate d t o pri or t her a pies (i ncl u di n g r a di ot her a py) 
t o  ≤  N CI-C T C A E  Gr a de  1  severity,  exce pt  f or  al o peci a, 
gr a de 2 f ati g ue, vitili g o, or e n d ocri n o p at hies o n re pl ace me nt 
t her a py ”. 
•  
A d diti o nal e xcl usi o n criteria  f or safet y meas ures: 
1 8.  “Previ o us  tre at me nt  wit h  v arlil u m a b  or  ot her  a nti -C D 2 7 
m A b ” 
1 9.  “Active  syste mic  i nfecti o n  re q uiri n g  tre at me nt.  I nfecti o n 
c o ntr olle d by or al t her a py will n ot be excl usi o n ary. N ote: 
micr osc o pic  ex a mi n ati o n  of  uri n alysis  is  re q uire d  d uri n g 
scree ni n g. If uri n ary i nfecti o n is s us pecte d, t he n a ne g ative 
uri ne c ult ure is re q uire d pri or t o e nr oll me nt ” 
2 0.  “Use of i m m u n os u p pressive me dic ati o ns wit hi n 4 weeks or 
syste mic c ortic oster oi ds wit hi n 2 weeks pri or t o first d ose of 
st u dy  tre at me nt.  
T o pic al,  i n h ale d  
or  i ntr a n as al 
c ortic oster oi ds ( wit h mi ni m al syste mic a bs or pti o n) m ay be 
c o nti n ue d if t he p atie nt is o n a st a ble d ose. N o n -a bs or be d 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 2 8  of 1 3 0  
i ntr a artic ul ar c ortic oster oi d a n d re pl ace me nt ster oi ds ( < 1 0 
m g/ d ay pre d nis o ne or e q uiv ale nt) will be per mitte d ” 
2 1.  “Active  a ut oi m m u ne  dise ase  or  a  d oc u me nte d  hist ory  of 
a ut oi m m u ne  dise ase,  or  hist ory  of  p ote nti al  a ut oi m m u n e 
sy n dr o me  
t h at  
re q uire d  
syste mic  
ster oi ds  
or 
i m m u n os u p pressive  me dic ati o ns,  exce pt  f or  p atie nts  wit h 
vitili g o, e n d ocri n o p at hies, ty pe 1 di a betes, or p atie nts wit h 
res olve d c hil d h o o d ast h m a/ at o py or ot her sy n dr o mes w hic h 
w o ul d n ot be ex pecte d t o rec ur i n t he a bse nce of a n exter n al 
tri g ger  (e. g.,  dr u g-rel ate d  ser u m  sick ness  or  p ost-
stre pt oc occ al  gl o mer ul o ne p hritis).  S u bjects  wit h  mil d 
ast h m a  w h o  re q uire  i nter mitte nt  use  of  br o nc h o dil at ors 
(s uc h  as  al b uter ol)  w h o  h ave  n ot  bee n  h os pit alize d  f or 
ast h m a i n t he prece di n g 3 ye ars will n ot be excl u de d fr o m 
t he st u dy.” 
•  
Criteria f or safet y e val uati o n  f or i m m u n ot hera p y 
•  
Statistical met h o ds  
•  
Secti o n  5. 3  Varlil u ma b:  n o ncli nical  a n d  cli nical  s u m maries; 
rati o nale f or st u d y desi g n, d os e , a n d c o nti n ue d treat me nt  
•  
Secti o n  8. 2  Va rlil u ma b: ne w  secti o n  o n descri pti o n  of  dr u g 
pr o d uct; st ora ge; pre parati o n a n d a d mi nistrati o n  
•  
Secti o n 8. 3. 2: ne w secti o n o n d ose m o dificati o ns  
•  
Secti o n 8. 4: ne w secti o n o n tre at me nt-li miti n g t o xicit y defi niti o n 
a n d  r ules 
•  
Secti o n s 8. 5. 2 a n d  8. 5. 3 : ne w  secti o ns o n  p re vi o usl y  o bser ve d 
a n d ma na ge me nt of t o xicities a d de d f or i n vesti gat or g ui da nc e  
3 S y n o psis  
4 Sc he d ule of Assess me nts F o ot n ote 
5 
5. 4. 2. 1 Rati o nale f or P er mitti n g 
C o nti n ue d Treat me nt i n Cases of 
S us pecte d Pr o gressi ve Diseas e  
7. 1 O verall Desi g n a n d Pl a n of t he 
St u d y  
7. 2. 4. 1 . 1 All o wa nce  f or P er mitti n g 
C o nti n ue d Treat me nt i n Cases of 
S us pecte d Pr o gressi ve Diseas e  
All o we d  f or  c o nti n ue d  treat me nt  a d mi nistrati o n  i n  C o h ort  2  f or 
a p pare nt disease  pr o gressi o n d ue t o p ote ntial i nfla m mat or y r es p o nses 
a n d/ or ki ne tics of i m m u n ot hera p y res p o nse 
2  Gl ossar y of A b bre viati o ns  
1 5  Refere nces  
I ncl u de d ter ms a n d refere nces  rele va nt t o varlil u ma b a n d 
i m m u n ot hera p y 
4  Sc he d ule of Assess me nts  
Wit h a d diti o n of C o h ort 2:  
•  
T a ble 1, F o ot n ote 1 5: F or c o nsiste nc y wit h e xcl usi o n criteri o n 1 9, 
a d de d t he re q uire me nts of micr osc o pic e xa mi nati o n of uri nal ysis 
at  baseli ne  a n d  ne gati ve  uri ne  c ult ure  pri or  t o  e nr oll me nt  if 
i nfecti o n is s us pecte d; i ncl u de d t h yr oi d f u ncti o n tests 
•  
T a ble 1, F o ot n ote 2 5: a d de d he mat ol o g y , c he mistr y, a n d a d verse 
e ve nt m o nit ori n g o n C ycle 1 Da ys 7 a n d 1 4 f or safet y meas ures; 
t o mi ni mize patie nt b ur de n f o ot n ote 2 5 states t hat A E m o nit ori n g 
c o ul d be perf or me d i n pers o n or b y tele p h o ne call  
•  
T a ble  1 , F o ot n otes  1 8,  1 9: ad de d  P B M C  a n d  P K  c ollecti o n  at 
c ycles  1,  2, a n d 5 as  t his  d osi n g  re gi me n  has  n ot  bee n 
i n vesti gate d; als o delete d P M B C c ollecti o n at E O T f or C o h ort 1 
•  
T a ble  1 , F o ot n ote s  3,  2 2: s pecifie d treat me nt  visits a n d 
varlil u ma b a d mi nistrati o n   
•  
F o ot n ote 2 1: p r o vi de d details o n se q ue nce of i nf usi o ns  f or clarit y 


Pr ot oc ol C D X 0 1 1 -0 5  
Cell de x T hera pe utics, I nc.  
A me n d me nt 4  
C O N FI D E N TI A L I N F O R M A TI O N  
Se pte m ber 2 8 , 2 0 1 7 
P a ge 1 2 9  of 1 3 0  
F or bi o mar ker a nal yses:  
•  
T a ble  1,  F o ot n ote 2  7 , 8:  for  c o nsiste nc y  wit h  re vise d  i ncl usi o n 
criteri o n  5,  a d de d  t he  re q uire me nt  of  s ki n  f ol d  bi o ps y  o btai n e d 
wit hi n 1 2 wee ks of st u d y e ntr y  
•  
F o ot n ote  9:  a d de d  la n g ua ge  t o  e nc o ura ge  s u b missi o n  of  t u m or 
tiss ue at rec urre nce  
8. 1. 3 Pre parati o n a n d A d mi nistrati o n  
8. 5 P ote ntial T o xicit y a n d 
Ma na ge me nt of T o xicit y  
A d de d g ui deli nes f or t he pre ve nti o n, m o nit ori n g, a n d ma na ge me nt 
of i nf usi o n site e xtra vasati o n f or safet y  
Re vise d Secti o n 8. 5 (f or merl y Secti o n 8. 1. 7) t o i ncl u de a n d 
ma na ge me nt of m ost c o m m o n a n d se vere t o xicities; referral t o 
I n vesti gat or’s Br oc h ure w hic h is u p date d o n a n a n n ual basis 
9 C o nc o mita nt T hera p y  
Pr o vi de d g ui da nce c o nsiste nt wit h la n g ua ge i n ot her varlil u ma b 
pr ot oc ols  
1 0. 2. 1. 1 A nti -T u m or Acti vit y  
1 1. 1 A na l ysis E n d p oi nts 
I ncl u de d irR E CI S T criteria as a d diti o nal a nal ysis as varlil u ma b is a n 
i m m u n ot hera p y 
1 0. 2. 1. 4 P har mac o d y na mics  
Pr o vi de d f urt her detail t hat i m m u ne res p o nse assess me nts ma y be 
perf or me d d ue t o a d diti o n of i m m u n ot hera p y t o pr ot oc ol  
1 0. 2. 2. 3 A E/ S A E re p orti n g  
1 0. 2. 2. 4 Ra pi d N otificati o n of A E of 
I nterest 
1 0. 2. 2. 6 Ot her Safet y Data  
F urt her defi ne d re p orti n g peri o d after varlil u ma b treat me nt  
A d de d ne w Secti o n 1 0. 2. 2. 4 a n d la n g ua ge o n A E m o nit ori n g  a n d 
re p orti n g f or safet y c o nsi derati o ns 
Delete d n o w re d u n da nt te xt i n Secti o n 1 0. 2. 2. 2  
S y n o psis, Statistical Met h o ds  
1 1. Statistical C o nsi derati o ns  
I ncl u de d a nal yses a n d met h o ds f or C o h ort 2, n u m ber of pati e nts, a n d 
ir R E CI S T criteria 
T hr o u g h o ut  
F or matti n g m o dificati o ns a n d t y p o gra p hical c orrecti o ns; a d d e d 
varlil u ma b as a p pr o priate w he n st u d y treat me nt was refere nc e d  
 
T he f oll o wi n g c ha n ges ha ve bee n ma de t o Pr ot oc ol C D X 0 1 1- 0 5 as A me n d me nt 1: 
S E C TI O N( S)  
C H A N G E/ R A TI O N A L E  
Pr ot oc ol S y n o psis, N u m ber of St u d y Ce nters  
I ncrease d n u m ber of partici pati n g ce nters fr o m ‘ u p 
t o 1 0’ t o ‘a p pr o xi matel y 1 5’; a d diti o nal ce nters are 
bei n g p urs ue d t o e n ha nce e nr oll me nt.  
Pr ot oc ol S y n o psis, Eli gi bilit y Criteria  
Secti o n 7. 2. 2. S u bj ect Eli gi bilit y  
I ncl usi o n Criteria # 3: C ha n ge d t he ti mi n g of 
d oc u me nte d pr o gressi ve disease fr o m  ‘at st u d y 
e ntr y’ t o ‘ d uri n g or s u bse q ue nt t o t he last a ntica ncer 
t hera p y’ f or clarificati o n. 
 
I ncl usi o n Criteria # 4:  
-Delete d li mit of n o m ore t ha n f o ur pri or a ntica ncer 
re gi me ns t o reflect c ha n gi n g sta n dar d of care a n d t o 
facilitate e nr oll me nt.  
 
-Delet e d “l ocall y a d va nce d/re c urre nt/ metastatic” 
w hic h are e xa m ples of a d va nc e d disease setti n gs b ut 
are n ot i nte n de d t o be strict criteria.  
 
-Delete d pri or i pilim u ma b re q uire me nt a n d i nserte d 
“at least o ne pri or c hec k -p oi nt i n hi bit or  (e. g., a nti -
C T L A -4, P D -1, P D- L 1 tar gete d i m m u n ot hera p y)” t o 
reflect c ha n gi n g sta n dar d of care/re vise d N C C N 
g ui deli nes, a n d t o facilitate e nr oll me nt.   
I ncl usi o n Criteria # 5: C ha n ge d ‘c o nfir mati o n’ of 
g p N M B e x pressi o n t o ‘e val uati o n’ f or clarit y.  
 
       E xcl usi o n Criteria # 4 : C orrecte d t y p o gra p hical err or 


Protocol CDX011-05 
Celldex Therapeutics, Inc. 
Amendment 4 
CONFIDENTIAL INFORMATION 
September 28, 2017 
Page 130 of 130 
by changing the wash-out period for the use of 
chemotherapy to be ‘within 2 weeks or 5 half-lives 
(whichever is longer)’ from ‘(whichever is shorter)’ 
 
Protocol Synopsis, Criteria for Evaluation 
Added ECOG assessment to Safety evaluations for 
consistency with ECOG assessment in Section 
10.2.2.5 
 
Added “such as gpNMB-expressing myeloid-derived 
suppressor cells” as an example of immune response 
cells of interest. 
Protocol Synopsis, Statistical Methods 
11. Statistical Considerations (and all sub-sections) 
 
 
Added “ECG parameters” and “ECOG performance 
status” to safety analysis endpoints for consistency 
with Protocol Synopsis and Section 10.2.2.5. 
 
Clarified that the evaluable population will be used 
for the primary analysis of ORR, but that additional 
efficacy analyses will be based on the ITT (treated) 
population. 
 
Deleted the Atkinson & Brown reference as the 
statistical methodology in this reference is not 
relevant. 
 
Changed significance level from 1% to 5% to reflect 
one-stage study design: A one-sample exact binomial 
test with one-sided significance level of 5% will be 
used to test the response rate under the null and 
alternative hypotheses. 
4. Schedule of Assessments 
Table 1 
Footnote 18 
Deleted time point for PD sample collection at cycles 
3, 4, 5, etc. to reduce study burden while still 
allowing for adequate PD assessment through cycle 
2 and end of treatment. 
Clarified time points accordingly in footnote. 
5.1 Advanced Melanoma, Table 2 
Appendix 6 
E Expanded this section to update with FDA-
approval of nivolumab and pembrolizumab in 2014 
and included results of the pivotal trials; updated 
relevant tables. 
5.3 Glembatumumab Vedotin 
Table 4, Figure 1 
Updated Table 4 and Figure 1 with final results from 
the CDX011-03 “EMERGE” study according to ITT 
methodology, which includes all enrolled patients, 
but does not include cross-over phase data. 
5.5 Study Rationale 
Added nivolumab and pembrolizumab to the list of 
check-point inhibitors that patients enrolled in this 
trial have previously received for consistency with 
revised inclusion criteria.  
Throughout 
Formatting adjustments and typographical 
corrections 
 

SAP_001.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
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 
 
 
 
IND#: 74907 
 
 
 
 
 
 
 
 
 
 
    
                
Version: Final v1.0 
Date:    Jan 22th, 2018 
 
 
 
This document is prepared according to protocol amendment 3, dated November 17th, 2016. 
 
Confidential Information 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed 
unless such disclosure is required by applicable laws and regulations. In any event, persons to whom the information is disclosed must be informed 
that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to 
all future information supplied to you which is indicated as privileged or confidential. 




Statistical Analysis Plan/ Protocol: CDX011-05 
Celldex Therapeutics, Inc. 
Version Final v1.0 (Jan 22, 2018)            CONFIDENTIAL 
Page 3 of 26 
 
 
TABLE OF CONTENTS 
 
LISTING OF ABBREVIATIONS ...................................................................................................5 
1 
INTRODUCTION .....................................................................................................................7 
2 STUDY OBJECTIVES AND ENDPOINTS .............................................................................8 
2.1 
Study Objectives ......................................................................................................8 
2.1.1 Primary objective(s) .....................................................................................8 
2.1.2 Secondary objective(s) .................................................................................8 
2.1.3 Exploratory objective(s)...............................................................................8 
2.2 
Study Endpoints .......................................................................................................8 
2.2.1 Primary endpoint(s) .....................................................................................8 
2.2.2 Secondary endpoint(s) .................................................................................8 
Safety Endpoints ......................................................................................................9 
2.2.3 Exploratory endpoint(s) ...............................................................................9 
3 DETERMINATION OF SAMPLE SIZE ..................................................................................9 
4 ANALYSIS POPULATIONS .................................................................................................10 
4.1 
Safety Population ...................................................................................................10 
4.2 
Response Evaluable Population .............................................................................10 
4.3 
Per-protocol Population .........................................................................................10 
5 GENERAL CONSIDERATIONS ...........................................................................................10 
5.1 
Pooling of Centers..................................................................................................11 
5.2 
Multiplicity Adjustment .........................................................................................11 
5.3 
Subgroups ..............................................................................................................11 
5.4 
Adjustments for Covariates....................................................................................12 
5.5 
Handling of Missing Data ......................................................................................12 
6 STUDY SUBJECTS ................................................................................................................12 
6.1 
Disposition and Withdrawals .................................................................................12 
6.2 
Protocol Deviations ................................................................................................12 
7 DEMOGRAPHICS AND BASELINE CHARACTERISTICS ..............................................13 
7.1 
Demographics ........................................................................................................13 
7.2 
Disease Characteristics ..........................................................................................13 
7.3 
Prior Therapy and Medical History .......................................................................14 
7.4 
Prior and Concomitant Medications ......................................................................14 
8 EFFICACY ANALYSES ........................................................................................................15 
8.1 
Analyses of the Primary Endpoint .........................................................................15 
8.2 
Analyses of Secondary Endpoints .........................................................................16 
8.2.1 PFS .............................................................................................................16 
8.2.2 Duration of response (DOR) and disease control rate (DCR) ...................17 
8.2.3 Overall Survival (OS) ................................................................................17 
8.3 
Exploratory Analysis .............................................................................................17 


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9 SAFETY ANALYSES.............................................................................................................18 
9.1 
Extent of Exposure .................................................................................................18 
9.2 
Adverse Events ......................................................................................................19 
9.2.1 Treatment emergent AE .............................................................................19 
9.2.2 Serious Adverse Events .............................................................................20 
9.2.3 AE with outcome of death .........................................................................20 
9.2.4 Grouped AE ...............................................................................................20 
9.3 
Laboratory Parameters ...........................................................................................20 
9.3.1 Hematology and Clinical Chemistry ..........................................................20 
9.3.2 Urinalysis ...................................................................................................21 
9.4 
Vital Signs ..............................................................................................................21 
9.5 
Electrocardiograms ................................................................................................21 
9.6 
ECOG PS ...............................................................................................................21 
10 PHARMACOKINETIC,  PHARMACODYNAMIC AND IMMUNOGENICITY 
ANALYSES .......................................................................................................................21 
11 INTERIM ANALYSES ...........................................................................................................21 
12 CHANGES FROM THE PLANNED ANALYSES ................................................................21 
13 SOFTWARE ............................................................................................................................22 
14 TABLES, LISTINGS, AND GRAPHS (TLGS) SHELLS AND PROGRAMMING 
SPECIFICATIONS ............................................................................................................22 
15 REFERENCES ........................................................................................................................22 
16 APPENDICES .........................................................................................................................23 
16.1 
Schedule of Assessment .........................................................................................23 
 
LIST OF TABLES 
• 
Table 1 Cohorts in Study CDX011-05.......................................................................................7 
• 
Table 2: Date of Event or Censoring for the Primary PFS analysis ........................................16 
 
 
 


Statistical Analysis Plan/ Protocol: CDX011-05 
Celldex Therapeutics, Inc. 
Version Final v1.0 (Jan 22, 2018)            CONFIDENTIAL 
Page 5 of 26 
 
LISTING OF ABBREVIATIONS  
 
ADaM 
Analysis Data Model 
ADC 
Antibody-Drug Conjugate 
ADI 
Actual Dose Intensity 
AE 
Adverse Event 
ALT (SGPT) 
Alanine Transaminase (Serum Glutamic Pyruvate Transaminase) 
AST (SGOT) 
Aspartate Transaminase (Serum Glutamic Oxaloacetic Transaminase) 
ATC 
Anatomical Therapeutic Class 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CDISC 
Clinical Data Interchange Standards Consortium  
CMH 
Cochran-Mantel-Haenszel 
CPI 
Checkpoint Inhibitor 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ER 
Estrogen Receptor 
FDA 
Food and Drug Administration 
GpNMB 
Glycoprotein NMB 
HRQOL 
Health-Related Quality of Life 
IHC 
Immunohistochemistry 
irRECIST 
Immune-Related RECIST 
ITT 
Intention-to-Treat 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
Monomethyl auristatin E 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute (of the United States) 
NE 
Not Evaluable 


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ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Pharmacodynamic / Progressive Disease 
PDI 
Planned Dose Intensity 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PR 
Partial Response / Progesterone Receptor 
PS 
Performance Status 
PT 
Preferred Term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROC 
Receiver Operating Curve 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation / Stable Disease 
SE 
Standard Error  
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
TLG 
Tables, Listings, and Graphs 
WHO 
World Health Organization 
 
 


Statistical Analysis Plan/ Protocol: CDX011-05 
Celldex Therapeutics, Inc. 
Version Final v1.0 (Jan 22, 2018)            CONFIDENTIAL 
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1 INTRODUCTION 
This statistical analysis plan (SAP) describes the planned data analysis specifications for 
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” for the completion of the Clinical Study Report (CSR). 
This is an open-label Phase II study of glembatumumab vedotin administered at a starting dose 
of 1.9 mg/kg, as monotherapy or in combination with the agonist anti-CD27 antibody, 
varlilumab, or PD-1 targeted checkpoint inhibition (nivolumab or pembrolizumab), in patients 
with unresectable Stage III or IV melanoma who have previously received CPIs. This study 
consists of 3 cohorts (Table 1).  
 
Table 1 Cohorts in Study CDX011-05 
Cohort 
Treatment 
Glembatumumab 
Vedotin 
Varlilumab 
PD-1 CPI 
Dose 
Patients 
(n) 
1 
Glembatumumab 
vedotin 
1.9 mg/kg 
- 
- 
Approx. 
60 
2 
Glembatumumab 
vedotin + Varlilumab 
1.9 mg/kg 
3.0 mg/kg 
- 
Approx. 
30 
3 
Glembatumumab 
vedotin + PD-1 
targeted CPI 
1.9 mg/kg 
- 
As per 
institutional 
standard of 
care with 
reference to the 
package insert 
Approx. 
30 
 
Tumor assessments will be performed every 6 weeks (±1 week) for the first 6 months, and every 
9 weeks (±2 weeks), thereafter, until documented progression of disease or initiation of alternate 
anticancer therapies. Tumor response will be assessed by the investigator in accordance with 
RECIST 1.1 guidelines (Appendix 3) (Eisenhauer, Therasse et al. 2009). For Cohorts 2 and 3, 
supplementary retrospective analyses of tumor response and progression may also be performed 
using Immune-Related RECIST (“irRECIST”) criteria (in which new lesions do not constitute 
progression, but contribute to the calculated sum of diameter of all measurable disease) (Nishino, 
Giobbie-Hurder et al. 2013). Patients who discontinue treatment in the absence of progression 
will continue to have tumor assessments until documented progression or initiation of alternate 
anti-cancer therapies. 
For Cohorts 2 and 3, in cases of apparent progression that may reflect enhanced inflammation 
and/or an initial imbalance in the kinetics of tumor growth and anti-cancer immune activity, 
continued combination treatment may be allowed with consent of the patient and permission 
granted from the Celldex Medical Monitor, until a second radiologic confirmation of progression 
performed at the next scheduled disease assessment (or sooner if clinically indicated). In 
addition, the following criteria must be met: 1) the patient experiences Investigator-assessed 
clinical benefit; and 2) the patient is tolerating the study treatment.  Refer to Appendix 1 for the 
detailed schedule of assessments. 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Primary objective(s) 
The primary objective of the study is to evaluate the anti-cancer activity of glembatumumab 
vedotin as monotherapy and in combination with varlilumab, or in combination with a PD-1 
targeted checkpoint inhibitor (CPI), in advanced melanoma as measured by the objective 
response rate (ORR) per RECIST 1.1. 
2.1.2 Secondary objective(s) 
• To further assess the anti-cancer activity of glembatumumab vedotin as monotherapy and 
in combination with varlilumab, or in combination with a PD-1 targeted CPI, in advanced 
melanoma, as assessed by progression free survival (PFS), duration of response (DOR) 
and overall survival (OS) 
• To investigate if the anti-cancer activity of glembatumumab vedotin as monotherapy and 
in combination with varlilumab, or in combination with a PD-1 targeted CPI, in advanced 
melanoma is dependent upon the degree of gpNMB expression in tumor tissue 
• To further characterize the safety of glembatumumab vedotin as monotherapy 
• To characterize the safety of the combination of glembatumumab vedotin with 
varlilumab, or in combination with a PD-1 targeted CPI, in advanced melanoma 
2.1.3 Exploratory objective(s) 
• To examine the range of gpNMB expression in advanced melanoma, and to assess 
whether gpNMB expression changes over time and/or with specific prior therapies 
• To examine pharmacodynamic effects of treatment, including types and number of 
immune cells infiltrating the tumor; localization of glembatumumab vedotin, CR011, and 
MMAE in the tumor; soluble mediators, gpNMB expression levels and/or other potential 
biomarkers in both normal and tumor tissue; and analysis of peripheral blood subsets 
• To further characterize the pharmacokinetics and immunogenicity of glembatumumab 
vedotin and varlilumab in patients with advanced melanoma, and to explore the 
relationships between patient-specific measures of exposure and safety and activity 
parameters 
• To assess the anti-cancer activity of the combination of glembatumumab vedotin and 
varlilumab, or the combination of glembatumumab vedotin with a PD-1 targeted CPI, as 
measured by the ORR and PFS per irRECIST 
2.2 Study Endpoints 
2.2.1 Primary endpoint(s) 
Efficacy  
• Objective response rate (ORR), defined as the proportion of patients whose best overall 
tumor response are confirmed complete response or partial response by RECIST 1.1.  
 
2.2.2 Secondary endpoint(s) 
Efficacy 
• Duration of response (DOR), defined as the time from response criteria are first met for 
either complete response (CR) or partial response (PR), until the first date that 


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Page 9 of 26 
 
progressive disease (PD) is objectively documented, or until death (if death occurs within 
9 weeks of the last evaluable scan), for subjects who achieve confirmed CR or PR.   
• Progression-free survival (PFS), defined as the time from first dose of study treatment 
date to first documentation of objective progression or death due to any cause, whichever 
occurs first.  
• Overall survival (OS), defined as the time from first dose of study treatment to death due 
to any cause. 
Safety Endpoints  
• 
Incidence of adverse events  
• 
Deaths on study  
• 
Discontinuations of study drug due to adverse events  
• 
Changes in vital sign parameters  
• 
Changes in hematology, chemistry, and other laboratory parameters  
• 
ECG parameters  
• 
ECOG performance status  
 
2.2.3 Exploratory endpoint(s) 
Efficacy  
• 
Immune-related RECIST ORR and PFS (Cohorts 2 and 3)  
Correlative:  
• 
Concentration of antibody-drug conjugate(ADC), total antibody (TA), and free Monomethyl 
auristatin E (MMAE).  
• 
Pharmacodynamic parameters, including gpNMB expression levels and other biomarkers in 
serum and both normal and tumor tissue; localization of glembatumumab vedotin, CR011, or 
MMAE at the tumor site; evaluation of tumor infiltrating and peripheral leukocytes, 
circulating tumor cells, and other immune response cells of interest. Additional analysis may 
include immune response assessment to potentially relevant tumor antigens.  
3 DETERMINATION OF SAMPLE SIZE 
Three cohorts of patients will be enrolled and treated. In Cohort 1, approximately 52 evaluable 
patients may be enrolled and treated with glembatumumab vedotin monotherapy with objective 
response rate (ORR) as the primary endpoint. As patients who discontinue study prior to the first 
disease assessment without symptomatic deterioration or death will not be evaluated and will be 
replaced, it is anticipated that approximately 60 patients will be enrolled in this cohort. 
For Cohort 1, the sample size was determined to estimate the ORR with one-sided significance 
level of 5% and power of 80%, using exact binomial test, to determine if the ORR exceeds a 
predefined minimum. A sample size of 52 patients will test the null hypothesis of an ORR of 5% 
versus 15% under the alternative hypothesis. If the number of responses (CR or PR) is 6 or more, 
the null hypothesis will be rejected with the actual error rate of 0.045. If the number of responses 
is 5 or less, the alternative hypothesis will be rejected with an actual error rate of 0.188. 
For Cohorts 2 and 3, ORR by RECIST 1.1 remains the primary endpoint. Supplementary 
analyses of tumor response and progression may also be performed using irRECIST criteria (in 
which new lesions do not necessarily constitute progression, but contribute to the calculated sum 
of diameter of all measurable disease) (Nishino, Giobbie-Hurder et al. 2013). 


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For Cohorts 2 and 3, 30 patients per cohort, to achieve 25 evaluable, will be enrolled to have the 
maximum width of the 95% confidence interval (CI) of the estimated ORR to be no greater than 
41%. If 7, 8, or 9 responses are observed (i.e., the estimated ORR is 28%, 32%, or 36%) among 
the 25 evaluable patients, then the lower limits of the two-sided 95% CIs of the estimated ORR 
are 12%, 15%, and 18% respectively. These calculations are based on the Clopper-Pearson 
method for exact confidence intervals. As a secondary consideration, 25 evaluable patients can 
achieve 90% power for ORR of 25% comparing to 5% and 79% power comparing to 10% ORR 
with 1-sided type I error of 0.1 based on exact binomial test. Patients in Cohorts 2 and 3 who 
experience an event determined to be a treatment-limiting toxicity will not be replaced and will 
be considered evaluable. 
4 ANALYSIS POPULATIONS 
The three treatment cohorts will be analyzed separately. 
4.1 Safety Population 
The safety population will include all patients who receive at least one dose of study treatment of 
glembatumumab vedotin or varlilumab or a PD-1 targeted CPI. A baseline measurement and at 
least one laboratory, vital sign, or other safety-related measurement obtained after at least one 
dose of study treatment may be required for inclusion in the analysis of a specific safety 
parameter. For each cohort, the safety population constitutes all treated patients and will be used 
for secondary analyses of ORR and all other endpoints. The safety population is equivalent to the 
ITT population defined in the protocol. 
4.2 Response Evaluable Population 
Response evaluable population includes subjects who have measurable disease at baseline and 
receive study treatment, and excludes subjects who discontinue study prior to the first disease 
assessment without symptomatic deterioration or death. Specifically, patients who discontinue 
study prior to the first disease assessment for reasons unrelated to study treatment (i.e., adverse 
events deemed unrelated to study treatment, withdrawal of consent, lost to follow-up, withdrawal 
due to administrative reasons, etc.) will be excluded from the response-evaluable population and 
may be replaced. Patients who discontinue study prior to the first disease assessment due to 
treatment-related adverse events, symptomatic deterioration (adverse events due to progression), 
or death will be included in the response evaluable population. The primary ORR analysis is 
based on evaluable population and the secondary analysis will be based on safety (treated) 
population.  
4.3 Per-protocol Population 
The per-protocol population, as a subset of Safety Population, excludes subjects who 
experienced important deviations from the protocol that may substantially affect the results of 
the primary analysis. A supportive analysis using the per-protocol population may be performed 
for efficacy. The final determination on important protocol deviations, and thereby the per-
protocol population, will be made prior to locking the clinical database. 
5 GENERAL CONSIDERATIONS 
Analysis datasets will be created according to Clinical Data Interchange Standards Consortium 
CDISC/Analysis Data Model (ADaM) standards. SAS v9.4 or higher software will be used to 
perform all data analyses (ADaM datasets, tables, figures, and listings). 


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Baseline will be defined as the most recent non-missing value prior to or on the same day of the 
first dose of glembatumumab vedotin. Generally, only pre-specified planned visits will be used 
in the by-visit summaries, statistical analyses and calculations of any derived safety parameters 
except for lab summary tables. All post baseline measurements including scheduled and 
unscheduled assessments will be used to derive the worst / best assessment for lab summary 
tables. 
The primary response criterion is RECIST 1.1. Confirmation of response is required in defining 
best overall response (BOR) as the primary endpoint. The irRECIST is used as a secondary 
analysis for all efficacy endpoints except for OS. 
All analyses specified in this plan will be performed by cohort. All baseline tables will include a 
column for each cohort and a column for overall. Unless otherwise stated, continuous variables 
will be summarized with n, mean, median, standard deviation, Q1, Q3, minimum and maximum, 
and categorical variables will be summarized with frequency counts and percentages.  
Unless otherwise stated, all listings will be sorted by cohort, subject number, and then by visit 
date if applicable. 
 
5.1 Pooling of Centers 
Data from all study centers will be pooled together for analyses in this study. 
 
5.2 Multiplicity Adjustment 
This is an early phase exploratory study and adjustment for multiplicity is not planned. 
5.3 Subgroups 
Subgroup analyses will be performed to explore the correlation between degree of gpNMB 
expression and anti-cancer activity of glembatumumab vedotin in advanced melanoma for 
efficacy endpoints. Rash developed in treatment cycle 1 will also be explored as another 
subgroup variable. Specifically, the following subgroup analyses will be performed for ORR, 
PFS and OS: 
• Age group (<65, >=65) 
• Gender (Female, Male) 
• CNS involvement (Yes, No) 
• Number of disease site (<=3, >3) 
• ECOG PS (0, 1) 
• GpNMB Expression (<95%, >=95%)  
• Rash in cycle 1 (Yes, No). The medical term of rash is to be defined by medical manual 
review and documented prior to analysis. Only treatment-related rash is considered. If a 
subject only has 1 cycle of treatment, rash onset within 21 days from the first dose will be 
considered as rash in cycle 1.  
• Time between last prior CPI and initiation of study treatment (<=3 months, >3 months).  
• Duration of last prior CPI (<=3 months, >3 months). 


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• Cohort 3 only: PD-L1,  positive (positive in >=1% tumor cells) vs negative 
5.4 Adjustments for Covariates 
No analysis adjusting for covariates are planned for this study.  
5.5 Handling of Missing Data 
Partially missing date of diagnosis needs to be imputed for calculating time from diagnosis to 
baseline. The following imputation rules will be applied: 
• If only day is missing, impute as the first day of the month. 
• If both day and month are missing, impute as Jan 1st.  
• If year is missing, no imputation will be performed. 
The above rules also apply to other diagnosis dates including date of metastatic disease, date of 
advanced disease, date of cancer surgery, radiation and prior cancer medications. 
For partially missing additional cancer therapy date, the imputation is same as above except 
when only day is missing and the month is the same as in on-study progression date, in which 
case the day of additional cancer therapy will be imputed as the day of progression + 1 to avoid 
censoring a progression event due to an uncertain anticancer therapy start date.  
For partially missing AE start dates (missing day and/or month), the following imputation rules 
will be applied: 
• If both day and month of the AE start date are missing, the day and month will be 
imputed with the day and month of the first study dose date if the year is equal to the year 
of the first dose given the AE end date is not prior to first dose. Otherwise, the month and 
day is imputed as the first day of the year (Jan 1st). 
• If only day is missing, and if the year and month are equal to the first dose date, the AE 
start date will be imputed as the first dose date given the AE end date is not prior to first 
dose. Otherwise, the day will be imputed as “01”. As a general consideration, imputed 
AE start date cannot be after AE end date if available. 
6 STUDY SUBJECTS 
6.1 Disposition and Withdrawals 
Subject disposition will be summarized by treatment cohort based on Safety Population. 
Disposition of subjects includes the number and percentage of subjects for the following 
categories: subjects who were treated, subjects who discontinued treatment, subject survival 
status, and subjects who discontinued from the study, with percentages based on the relevant 
cohort. 
The reasons for study discontinuation and treatment discontinuation will also be summarized. 
Subject disposition data will be presented in a data listing. 
6.2 Protocol Deviations 
The important protocol deviations and the Per Protocol (PP) population will be determined prior 
to the database lock. Protocol deviations will be listed by treatment cohort, patient number, and 
categorized according to the deviation reasons. All important protocol deviations will also be 
presented in a data listing. 


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7 DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Unless specified otherwise, the baseline values will be those values measured closest to but not 
after the first dose of study treatment.  
A summary of demographics and baseline information will be presented by study cohort. 
Continuous data will be summarized using number, mean, standard deviation (SD), median, Q1, 
Q3, minimum, and maximum. Categorical and ordinal data will be summarized using number 
and percentage of subjects in each treatment cohort. Percentages will be based on the total 
number of subjects in the Safety Population. 
Subject demographic and baseline characteristics will also be presented in a listing.  
7.1 Demographics 
The following demographic variables will be summarized: 
• Age (years) 
• Age category (<=18, 19 - 64, >=65) 
• Sex (male or female) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Height (cm) 
• Weight (kg) 
• Body Mass Index (kg/m2) 
• Baseline ECOG performance status (0, 1) 
 
7.2 Disease Characteristics 
The following baseline disease characteristics will be summarized: 
• Time since initial diagnosis (years) 
• Stage at initial diagnosis 
• Stage at study entry 
• Metastasis staging at study entry 
• Histopathologic Type 
• Mutations (BRAF, BRAF types and other mutations) 
• Number of organs (disease sites) involved 
• Most frequent disease site 
• Historical or current CNS involvement 
• Time since advanced and/or metastatic disease (calculated relative to first dose date) 
• Number of Subjects with at Least One Additional Relapse or Disease Progression 


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• Tumor burden as measured by sum of diameter 
• Elevated Lactate Dehydrogenase (LDH) (Yes, No) 
• Cohort 3 only: PD-L1, positive (positive in >=1% tumor cells) vs negative 
• % positive gpNMB in epithelial cells (descriptive statistics and categories: 100% vs 
<100%) 
 
7.3 Prior Therapy and Medical History 
Prior medical and surgical history will be coded by MedDRA (Medical Dictionary for 
Regulatory Activities) and will be summarized by treatment cohorts. 
The following prior anti-cancer treatment parameters will be summarized: 
• Number of prior systemic anti-cancer regimens 
• Prior cancer treatment class: check point inhibitor (CPI) with subcategories including 
CTLA-4 and PD-1/PD-L1, other immunotherapy, BRAF related TKI, cytokines and 
cytotoxic-containing therapy 
• Number of prior CPI containing regimens  
• Best response to first prior CPI treatment 
• Best response to and duration of last prior CPI treatment 
• Surgery/Biopsy description (Resection, Biopsy or Other) 
• Prior radiation therapy (Yes or No) 
• Prior cancer surgeries (Yes or No, biopsy excluded) 
• Time from last anti-cancer therapy to first dose of glembatumumab vedotin (≤ 2 or >2 
months) 
• Time from CPI as last anti-cancer therapy to first dose of glembatumumab vedotin (≤ 2 
months, >2 month to ≤6 months, or >6 months) 
 
7.4 Prior and Concomitant Medications 
All medications will be documented on the case report form (CRF) if taken within 28 days prior 
to the first dose of study treatment through (whichever occurs first) either a) 28 days after the last 
dose of study treatment, or b) initiation of alternate anticancer therapy. In addition, all anticancer 
therapies should be recorded throughout the duration of study follow-up. 
All medications will be coded using the World Health Organization (WHO) drug dictionary. 
Prior medications are defined as medications that received before the first dose of study drug. 
Concomitant medications are defined as medications that (1) started before the first dose of study 
drug and were continuing into the treatment period, or (2) started on or after the date of the first 
dose of study drug up to 28 days after last dose.   
The number (%) of subjects who took prior and concomitant medications will be summarized on 
the anatomical class (ATC) and preferred term (PT) by dose cohorts. A summary of concomitant 
anti-cancer therapies will be summarized separately by PT. 


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8 EFFICACY ANALYSES 
8.1 Analyses of the Primary Endpoint 
The primary endpoint is objective response rate (ORR). ORR will be estimated based on the 
proportion of evaluable subjects who achieve best overall response (BOR) of complete response 
(CR) or partial response (PR) per RECIST 1.1 that are confirmed at an interval of at least 28 
days. The estimate of the objective response rate will be accompanied by one-sided and two-
sided 95% Clopper-Pearson confidence intervals. For Cohort 1, a one-sample exact binomial test 
with one-sided significance level of 0.05 will be used to test the response rate under the null (H0: 
ORR=5%) and alternative (Ha: ORR=15%) hypotheses (5% vs. 15%, respectively). For each of 
Cohorts 2 and 3, the estimate of ORR will be compared with the fixed rates of 5% and 10% with 
one-sided significance level of 0.10. The primary ORR analysis is based on evaluable population 
and secondarily on Safety Population.  The analysis of ORR will also be summarized for the PP 
population. 
In this study, a minimum interval of 5 weeks from first dose date is required for stable disease 
(SD) status. Subjects with Not Evaluable (NE) or missing response will be treated as non-
responders (i.e., they will be included in the denominator when calculating ORR).  
Secondary analyses of ORR will include responses observed at a single time point (i.e., analysis 
of ORR will be summarized based on confirmed and unconfirmed CR or PR) based on Safety 
Population.  
Waterfall plots will be used to depict graphically the maximum percent decrease from baseline in 
the sum of longest diameters of target lesions.  A spider plot will be generated to depict changes 
in the sum of longest diameters of target lesions over time.  A swimmer plot will also be used to 
show the effect of study treatment on tumor response for individual subjects.  
Tumor assessment data after initiation of other anticancer therapy will be excluded for response 
related efficacy endpoints including BOR, DOR, PFS, waterfall plot, spider plot and swimmer 
plot.  
For Cohorts 2 and 3, supplementary analyses of tumor response and progression will be 
performed using irRECIST criteria (in which new lesions do not necessarily constitute 
progression, but contribute to the calculated sum of diameter of all measurable disease). To be 
noted, if not all target lesions are measured at a visit, the sum of diameters should not be 
calculated. 
As a secondary exploratory analysis, BOR and ORR by irRECIST criteria will be derived and 
summarized in a similar fashion as in the primary analyses. Specifically, for Cohorts 2 and 3, 
ORR will be compared with reference levels of 5% and 10%. One-sample exact binomial test 
with one-sided significance level will be provided for each test. Waterfall plots, spider plots and 
swimmer plots will be used to depict graphically the maximum percent decrease from baseline , 
changes in tumor burden (sum of longest diameters of target lesions and new lesions) over time 
and the effect of study treatment on tumor response, by irRECIST criteria for individual subjects. 
 


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8.2 Analyses of Secondary Endpoints 
8.2.1 PFS 
Progression Free Survival (PFS) is defined as the time from the study treatment first dose to the 
earlier of disease progression or death due to any cause. Disease progression will be assessed 
using RECIST 1.1. The progression and censoring dates will be based on the May 2007 FDA 
Guidance for Industry, ‘Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics’. Determination rules for events or censored PFS is summarized in Table 2. 
Table 2: Date of Event or Censoring for the Primary PFS analysis 
Situation 
Date of Event or Censoring 
Outcome 
Disease progression between scheduled 
disease assessments 
Date of progression 
Event 
Death between scheduled disease 
assessment 
Date of death 
Event 
Death before the first planned disease 
assessment at 6 weeks (plus 1 week 
window) without any disease 
assessment  
Date of death 
Event 
No baseline disease assessments 
Date of first dose 
Censored 
No post-baseline disease assessments 
without death before the first planned 
disease assessment 
Date of first dose 
Censored 
Discontinuation of study treatment 
without progression (i.e., due to 
toxicity, withdrew consent, or lost to 
follow-up) and no further radiographic 
assessmenta 
Date of last radiological 
assessment  
Censored 
Alternate anticancer treatment started 
without documentation of disease 
progression beforehandb 
Date of last radiological 
assessment prior to start of 
further anticancer treatment 
Censored 
Death or disease progression after 
missing two or more consecutively 
scheduled disease assessmentsc 
Date of last radiological 
assessment without documented 
progression disease prior to 
death/progression 
Censored 
Patients who have not progressed and 
are alive  
Date of last radiological 
assessment without documented 
progression disease 
Censored 
a. 
For a patient who discontinues study treatment without PD and continues to have radiographic assessments, post-
treatment radiographic assessments will be considered for PFS analyses according to the rules in this table. 
b. 
Alternate anticancer treatment interventions that are diagnostic (e.g. biopsy) or palliative (e.g., local radiation for 
painful nodule), as determined by medical review, will not routinely require censoring unless they are determined to 
interfere with the assessment of the patients’ disease status. 
c. 
Disease assessments are planned every 6 (±1) weeks for the first 6 months (24 weeks); and every 9 (±2) weeks, 
thereafter, until disease progression. The interval of two missed scheduled assessments is calculated according to the 


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Situation 
Date of Event or Censoring 
Outcome 
scheduled assessment frequency and the corresponding window (1 or 2 weeks depending on assessments scheduled 
before or after 6 months). 
 
PFS will be summarized descriptively using the Kaplan-Meier method. Median PFS and its 
corresponding 95% confidence interval will be reported. Greenwood’s formula will be used to 
calculate the standard errors of the Kaplan-Meier estimate and upper and lower limits of the 95% 
confidence interval.  
The PFS rate and its corresponding 95% confidence interval for various landmark time points 
(i.e., 6 months and 1 year) will also be estimated using the Kaplan-Meier method. The Kaplan-
Meier curve of PFS will be provided. 
Subgroup analyses for PFS will be performed, Kaplan-Meier curves and a forest plot will be 
presented. 
8.2.2 Duration of response (DOR) and disease control rate (DCR)  
Duration of Response (DOR) will be calculated for subjects who achieve confirmed CR or PR. 
For such subjects, DOR is defined as the time from response criteria are first met for either CR 
or PR, until the first date PD is objectively documented, or until death. DOR will be right-
censored based on the same rules as described for PFS above.  
DOR will be summarized descriptively and the median DOR will be estimated using the Kaplan-
Meier method.  
Swimmer plots will be provided depicting graphically the duration of response for patients who 
achieve complete response or partial response per RECIST 1.1 in each cohort. For Cohorts 2 and 
3, swimmer plots of tumor response will also be provided per irRECIST criteria.  
Disease control rate (DCR) is defined as the proportion of evaluable subjects who achieved BOR 
of CR or PR with any duration or SD with duration of at least 3 months (i.e., >=3 months). The 
estimate of the DCR will be accompanied by one-sided and two-sided 95% Clopper-Pearson 
confidence intervals. Additionally, DOR and DCR will be derived and summarized based on the 
irRECIST criteria for Cohorts 2 and 3 subjects.    
8.2.3 Overall Survival (OS)  
Overall survival (OS) is defined as the time from first dose to death due to any cause. Subjects 
who are alive or lost to follow-up as of the data analysis cutoff date will be censored at the last 
known alive date.  
The OS will be summarized descriptively using the Kaplan-Meier method; median OS and its 
corresponding 95% confidence interval will be reported. Median follow-up for OS will be 
estimated according to the Kaplan-Meier estimate of potential follow-up (Schemper and Smith 
1996). Kaplan-Meier curve of OS will be provided.  
8.3 Exploratory Analysis 
GpNMB expression will be summarized over time and/or by specific prior therapies. 
If feasible, based on the range of gpNMB expression, the correlation between gpNMB 
expression level and maximum percent decrease from baseline in the sum of longest diameters of 
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data distribution is not normal. For this analysis, all subjects will be used, with gpNMB 
expression measured on a continuous scale (percentage of gpNMB-positive tumor cells).  
To examine the predictive power of various cut-off values for gpNMB expression, a receiver 
operating curve (ROC) analysis for response data (Gönen and SAS Institute. 2007) will be 
performed. 
The correlation between gpNMB expression levels and efficacy endpoints including ORR, PFS, 
and OS will be explored using subgroup analyses by gpNMB level categories. Descriptive 
statistical tests may be used to compare the efficacy endpoint in subjects with different gpNMB 
level categories, if appropriate. Cox proportional hazard model may also be used to assess the 
gpNMB effects on PFS and OS by considering gpNMB expression in a continuous and/or 
categorical scale. 
For the above analyses, the most recent tumor sample will be utilized to determine the tumor 
gpNMB expression level for each patient. Additional exploratory analyses may be performed to 
examine the distribution and intensity of gpNMB expression (i.e., staining intensity and 
percentage of positive tumor and stromal cells) relative to outcome, as well as comparison of 
Historic and Pre-Study samples to determine whether gpNMB expression changes over time 
and/or with specific prior therapies.     
ORR, PFS and OS will be summarized by whether patients experienced rash in cycle 1 which is 
defined in Section 5.3. A by-subject listing will be provided for gpNMB expression data and 
related efficacy endpoints.   
Gene signature from skinfold biopsy samples for cohorts 2 and 3 patients will be analyzed for its 
correlations with rash in cycle 1 and with ORR and PFS.   
9 SAFETY ANALYSES 
Unless otherwise specified, all the safety analyses will be based on the safety population by 
cohort. 
 
9.1 Extent of Exposure 
The duration of exposure to study treatment, total number of doses and cumulative dose 
administered will be summarized for each treatment within each cohort. Relative dose intensity 
will be additionally calculated for Glembatumumab exposure. The individual dose is calculated 
using the actual body weight of the patient at baseline, and the dose may remain constant 
throughout the study unless a greater than 10% change in weight is observed, in which case the 
weight at the cycle will be used. 
The calculations for the above statistics for each treatment in each cohort are as follows: 
• Duration of Exposure (days) = Date of Last Dose – Date of First Dose + 1 
• Total number of doses= the total number of doses with volume added to bag>0 and total 
volume infused>0  
• The actual dose at each cycle (mg/kg) = 
o Glembatumumab:  Total Volume infused (mL) / [Volume of Infusion bag (mL)] 
* Volume of Glembatumumab Vedotin added to bag (mL) * 5 (mg/mL) / weight 
(kg) 
o Varlilumab: Total Volume infused (mL) / [Total volume prepared (mL)] * 
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o Nivolumab: Total Volume infused (mL) / [Total volume prepared (mL)] * 
Volume of Nivolumab added to bag (mL) * 10 (mg/mL) / weight (kg) 
o Pembrolizumab: Total Volume infused (mL) / [Total volume prepared (mL)] * 
Volume of Pembrolizumab added to bag (mL) * 25 (mg/mL) / weight (kg) 
• Cumulative dose for each treatment is the sum of all actual doses for all cycles in mg/kg 
• For Glembatumumab, Relative Dose Intensity = Actual Dose Intensity (ADI) / Planned 
Dose Intensity (PDI), where ADI (mg/kg/3 weeks) = Cumulative Dose (mg/kg) / ((Date 
of Last Dose – Date of First Dose + 21) / 21) and PDI (mg/kg/3 weeks) = 1.9 mg/kg/3 
weeks. 
9.2 Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
Terminology (using latest MedDRA version). All AEs will be presented in a by-subject listing.  
Safety evaluations will be based on the incidence, severity, type of AEs, clinically significant 
changes or abnormalities in the subject’s physical examination, vision examination, vital signs, 
ECG, and clinical laboratory results.  
These analyses will be performed using the safety population by cohort. 
9.2.1 Treatment emergent AE 
Treatment emergent AEs (TEAEs) include all AEs that occurred or increased in severity from 
first dose of study treatment up to 28 calendar days after the last administration of 
glembatumumab vedotin or 70 calendar days after the last administration of varlilumab 
(whichever occurs later, Cohort 2); 70 days after last dose of the PD-1 targeted checkpoint 
inhibitor (whichever occurs later in Cohort 3). In addition, if an AE cannot be determined as 
treatment-emergent or not due to incomplete/missing data, conservatively, it will be considered 
as treatment emergent and included in the summary tables. Any AE summary tables described in 
this plan are based on treatment-emergent AEs unless specified otherwise. The number and 
percentage of subjects experiencing at least one treatment emergent adverse event will be 
tabulated by MedDRA primary system organ class, preferred term and cohort. For the number of 
subjects with AEs, subjects reporting the same event more than once will have that event counted 
only once within each body system, and once within each preferred term.   
A separate summary will be provided for study treatment-related AEs. A study treatment-related 
AE is defined as an AE for which the investigator classifies the relationship to study treatment as 
“Related”. A worst-case scenario approach will be taken to handle missing relatedness data, i.e., 
the summary table will include events with the relationship to study treatment as “Related”. The 
number and percentage of subjects experiencing at least one treatment emergent AE considered 
related to treatment will also be summarized.  
TEAEs will also be summarized by NCI-CTCAE version 4.0 grade.  Again, multiple occurrences 
of the same event are counted once per subject using the maximum severity.  If the grade of an 
AE is missing, the event will be included in the total column for the corresponding cohort. 
TEAEs with actions of study treatment delayed/interrupted, reduced, or discontinued will be 
summarized in by CTCAE grade. Summary statistics of the number and percentage of subjects 
experiencing at least one treatment emergent AE by study visit will be presented as well.   The 
subject incidence count for each visit will be from the time of the pervious visit, except the 
baseline visit, where it counts from the time of first dose.   


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9.2.2 Serious Adverse Events 
The number and percentage of subjects experiencing at least one treatment emergent serious AE 
(SAE) will be summarized by MedDRA primary system organ class and preferred term for each 
cohort. 
In addition, a by-subject listing of the SAEs will be presented (the subject listing will contain all 
SAEs regardless of treatment emergent AE status). 
 
9.2.3 AE with outcome of death 
A by-subject listing of the deaths will be presented.  All deaths occurring on-study and during 
follow-up will be displayed (regardless of treatment emergent AE status). The primary cause of 
death will also be summarized. 
 
9.2.4 Grouped AE 
Grouped AEs including Anemia, Neutropenia, Thrombocytopenia, Leukopenia, Neuropathy and 
Rash will be determined by medical review of the AEs, and will be summarized in the AE tables 
in a similar fashion as AE preferred terms.   
 
9.3 Laboratory Parameters 
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units.  If a lab value is reported using a non-numeric qualifier (e.g., 
less than (<) a certain value, or greater than (>) a certain value), the given numeric value will be 
used in the summary statistics, ignoring the non-numeric qualifier.   
If a subject has repeated laboratory values for a given time point, the value from the last 
evaluation will be used. 
The actual values in clinical laboratory parameters will be summarized at baseline and over time 
on study by treatment group; summary statistics for change from baseline of hematology, clinical 
chemistry, and urinalysis values will also be presented.   
 
9.3.1 Hematology and Clinical Chemistry 
The descriptive summary table with actual lab values and change from baseline values will be 
generated based on protocol defined hematology parameters (i.e., Hemoglobin, Hematocrit, 
Mean corpuscular volume (MCV), Erythrocyte count (RBC), Leukocytes (WBC), Platelets, 
Neutrophils, Lymphocytes, Monocytes, and Eosinophils) and chemistry parameters (i.e., 
Sodium, Potassium, Chloride, Bicarbonate, Glucose (nonfasting), Blood urea nitrogen (BUN), 
Creatinine, Calcium, Phosphate, Alkaline phosphatase, Alanine transaminase/ Serum Glutamic 
Pyruvate Transaminase (ALT/SGPT), Aspartate transaminase/ Serum Glutamic Oxaloacetic 
Transaminase (AST/SGOT),Total protein, Albumin, Lactate Dehydrogenase (LDH), Total 
Bilirubin).  For hematology and chemistry parameters, shift tables of the change in NCI CTCAE 
grade from baseline to the post-baseline by visit and worst CTCAE grade will be generated. The 
number and proportion of patients with directional shifts above or below the standard normal 
range will be summarized for selected laboratory tests. 


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By-subject listings of hematology and chemistry data will be presented. Laboratory values 
outside of normal limits will be identified in data listings and will be flagged for high and low 
values. 
9.3.2 Urinalysis  
A by-subject listing of Urinalysis data will be presented. The parameters to be listed include: pH, 
protein, glucose, blood, specific gravity, microscopic evaluations (available only if urinary 
infection is clinically indicated). For cohort 2, thyroid function test parameters including TSH, 
free T4 and T3 will be listed additionally.  
9.4 Vital Signs 
The actual values of vital sign parameters including temperature (Celsius), pulse rate (beats/min), 
respiration rate (breaths/min), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), 
and weight (kg) will be summarized over time.  Changes from baseline will also be presented.  A 
by-subject listing for vital sign data will also be presented according to eCRFs. 
9.5 Electrocardiograms 
Electrocardiogram (ECG) assessments are planned at Screening, Day 1 of Cycle 1, and End of 
Treatment visit.  ECG results will be summarized using shifts from baseline for the number and 
percentage of subjects with abnormal (clinically significant and not clinically significant, 
separately) and normal findings, as reported by the local investigator.  
A by-subject listing for ECG data will also be presented according to eCRFs. 
9.6 ECOG PS  
Eastern Cooperative Oncology Group (ECOG) performance status will be evaluated at 
Screening, Day 1 of each treatment cycle, and End of Treatment visit.  ECOG performance status 
will be summarized at baseline and each post baseline scheduled visit. Summaries will use 
frequency and percentage of subjects at each planned assessment time. In addition, post-baseline 
scores will be summarized descriptively using shifts from baseline. 
A by-subject listing for ECOG data will also be presented according to eCRFs. 
10 PHARMACOKINETIC,  PHARMACODYNAMIC AND 
IMMUNOGENICITY ANALYSES 
All planned analyses for PK, PD and immunogenicity will be provided in a separate report. Data 
listings and/or basic descriptive summaries may be presented in the Clinical Study Report. 
11 INTERIM ANALYSES 
No interim analysis is planned. 
12 CHANGES FROM THE PLANNED ANALYSES 
In the protocol, ITT population and Safety population are equivalent. For simplicity of reporting, 
the term of ITT Population is retired. 


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13 SOFTWARE 
14 TABLES, LISTINGS, AND GRAPHS (TLGS) SHELLS AND 
PROGRAMMING SPECIFICATIONS 
15 REFERENCES 
Eisenhauer, E. A., P. Therasse, et al. (2009). "New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1)." Eur J Cancer 45(2): 228-247. 
Gönen, M. and SAS Institute. (2007). Analyzing receiver operating characteristic curves with SAS. 
Cary, NC, SAS Pub. 
Nishino, M., A. Giobbie-Hurder, et al. (2013). "Developing a common language for tumor 
response to immunotherapy: immune-related response criteria using unidimensional 
measurements." Clin Cancer Res 19(14): 3936-3943. 
 
 


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16 APPENDICES 
16.1 Schedule of Assessment 
 
Visit 
Screening2 
Treatment Visits3 
Cycle 1/ 
Day 1 
Cycle 1/ 
Day 7 
(Cohorts 2 
and 3) 
Cycle 1/ 
Day 14 
(Cohorts 2 
and 3) 
Cycle 2/ 
Day 1 
Cycle 3, 4, 5, etc./ 
Day 1 
End of 
Treatment4 
Visit window1 
Day -28 to 
Day -1 
+/- 1 day 
+/- 1 day 
+/-3 days 
+/-3 days 
Within 28 days 
post-dosing 
Informed Consent, and, if applicable, 
HIPAA 
X 
Tumor tissue7 
X8 
X9 
Skin fold biopsy7 
X8 
Medical history10 
X 
X 
Physical examination11 
X 
X12 
X 
X 
X 
Vital signs13 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X12 
X 
X 
X 
Electrocardiogram (ECG) 
X 
X 
Pregnancy test14 
X 
X12 
Hematology15 
X 
X12 
X 
X 
X 
X 
X 
Blood chemistry15 
X 
X12 
X 
X 
X 
X 
X 
Urinalysis/dipstick15 
X 
X12 
X 
Thyroid function test (Cohort 2)15 
X 
X12 
X (Odd cycles) 
X 
Immunogenicity16, 17 
X 
X (Odd cycles) 
X 
PBMC collection17, 18 
X 
X 
X (Cohorts 2 and 3, 
Cycle 5 only) 
PK sample collection17, 19 
X 
X 
X (Odd cycles) 
X 
PD sample collection17 
X 
X 
X 
Disease assessment20 
X 
Administration of glembatumumab 
vedotin21 
X 
X 
X 
Administration of varlilumab22 
(Cohort 2) 
X 
X 
X21 
Administration of PD-1 targeted CPI 
(Cohort 3)23 
X 
X23 
Survival status 
Concomitant medication review24 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring25 
X 
X26 
X26 
X 
X 
X 
1. 
Imaging-based evaluation per RECIST 1.1 should be performed. Contrast-enhanced Computed Tomography (CT) of the 
chest, abdomen, and pelvis, as well as all other suspected disease sites is required. Magnetic Resonance Imaging (MRI) 
exams of the brain, abdomen, and pelvis can be performed in lieu of a CT; however, MRI exams of the chest are not 
recommended. In the event that a chest MRI is performed, a non-contrast chest CT is strongly recommended to evaluate 
the lung parenchyma. Brain and/or bone scans are required for any patients with a history of metastases to bone and/or 
brain or where symptomatology raises the suspicion for bone and/or brain metastases. Lesions identified on bone scans 
should be confirmed by a CT or MRI at baseline, and, if identified as target lesions due to soft tissue component, they 
should continue to be followed by the same methodology (i.e., CT or MRI scan). However, bone lesions followed as non-
target disease may be subsequently followed by bone scans only. Lesions that cannot be imaged but are assessable by 
clinical exam may be assessed by color photography including a ruler (preferred method) or measured with calipers. 
Normally, all target and non-target disease sites should be evaluated at each assessment. However, for patients with non-
target bone disease, bone scans need only be repeated every twelve to eighteen weeks, or more frequently if clinically 
indicated. The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up. Target lesions selected for tumor measurements should be those where 
surgical resection or radiation are not indicated or anticipated. 
2. 
Unless otherwise specified, all study assessments should be performed prior to administration of study treatment(s), and 
may be performed up to 24 hours prior to treatment administration if assessments remain within the specified visit window. 


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3. 
In Cohort 2, varlilumab and glembatumumab vedotin will be administered as separate infusions with a break of at least 30 
minutes between infusions. Varlilumab should be infused over 90 (±10) minutes and administered before glembatumumab 
vedotin, also infused over 90 (±10) minutes. Varlilumab will be administered on Day 1 of Cycles 1, 2, 4, 6, 8, and 10 only. 
Patients in Cohort 1 should be monitored for at least 1 hour following the last administration of study drug to monitor for 
infusion reaction/cytokine release syndrome/hypersensitivity reaction. Patients in Cohort 2 should be observed on Cycle 1 
Day 1 for at least 2 hours after the last study drug, and for at least 1 hour at all subsequent dosing visits. Infusions should 
be given in a monitored setting that has ready access to an intensive care unit in case of a severe infusion reaction 
4. 
Administration of the PD-1 targeted CPI should be continuous from the prior standard of care treatment regimen during 
which the most recent disease progression occurred. No more than 1 dose of a PD-1 targeted CPI should be missed between 
the most recent disease progression and initiation of treatment on study. Day 1 of Cycle 1 occurs with the first dose of 
glembatumumab vedotin which is administered on the same day as the PD-1 targeted CPI. When both glembatumumab 
vedotin and the PD-1 targeted CPI are administered on the same day, the drugs will be administered as separate infusions. 
The PD-1 targeted CPI should be the first infusion and glembatumumab vedotin administered at least 30 minutes later as 
the second infusion. Patients in Cohort 3 should be observed on Cycle 1 Day 1 for at least 2 hours after the last study drug, 
and for at least 1 hour at all subsequent dosing visits. Infusions should be given in a monitored setting that has ready access 
to an intensive care unit in case of a severe infusion reaction. The PD-1 targeted CPI will be administered in combination 
with glembatumumab vedotin until disease progression (using study screening disease assessment as baseline reference) 
or intolerance. 
5. 
Additional clinic visits and monitoring (such as laboratory assessments) relevant to the administration of the PD-1 targeted 
CPI will be conducted in accordance with standard of care when appropriate. However, all CPI dosing and adverse events 
occurring between study visits will be documented in the eCRF. 
6. 
All concomitant medication will be documented in the Case Report Form (CRF) if taken within 28 days prior to Study Day 
1, and either (whichever occurs sooner): a) 28 days after last dose of study treatment or b) initiation of alternate anti-cancer 
therapy. In addition, all anti-cancer medications should be recorded throughout the duration of study follow-up. 
7. 
For patients who develop grade 3 treatment-related rash and who provide appropriate consent, punch biopsies and 
photographs of the rash, as well as uninvolved skin, are strongly encouraged. Samples may be analyzed centrally; in these 
cases, collection, processing and shipping instructions will be provided separately. 
8. 
Adverse event monitoring on Cycle 1 Day 7 and Cycle 1 Day 14 for patients in Cohorts 2 and 3 can be performed in person 
or by telephone to determine if the patient is experiencing any adverse events. 
9. 
Events occurring >28 days after discontinuation of glembatumumab vedotin, >70 days after discontinuation of varlilumab 
(Cohort 2), or >70 days after discontinuation of the PD-1 targeted CPI (Cohort 3) are only reportable if both serious (SAE) 
and potentially treatment-related. 
10. A delay in study treatment or performance of study visits due to holidays, weekends, inclement weather or other 
unforeseen circumstances will be permitted and not considered a protocol violation. However, significant delays (i.e., 
greater than one week) due to these reasons should be discussed with the study medical monitor to reach consensus on 
subsequent scheduling. See (Protocol Section 8.5) and (Protocol Section 8.7) for management of dosing delays due to 
toxicity. 
11. Informed consent may be signed at any time prior to or during the screening period. No study-specific procedures will be 
performed prior to receipt of signed Informed Consent. However, assessments performed according to standard of care 
prior to receipt of Informed Consent may be utilized to fulfill the screening requirement, if completed within the required 
window for screening. 
12. Patients will receive study treatment until intolerance, progression of disease, or any of the other criteria for 
discontinuation of study treatment (Protocol Section 7.2.4.1.1) are met. All cohorts will receive glembatumumab vedotin 
on a three-week cycle. Cohort 2 patients will also receive varlilumab on Day 1 of Cycles 1, 2, 4, 6, 8, and 10. Cohort 3 
patients will also receive a PD-1 targeted CPI per institutional standard of care. 
13. The End of Treatment Visit should be performed within 28 days after last dose of study treatment and prior to initiation of 
alternate therapies. 
14. Disease assessments will be performed every 6 weeks (±1 week) for 6 months and every 9 weeks (±2 weeks) thereafter, 
scheduled based on the first dose of glembatumumab vedotin at C1D1, until documented progression of disease or 
initiation of alternate anticancer therapies. For Cohorts 2 and 3, in cases of apparent progression that may reflect 
enhanced inflammation and/or an initial imbalance in the kinetics of tumor growth and anti-cancer immune activity, 
continued combination treatment may be allowed with permission granted from the Celldex Medical Monitor, until a 
second radiologic confirmation of progression performed at the next scheduled disease assessment (or sooner if clinically 
indicated) (Protocol Section 5.5.3 and Protocol Section 7.2.4.1.1). If a partial or complete response is noted, a follow-up 
disease assessment must be done no sooner than 28 days later to confirm response. Patients who discontinue treatment in 
the absence of progression will continue to have tumor assessments until documented progression or initiation of 
alternate anti-cancer therapies. If surgical intervention or localized radiation are indicated (either for palliation or 
down-staging of previously non-resectable tumor), these interventions should be avoided if clinically feasible until after 
the 12-week response assessment. Prior to any intervention (such as surgical resection, palliative radiation or alternate anti-
cancer therapy), every effort should be made to perform a tumor response assessment in order to document progression 
and/or confirm an objective response. Patients who undergo surgical resection or radiation in the absence of progression 
may continue to receive study treatment until remaining lesions meet criteria for progression of disease. 


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15. Subsequent to disease progression, all patients will be followed at 12 (±2) week intervals until study closure. Patients who 
discontinue treatment in the absence of progression will continue to have tumor assessments until documented 
progression or initiation of alternate anti-cancer therapies. These visits may be performed by telephone. 
16. Assessment of gpNMB expression will be performed by IHC, retrospectively, at a central laboratory on FFPE Historic and 
Pre-entry (tumor and skin fold [axilla or groin] biopsy) samples. Skin biopsy should be 3-5 mm in diameter. Additional 
analyses performed centrally may also include, but are not limited to, gpNMB expression by Reverse Transcriptase 
Polymerase Chain Reaction (RT-PCR), examination of tumor markers using IHC or other molecular analyses, evaluation 
of tumor infiltrating leukocyte populations, biomarkers related to immune activation and localization of glembatumumab 
vedotin, CR011, or MMAE at the tumor site in post-treatment samples. Sample collection, processing and shipping 
instructions will be provided separately. 
17. Historic FFPE samples must represent the advanced stage of disease (Stage III or IV). Pre-entry FFPE samples must be 
obtained within 12 weeks prior to study entry, be subsequent to the last systemic anticancer therapy received, and be post-
tumor progression. For patients who must undergo biopsy to obtain a FFPE Pre-entry sample, biopsy sites must be soft 
tissue tumor or visceral lesions that can be biopsied with acceptable clinical risk (as judged by the investigator). 
The biopsy site chosen should not have been previously irradiated and must be distinct from RECIST 1.1 target lesions. 
Tissue from multiple previous collection dates should also be submitted, when available/feasible, in order to further 
understand how gpNMB levels may change over time and/or with cancer stage. Skin biopsies (Cohort 2) must be obtained 
within 12 weeks of study entry. 
18. At recurrence, biopsy and central analysis of recurrent tumor is optional but strongly encouraged. Similarly, in the event of 
tumor resection or biopsy performed per standard of care anytime during treatment or following tumor progression, 
submission of these tissue samples for central analysis is strongly encouraged. 
19. Medical history includes demography, melanoma history, previous surgeries/therapy, and pre-existing diseases. At Cycle 
1, Day 1, medical history is updated prior to administration of study drug. 
20. Complete physical exam should be performed at screening; thereafter, symptom-directed exams are acceptable. 
21. Assessments do not need to be repeated if completed within the previous 24 hours as part of the screening assessment. 
22. Vital signs to include height (at screening only), weight, respiration, pulse, temperature, and resting systolic and diastolic 
blood pressure. In Cohort 2 on glembatumumab vedotin and varlilumab dosing days, vital signs should be assessed pre-
infusion, at 45 (±15) minutes during each infusion, and within one- half hour following completion of each infusion. In 
Cohort 3, vital signs should be assessed for each glembatumumab vedotin infusion as follows: pre-infusion, at 45 (±15) 
minutes during the infusion, and within one-half hour following completion of the glembatumumab vedotin infusion. 
Additionally, when the PD- 1 targeted CPI is administered with or without glembatumumab vedotin dosing, vital signs 
should be assessed prior to each PD-1 targeted CPI infusion and additionally, as necessary, per clinical and institutional 
standards. (Note: weight is only assessed once per visit.) 
23. Serum or urine pregnancy test only for women of childbearing potential. Patients of non-childbearing potential include 
those who are ≥60 years, surgically sterilized, or postmenopausal with absence of menses for at least 1 year. However, 
women <60 with therapy-induced amenorrhea will require a pregnancy test unless additional evidence (oophorectomy or 
serial measurement of FSH and/or estradiol) are available to ensure postmenopausal status. 
24. Laboratory assessments must include the following, when indicated. Hematology results must be reviewed prior to dosing. 
For patients in Cohort 2, liver function tests (i.e., ALT, AST, and total bilirubin) and creatinine must also be reviewed prior 
to dosing. In addition, in Cohort 2, thyroid function tests must be performed at screening, at Cycle 1, at every odd cycle 
(i.e., Cycles 3, 5, 7, etc.), and at End of Treatment. 
Clinical Chemistry: 
Urinalysis 
n 
Sodium 
pH 
Potassium 
Protein 
uscular volume (MCV) 
Chloride 
Glucose 
e count (RBC) 
Bicarbonate 
Specific gravity 
 (WBC) 
Glucose (nonfasting) 
Blood 
l: 
s 
es 
s 
l should be reported consistently 
t the study as either an absolute 
erred) or as a percentage. 
Blood urea nitrogen (BUN) 
Creatinine Calcium 
Phosphate 
Alkaline phosphatase 
Alanine transaminase (ALT/SGPT) Aspartate 
transaminase (AST/SGOT) Total protein 
Albumin 
Lactate Dehydrogenase (LDH) 
Total Bilirubin 
Microscopic examination must be performed at 
baseline and, if clinically indicated, at subsequent visits 
(if urinary infection is suspected then a negative urine 
culture is required prior to enrollment.) 
Thyroid Function Test (Cohort 2 only) 
TSH 
Free T4 and T3 
Free T4 and free T3 performed at screening, and then 
only if TSH is abnormal at subsequent visits. 
25. Samples for immunogenicity will be collected prior to dosing on Day 1 of “odd” cycles (i.e., Cycles 1, 3, 5, 7, etc.). 
26. Analyses will be performed centrally. Sample collection, processing and shipping instructions will be provided separately. 
27. For Peripheral Blood Mononuclear Cell (PBMC) collection on Cycle 1/Day 1 and Cycle 2/Day 1, samples are collected 
prior to dosing. For Cohort 1 an additional sample is collected at End of Treatment. For Cohort 2s and 3 an additional 


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sample is collected on Cycle 5/Day 1 prior to dosing. Analyses may include (but are not limited to) examination of gpNMB 
expression (and/or potential binding partners for gpNMB) on myeloid suppressor cells; peripheral leukocytes; circulating 
tumor cells; and other immune response cells of interest. Additional analysis may include response assessment to 
potentially relevant tumor antigens and analysis of myeloid derived suppressor cells. Details on sample collection and 
handling will be provided separately. PBMC samples will be collected until such time Celldex informs the sites that further 
data is not needed. 
28. Cohort 1: On Day 1 of Cycle 1 and 2 only, glembatumumab vedotin PK samples will be collected prior to dosing and at 
end of infusion (at or within 30 minutes after completion of infusion). A PK sample will also be collected at the End of 
Treatment visits.  
29. Cohort 2: On Day 1 of Cycles 1, 2, and 5, a total of three PK samples will be collected on each day for glembatumumab 
vedotin and varlilumab PK analysis. PK samples will be collected prior to dosing of varlilumab, at end of varlilumab 
infusion (at or within 10 minutes after completion of infusion), and at end of glembatumumab vedotin infusion (at or within 
10 minutes after completion of infusion). On Day 1 of Cycles 3, 7, and subsequent odd cycles, only one PK sample will 
be collected prior to the first infusion. An additional sample should be drawn as soon as possible for any patients who 
experience an infusion reaction. A PK sample will also be collected at the End of Treatment visits.  
30. Cohort 3: On Day 1 of Cycles 1, 2, and 5, a total of two PK samples will be collected on each day for glembatumumab 
vedotin PK analysis. PK samples will be collected prior to dosing of glembatumumab vedotin and at end of infusion (at or 
within 10 minutes after completion of infusion). On Day 1 of Cycles 3, 7, and subsequent odd cycles, only one PK sample 
will be collected prior to the first infusion. An additional sample should be drawn as soon as possible for any patients who 
experience an infusion reaction. A PK sample will also be collected at the End of Treatment visits. 
31. For Cohorts 1, 2, and 3, analysis may also include circulating soluble gpNMB levels or other soluble molecules.