Conditions: Squamous Cell Carcinoma of the Lung
Keywords: gpNMB-Expressing Squamous Cell Carcinoma of the Lung Stage IIIb Stage IV Advanced Squamous Cell Cancer of the Lung Metastatic Squamous Cell Cancer of the Lung gpNMB-Expressing Glembatumumab Vedotin
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 13
Healthy volunteers: no

Brief summary:
Patients with advanced or metastatic, gpNMB-expressing Squamous Cell Carcinoma (SCC) of the lung who have failed a prior platinum-based chemotherapy regimen will receive glembatumumab vedotin.

Glembatumumab vedotin consists of an antibody (a type of human protein) attached to a drug called Monomethyl Auristatin E (MMAE) that can kill cancer cells. Glembatumumab vedotin is intended to work by specifically directing the drug to the cancer cell. It attaches to a molecule on the cancer cell called gpNMB, and then releases the MMAE inside the tumor cell, which in turn causes the cell to die.

The purpose of this study is to see whether glembatumumab vedotin is effective in treating people who have advanced or metastatic squamous cell lung cancer that contains gpNMB, to examine how the body handles the drug and the side effects associated with glembatumumab vedotin.

Detailed description:
Lung cancer is the most frequent cancer in the world, with annual cases worldwide currently estimated at one million and increasing to 10 million by the year 2025. In the United States, despite the declining incidence in white males in recent years, lung cancer is still the second most frequent cancer in both men (next to prostate) and women (next to breast cancer).

This is an open-label, single arm study of glembatumumab vedotin, a fully-human IgG2 monoclonal antibody. The activity of glembatumumab vedotin may be greatest in patients who overexpress the target, gpNMB.

This study will include a dose-escalation phase to determine the maximum safe and tolerated dose. This will be followed by a 2-stage Phase II expansion. During Phase II Stage 1, approximately 20 eligible, treated patients will be enrolled. If ≥ 2 patients achieve a tumor response \[Partial Response (PR) or Complete Response (CR)\]; an additional 15 eligible, treated patients will be enrolled in Stage 2, for a maximum total of 35 eligible, treated patients.

Glembatumumab vedotin will be administered once every 3 weeks, as a 90-minute intravenous (IV) infusion.

Patients will continue treatment until disease progression or intolerance. Tumor assessments will be performed every six (±1) weeks for six months, and every nine (±2) weeks thereafter, until progression.

A tumor tissue sample (i.e., obtained during a previous procedure or biopsy) will be sent to a central laboratory and tested for gpNMB. Research blood samples will also be required.

Arms:
arm 1: Glembatumumab vedotin once every three weeks (q3w) by 90-minute intravenous (IV) infusion, until disease progression or intolerance. The Dose-Limiting Toxicity (DLT) evaluation period for determination of the appropriateness of dose-escalation will be through the end of the second treatment cycle. arm 2: Glembatumumab vedotin once every three weeks (q3w) by 90-minute intravenous (IV) infusion, until disease progression or intolerance. The Maximum Tolerated Dose (MTD) determined in Phase I will be used in Phase II.

Interventions: intervention 1: Phase I: Glembatumumab Vedotin intervention 2: Phase II: Glembatumumab Vedotin
Intervention descriptions: intervention 1: Escalation Phase: Three to 6 patients will be enrolled in each dose cohort based on a standard Phase I dose escalation scheme. For the dose-escalation, the starting dose of glembatumumab vedotin will be 1.9 mg/kg q3w (Cohort 1). In the event of ≥ 2 DLTs, the dose will de-escalate to Cohort -1 (1.3 mg/kg).

Dose escalation from Cohort 1 to Cohort 2 (2.2 mg/kg) may proceed if three patients in Cohort 1 complete the DLT observation period with 0 DLTs, or if six patients in Cohort 1 complete the DLT observation period with 0 or 1 DLTs. intervention 2: In Stage 1, approximately 20 eligible, treated patients will be enrolled. If ≥ 2 patients achieve a tumor response (Partial Response \[PR\] or Complete Response \[CR\]), an additional 15 eligible, treated patients will be enrolled in Stage 2, for a maximum total of 35 eligible, treated patients.

Protocol document:
Prot_000.pdf: 


PrECOG Protocol Number: PrE0504 
IND Number: 128597 
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Date: 11/14/2017 
 
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TABLE OF CONTENTS 
PHASE I & PHASE II SCHEMA ................................................................................................ 5 
GLOSSARY OF ABBREVIATIONS ........................................................................................... 6 
1. PROTOCOL SYNOPSIS ....................................................................................................... 9 
2. SCHEDULE OF ASSESSMENTS ....................................................................................... 18 
3. BACKGROUND/RATIONALE ............................................................................................. 22 
3.1. Squamous Cell Lung Cancer......................................................................................... 22 
3.2. gpNMB .......................................................................................................................... 25 
3.3. Glembatumumab Vedotin .............................................................................................. 26 
3.4. Study Rationale ............................................................................................................. 33 
4. STUDY OBJECTIVES ......................................................................................................... 34 
4.1. Primary Objective .......................................................................................................... 34 
4.2. Phase I & II Secondary Objectives ................................................................................ 34 
4.3. Phase I & II Exploratory Objectives ............................................................................... 34 
5. INVESTIGATIONAL PLAN .................................................................................................. 35 
5.1. Overall Design and Plan of the Study ............................................................................ 35 
5.2. Selection of Study Population........................................................................................ 37 
6. STUDY TREATMENT ......................................................................................................... 42 
6.1. Glembatumumab Vedotin .............................................................................................. 42 
7. CONCOMITANT THERAPY ................................................................................................ 50 
8. STUDY PROCEDURES ...................................................................................................... 51 
8.1. Schedule of Investigations and Data Collection ............................................................. 51 
8.2. Methods of Assessment ................................................................................................ 52 
9. DATA SAFETY MONITORING BOARD (DSMB) ................................................................ 57 
10. STATISTICAL CONSIDERATIONS................................................................................... 58 
10.1. Analysis Endpoints ...................................................................................................... 58 
10.2. Sample Size and Power Calculation ............................................................................ 58 
10.3. Statistical Methods ...................................................................................................... 61 
11. LABORATORY AND PATHOLOGY CORRELATIVE STUDIES ........................................ 64 
11.1. Tumor Tissue Samples ............................................................................................... 64 
11.2. Blood Samples ............................................................................................................ 64 
11.3. Research Blood Samples Processing, Storage and Shipment .................................... 65 


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12. DATA HANDLING AND RECORD KEEPING .................................................................... 67 
12.1. Data Quality Assurance ............................................................................................... 67 
12.2. Electronic Case Report Form (eCRF) Information ....................................................... 67 
12.3. Archiving of Study Documentation .............................................................................. 67 
13. ETHICAL CONSIDERATIONS .......................................................................................... 68 
13.1. Institutional Review Board or Independent Ethics Committee ...................................... 68 
13.2. Ethical Conduct of the Study ....................................................................................... 68 
13.3. Patient Information and Informed Consent .................................................................. 68 
13.4. Protocol Amendments ................................................................................................. 69 
13.5. Safety Communication ................................................................................................ 69 
13.6. Confidentiality ............................................................................................................. 69 
14. REFERENCES ................................................................................................................. 70 
LIST OF APPENDICES 
Appendix 1: PrE0504 Eligibility Checklist ................................................................................ 73 
Appendix 2: ECOG Performance Status ................................................................................. 77 
Appendix 3: RECIST 1.1 Criteria ............................................................................................. 78 
Appendix 4: Cockroft and Gault Formula ................................................................................. 87 
Appendix 5: NYHA Classification ............................................................................................ 88 
Appendix 6: Investigator Signature .......................................................................................... 89 
LIST OF TABLES 
Table 1. Schedule of Assessments1 ........................................................................................ 18 
Table 2. NSCLC Clinical Trial Outcomes for Patients with Squamous Cell Histology .............. 24 
Table 3. Study CR011-CLN-20: Activity Data in Patients with Advanced Breast Cancer ......... 29 
Table 4. Study CDX011-03 (“EMERGE”): Response Data for Patients with Advanced 
gpNMB-Expressing Breast Cancer ......................................................................... 30 
Table 5. Study CR011-CLN-11: Activity Parameters by Dosing Schedule ............................... 32 
Table 6. Glembatumumab Vedotin Dose Levels (mg/kg) ........................................................ 44 
LIST OF FIGURES 
Figure 1. gpNMB Expression in Squamous and Adenosquamous Carcinoma of the Lung ...... 26 
Figure 2. Study CDX011-03 (“EMERGE”): Progression-Free and Overall Survival for 
Patient Subgroups of Interest .................................................................................. 31 
Figure 3. Study CR011-CLN-11: Outcomes by gpNMB Expression Level ............................... 32 
 
 


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PrECOG SITE CONTACT 
MEDICAL MONITOR 
Carolyn Andrews R.N. 
Project Manager 
PrECOG, LLC 
1818 Market Street 
Suite 1100 
Philadelphia, PA 19103 
Phone: 215-789-7001 
Email: candrews@precogllc.org 
 
1000 Continental Drive 
Suite 200 
King of Prussia, PA 19406 
During normal business hours 
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Phone: 484-574-2367 
Email: 
 
SAE Fax: 888-731-8999 
SAE Email: pre0504sae@qdservices.com 
 
 
 


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PHASE I & PHASE II SCHEMA 
Phase I Schema 
Phase I Only: Prior to discussing protocol entry with the patient, call the assigned PrECOG Project 
Manager to ensure a place on the protocol is open to the patient. Eligibility Criteria Checklist must 
be sent to the PrECOG PM/designee for review and approval prior to subject registration. Additional 
contact details are provided in the Study Reference Manual. 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
DLT is defined per Section 6.1.7 occurring through the end of the second treatment 
cycle (i.e., by day 42 (±3) days). 
2 
Amendment 2: A maximum of three additional patients were treated on Dose 
Level/Cohort 1 (1.9 mg/kg) for 9 patients at this dose level to verify the safety of this 
dosage regimen (Section 5.1.1 for details). 
3 Three patients completed treatment on Dose Level/Cohort -1 with no DLTs. 
4 
We will re-escalate to Dose Level/Cohort 1. An additional 3-6 patients will be treated 
on Dose Level 1 (up to 15 total). 
Phase I = maximum of 18 patients 
 
Phase II Schema 
 
 
 
 
 
 
 
 
 
 
 
1 MTD as determined during the dose-escalation phase. 
 
In Stage 1, approximately 20 eligible, treated patients will be enrolled. If ≥ 2 patients achieve 
a tumor response [Partial Response (PR) or Complete Response (CR)]; an additional 15 
eligible, treated patients will be enrolled in Stage 2, for a maximum total of 35 eligible, treated 
patients. To assure sufficient eligible, treated patients, up to 2 additional patients may be 
enrolled (total of 37 patients). There will be rigorous toxicity monitoring in Phase II – please 
see Statistical Considerations (Section 10.2.2.1) for details. 
Phase I & Phase II treatment should begin within 10 working days of registration. 
Dose Level/ 
Cohort 
Glembatumumab Vedotin 
IV every 3 weeks over  
90 minutes1 
-13 
1.3 mg/kg 
12,4 
1.9 mg/kg 
Stage 
Glembatumumab Vedotin 
IV every 3 weeks over  
90 minutes 
Patients 
(n) 
Stage 1 
MTD1 
20 
Stage 2 
MTD1 
15 
R 
E 
G 
I 
S 
T 
R 
A 
T 
I 
O 
N 
Treatment until 
Disease Progression 
or Intolerance 
R 
E 
G 
I 
S 
T 
R 
A 
T 
I 
O 
N 
Treatment until 
Disease Progression 
or Intolerance 


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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Definition 
ACS 
American Cancer Society 
ADC 
Antibody-Drug Conjugate 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
ALK 
Anaplastic Lymphoma Receptor Tyrosine Kinase 
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) 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CR 
Complete Response 
CNS 
Central Nervous System 
CT 
Computed Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DC-HIL 
Dendritic Cell-Heparin Integrin Ligand 
DCTD 
Division of Cancer Treatment and Diagnosis 
DHHS 
Department of Health and Human Services 
DLT 
Dose-Limiting Toxicity 
DOR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EST 
Eastern 
FDA 
Food and Drug Administration 
FNA 
Fine Needle Aspirate 
FSH 
Follicle-Stimulating Hormone 


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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
gpNMB  
Glycoprotein NMB 
HGFIN 
Hematopoietic Growth Factor Inducible Neurokinin-1 type 
HIPAA 
Health Insurance Portability and Accountability Act 
IC 
Investigator’s Choice 
ICH 
International Conference on Harmonization 
IgG2 
Immunoglobulin G, Subclass 2 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IRC 
Independent Review Committee 
IV 
Intravenous 
Kg 
Kilogram 
LCMS/MS 
Liquid Chromatography-Tandem Mass Spectrometry 
LDH 
Lactate Dehydrogenase 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
mL 
Milliliters 
MMAE 
Monomethylauristatin E 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
n 
number 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute (of the United States) 
NE 
Inevaluable 
NIH 
National Institutes of Health 
NR 
Not Reported 
NSCLC 
Non-Small Cell Lung Carcinoma 
NYHA 
New York Heart Association 
ORR 
Objective Response Rate 
OS 
Overall Survival 


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Abbreviation 
Definition 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR 
Partial Response 
q3w 
Every 3 Weeks 
RBC 
Red Blood Count 
RECIST 
Response Evaluation Criteria for Solid Tumors 
RNA 
Ribonucleic Acid 
ROC 
Receiver Operating Curve 
RT-PCR 
Reverse Transcriptase Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCC 
Squamous Cell Carcinoma 
SD 
Stable Disease 
SOPs 
Standard Operating Procedures 
SRM 
Study Reference Manual 
TA 
Total Antibody 
TEAE 
Treatment-Emergent Adverse Event 
TKI 
Tyrosine Kinase Inhibitor 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
vc 
Valine-Citrulline 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
WBC 
White Blood Count 
 
 
 


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1. PROTOCOL SYNOPSIS 
Protocol 
Number 
PrE0504 
Title 
A Phase I/II Study of Glembatumumab Vedotin in Patients with gpNMB-Expressing, 
Advanced or Metastatic Squamous Cell Carcinoma of the Lung 
Investigational 
Treatment 
 
 
 
 
 
 
 
Indication 
Patients with unresectable Stage IIIB or Stage IV, gpNMB-expressing squamous cell 
carcinoma (SCC) of the lung who have failed a prior platinum-based chemotherapy 
regimen. 
Number of 
Patients 
Approximately 55 patients will be enrolled 
Number of 
Study Centers 
Approximately 10 study centers will participate 
Objectives 
Primary: 
• 
Phase I: To evaluate the safety and tolerability and determine the Maximum 
Tolerated Dose (MTD) of glembatumumab vedotin in patients with advanced 
gpNMB-expressing SCC of the lung. 
• 
Phase II: Determine the anti-tumor activity, as assessed by objective response 
rate (ORR) in accordance with RECIST 1.1, of the MTD of glembatumumab 
vedotin in patients with advanced gpNMB-expressing SCC of the lung. 
Secondary: 
• 
To further characterize the safety of glembatumumab vedotin in advanced 
gpNMB-expressing SCC of the lung. 
• 
To further evaluate the anti-cancer activity of glembatumumab vedotin in 
advanced gpNMB-expressing SCC of the lung, as measured by duration of 
objective response (DOR), progression-free survival (PFS), and overall survival 
(OS). 
Exploratory: 
• 
To investigate if the anti-cancer activity of glembatumumab vedotin in advanced 
gpNMB-expressing SCC of the lung is dependent upon the degree of gpNMB 
expression in tumor tissue. 
• 
To examine pharmacodynamic effects of treatment, including tumor immune cell 
infiltrate type and number; localization of glembatumumab vedotin, CR011 or 
Monomethylauristatin E (MMAE) at the tumor site; soluble mediators and/or 
gpNMB expression levels in tumor tissue; and analysis of peripheral blood cell 
subsets. 
• 
To further characterize the pharmacokinetics and immunogenicity 
of 
glembatumumab vedotin in this patient population. 
Overview of 
Study Design 
This is an open-label, single arm study of glembatumumab vedotin in patients with 
unresectable, Stage IIIB or IV, gpNMB-expressing SCC of the lung who have failed a 
prior platinum-based chemotherapy regimen. This study will include a dose-escalation 
phase followed by a 2-stage Phase II expansion, as follows: 


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Study Phase 
Dose Level/ 
Cohort 
Glembatumumab Vedotin 
Dose (mg/kg) 
Patients (n) 
Phase I 
Dose-Escalation 
-12 
1.3 
3 
11,3 
1.9 
9 already 
treated; 3-6 
more to be 
added 
 
 
 
Phase II 
Stage 1 
MTD* 
20 
Stage 2 
MTD* 
15 
1 Amendment 2: A maximum of three additional patients were treated on Dose 
Level/Cohort 1 (1.9 mg/kg) for 9 patients at this dose level to verify the safety of this 
dosage regimen (Dose Escalation Phase below and Section 5.1.1 for details). 
2 Three patients completed treatment on Dose Level/Cohort -1 with no DLTs. 
3 We will re-escalate to Dose Level/Cohort 1. An additional 3-6 patients will be treated 
on Dose Level 1 (up to 15 total). 
* MTD as determined during the dose-escalation phase 
All patients will be seen in the clinic at scheduled intervals during the treatment phase 
of the study. Patients will not be permitted to have concurrent chemotherapy, 
immunotherapy or other experimental therapies during study treatment. 
Patients will receive glembatumumab vedotin in an open-label fashion, once every 
three weeks (q3w) by 90-minute intravenous (IV) infusion, until disease progression 
or intolerance. Tumor assessments will be performed every six (±1) weeks for six 
months, and every nine (±2) weeks thereafter, until progression. Tumor response will 
be assessed by the investigator in accordance with RECIST 1.1 guidelines 
(Eisenhauer, Therasse et al. 2009). 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. 
Dose-Escalation Phase: 
Original Plan: 
For the dose-escalation, the starting dose of glembatumumab vedotin will be 1.9 
mg/kg q3w (Cohort 1). This dose level is based upon the previously identified 
therapeutic dose of 1.88 mg/kg q3w, with rounding to 1.9 mg/kg for reasons of 
practicality and feasibility in preparation of the infusion. Notably, this rounded dose 
remains below the “intermediate” dose level of 2.0 mg/kg q3w, which was previously 
deemed tolerable in the Phase I/II melanoma study, CR011-CLN-11. 
Initially, three patients will be enrolled to Cohort 1. In the event of 1 dose-limiting 
toxicity (DLT), the cohort will be expanded to 6 patients. In the event of ≥ 2 DLTs, the 
cohort will have exceeded the MTD, and the dose will de-escalate. In this case, 3 
patients will be enrolled to Cohort -1 and the same DLT evaluation rules will apply, 
such that 1 DLT will require expansion to 6 patients; this dose level will be deemed 
the MTD if DLT occur in 0/3 or ≤ 1/6 patients; and the study will cease if ≥ 2 DLTs 
occur at dose level -1. 
Dose escalation from Cohort 1 to Cohort 2 may proceed if three patients in Cohort 1 
complete the DLT observation period with 0 DLTs, or if six patients in Cohort 1 
complete the DLT observation period with 0 or 1 DLTs. The MTD for the dose-


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escalation phase will be the highest dose-level where 0/3, or ≤ 1/6 patients in a cohort 
experienced a DLT. 
Amendment #2.0: 
As of February 14, 2017; of the 6 patients whom were enrolled on Cohort 1 
(1.9 mg/kg), 1 DLT was observed (Grade 5 respiratory failure deemed as possibly 
related to study drug [complicated by progressive disease at same time]). The deaths 
of two subjects were reported and appear most likely related to progressive disease 
and unrelated to the drug. However, dose escalation to Cohort 2 seemed premature. 
To further assess the safety signal and not put either subjects or the drug in jeopardy, 
it was PrECOG’s decision to modify the Phase I portion and treat a maximum of 3 
additional patients on Cohort 1 (1.9 mg/kg) for up to 9 patients at this dose level to 
verify the safety of this dosage regimen. If any of the 3 additional patients experience 
a DLT, the dose will de-escalate to Cohort -1. If none of the additional 3 patients 
experience a DLT, dose escalation may proceed from Cohort 1 to Cohort 2. The same 
DLT evaluation rules will apply as noted above. 
A second DLT was observed on Cohort 1. Patient experienced Grade 3 treatment-
related pruritus requiring hospital admission. Although a vital organ was not involved, 
due to the extent and intensity of the treatment required for pruritus, it was considered 
a DLT. Dose was de-escalated to Dose Level -1. 
Amendment #3.0: 
Three patients were enrolled to Dose Level -1 with no DLTs during the 42 day 
assessment period. 
Given the fact one of the previously reported DLTs at 1.9 mg/kg was complicated by 
the patient have progressive disease at the same time, and the other (pruritus) is a 
known and generally manageable adverse event associated with glembatumumab 
vedotin, it is reasonable to re-escalate, and re-explore the safety of the 1.9 mg/kg 
cohort. 
The protocol is being amended to include a plan to re-escalate to Dose Level 1. Upon 
re-escalation to Dose Level 1, 3 patients will be treated. This dose level will be 
deemed unsafe if at least 2 patients among the first 3 patients enrolled experiences a 
DLT, and Dose Level -1 will be deemed the MTD. If no DLTs are observed among the 
first 3 patients or if 1/3 patients experiences a DLT then we will enroll 3 more patients. 
This dose level will be determined to be the MTD in the event that <2/6 patients treated 
at Dose Level 1 experience DLT. If ≥ 2/6 patients experience DLT at Level 1, then 
Dose Level -1 will be declared the MTD. Note that Dose Level 2 is no longer part of 
the study effective with this amendment. 
The DLT evaluation period for determination of the appropriateness of dose-
escalation will be through the end of the second treatment cycle. Patients who 
discontinue safety follow-up before day 42 (±3 days) for reasons other than DLT will 
be replaced. 
Any DLT at any time point during the study must be reported to PrECOG (or designee) 
as soon as possible, but no later than 24 hours following the site becoming aware of 
the event, and PrECOG will distribute such notification to all participating sites within 
24 hours of notification. Site teleconferences between PrECOG and all participating 
sites will be held at frequent intervals and prior to dose-escalation to each cohort 
during the dose-escalation phase. PrECOG study personnel, including but not limited 
to the Study Chair(s), statistician, medical monitor and participating investigators, as 
applicable, will review toxicities from the current cohort during the site teleconferences 
before initiating enrollment into the next planned dose cohort. 
 
 


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DLT Definition: 
For escalation and MTD decisions, DLT is defined as any of the following conditions 
occurring through the end of the second treatment cycle (i.e., by day 42 (±3) days): 
• 
Grade 3 or 4 non-hematological drug-related toxicity not resolving to Grade 2 or 
less within 72 hours of initiation of supportive care. Exceptions to this criterion 
include asymptomatic lab abnormalities deemed not clinically significant and 
other toxicities of non-vital organs after discussion with PrECOG/medical monitor. 
• 
Grade 4 neutropenia lasting >5 days. 
• 
Grade 3 or higher neutropenia with associated fever >38.1˚C (100.5˚F). 
• 
Grade 4 thrombocytopenia. 
• 
Grade 3 irreversible peripheral sensory neuropathy that does not resolve or return 
to baseline status within 4 weeks of last dose of study drug. 
• 
Grade 4 neuropathy of any duration. 
• 
Anaphylaxis or Grade 4 infusion-related reaction. 
• 
Grade 5 toxicities considered possibly, probably, or definitely related to treatment. 
• 
Any 
treatment-related 
toxicity 
requiring 
permanent 
discontinuation 
of 
glembatumumab vedotin. 
Phase II: 
Following determination of the MTD, a Phase II study portion will enroll up to 35 
eligible, treated patients to further assess the safety and efficacy of glembatumumab 
vedotin. Patients who discontinue study for reasons other than symptomatic 
deterioration or death prior to a radiographic assessment will be considered 
unevaluable and will be replaced. 
Enrollment to the Phase II study portion will proceed according to a two-stage trial 
design (Simon 1989), so that enrollment may terminate early if the results are not 
sufficiently promising to warrant further study. In Stage 1, approximately 20 eligible, 
treated patients will be enrolled. If ≥ 2 patients achieve a tumor response (Partial 
Response [PR] or Complete Response [CR]), an additional 15 eligible, treated 
patients will be enrolled in Stage 2, for a maximum total of 35 eligible, treated patients. 
To assure sufficient eligible, treated patients, up to 2 additional patients may be 
enrolled (total of 37 patients). 
Additionally, we will monitor for the incidence of Grade 5 events. In particular, we will 
monitor the Grade 5 event rate among the first stage accrual of 20 patients. All Grade 
5 events deemed at least possibly related to treatment as well as any Grade 5 events 
occurring within 3 weeks of the first dose (Cycle 1) regardless of attribution are 
included as ‘events’ for the purpose of monitoring. See Section 10.2.2.1 for details. 
Study 
Treatment 
Dosing and 
Administration 
Glembatumumab vedotin will be administered on Day 1 of repeated 21-day cycles, 
as a 90-minute IV infusion using a 0.22 micron in-line filter. In the dose escalation 
phase, the starting dose for each patient is based on cohort assignment; Cohort 1 
(dose level 1) will be 1.9 mg/kg. In the Phase II study portion, the starting dose will be 
the MTD established in the dose escalation phase. 
Treatment may be delayed for up to three weeks (i.e., 1 cycle) to allow sufficient time 
for recovery from treatment-related toxicities. If a delay greater than three weeks is 
required, the Investigator should confer with PrECOG to determine the 
appropriateness of continued treatment. Prior to each treatment with glembatumumab 
vedotin, the following conditions must be met. 
• 
The absolute neutrophil count (ANC) must be ≥ 1500/mm3 and platelets 
≥ 100,000/mm3 prior to the start of each cycle. Growth factor support is permitted, 
and should be administered with consideration to the American Society of Clinical 


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Oncology (ASCO) guideline on the use of hematopoietic colony stimulating 
factors (Smith, Khatcheressian et al. 2006). 
• 
Drug-related non-hematological toxicities must have improved to baseline or NCI-
CTCAE ≤ Grade 2. Exceptions to this criterion include alopecia and other toxicities 
of non-vital organs after discussion with PrECOG. 
Dose adjustments in individual patients for toxicity are permitted. Any patient who 
requires a dose reduction will continue to receive a reduced dose for the remainder 
of the study. A maximum of two dose reductions are allowed. If a patient requires 
more than two dose reductions or reduction below the 1.0 mg/kg dose, they should 
be discontinued from treatment. Patients experiencing the following conditions require 
dose reduction: 
• 
DLT - Any toxicity defined as DLT (Section 6.1.7) occurring at any time during the 
course of treatment. 
• 
Patients who develop Grade 2 or 3 neuropathy will have dosing held until 
neuropathy improves to Grade 1 or baseline, and will be restarted with a dose 
reduction. Patients with Grade 4 neuropathy should have treatment discontinued 
permanently. 
• 
Other events that, in the opinion of the treating investigator, warrant dose 
modification. 
Eligibility 
Criteria 
*Phase I Only: Eligibility Criteria Checklist must be sent to the PrECOG 
PM/designee for review and approval prior to subject registration. 
Inclusion Criteria: 
1. Read, understood, and provided written informed consent and 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. Male or female patients with metastatic, histologically- or cytologically-confirmed 
unresectable Stage IIIB or IV non-small cell lung cancer (NSCLC) of squamous 
histology (Staging per American Joint Committee on Cancer [AJCC], Edition 7). 
Mixed histology adenosquamous NSCLC will also be permitted. 
3. Experienced progression/recurrence of disease during or subsequent to the most 
recent anti-cancer regimen. 
4. Any number of prior lines of systemic therapy may have been received for 
advanced (recurrent, locally advanced, or metastatic) SCC of the lung, but at least 
one must have been a platinum-based chemotherapy regimen. Platinum therapy 
may be given on-label or as part of a clinical trial. 
5. Lung 
cancer 
confirmed 
to 
express 
gpNMB, 
as 
assessed 
by 
immunohistochemistry at a central lab (using expression in ≥ 5% of tumor 
epithelial cells as a cut-off for positivity). This can be tested on archived tissue if 
available, although preferred tumor specimen is a biopsy after the most recent 
therapy. 
NOTE: Additional samples from previous collection dates should also be 
submitted when feasible. Submitted cytology samples such as pleural effusions, 
bronchial washings or fine needle aspirates (FNA) will be used to evaluate 
feasibility of gpNMB expression analysis and to investigate correlations with other 
samples for the patient, but they will not be used for determination of study 
eligibility. For patients with multiple samples submitted, eligibility will be based on 
the most recently obtained sample, or, if obtained on the same date, the sample 
with the highest level of gpNMB expression. However, in the event that disparate 
results are obtained for samples received within a similar timeframe (i.e., within a 
6-month period), the medical monitor may be consulted for determination of 
eligibility. 


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6. Age ≥ 18 years. 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1 
(Appendix 2). 
8. Measurable disease by RECIST 1.1 criteria (Eisenhauer, Therasse et al. 2009) 
(Appendix 3). Target lesions selected for tumor measurements should be those 
where surgical resection or radiation are not indicated or anticipated. 
9. Resolution of all toxicities related to prior therapies to ≤ NCI-CTCAE Grade 1 
severity, except for alopecia, vitiligo, or endocrinopathies on replacement therapy. 
10. Adequate bone marrow function as assessed by absolute neutrophil count (ANC) 
≥ 1500/mm3; hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100,000/mm3. 
11. Adequate renal function as assessed by serum creatinine ≤ 2.0 mg/dL; or 
calculated (Cockcroft and Gault Formula; Appendix 4) or 24-hour urine creatinine 
clearance >40 mL/min. 
12. Serum albumin ≥ 3 g/dL. 
13. Adequate liver function as assessed by total bilirubin ≤ 1.5x upper limit of normal 
(ULN), and alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5x 
ULN (≤ 5.0x ULN in the case of liver metastases). Patients with known Gilbert’s 
syndrome may be enrolled with total bilirubin ≤ 3.0 mg/dL. 
NOTE: The liver is a route of clearance for MMAE. Patients with mild hepatic 
impairment are excluded from Phase I (the dose escalation portion) to minimize 
the influence of hepatic impairment on tolerability and dose selection because a 
lower dose is recommended for other ADCs with a vc-MMAE moiety. See the 
acceptable liver function parameters for Phase I defined above. In Phase II 
(the dose expansion portion) a lower starting dose for patients with mild hepatic 
impairment will be determined based on the MTD recommended from the Phase 
I portion of this trial. The acceptable liver function parameters will be 
redefined for Phase II. 
14. Both male and female patients of childbearing potential enrolled in this trial must 
use adequate birth control measures during the course of the trial and for at least 
one month after discontinuing study drug. Adequate birth control measures are 
defined as double barrier contraception (e.g., condom plus spermicide in 
combination with a female condom, diaphragm, cervical cap, or intrauterine 
device), implants, injectables, combined oral contraceptives, sexual abstinence 
(abstinence from intercourse during the ovulation period), or vasectomized 
partner. Patients and/or partners who are surgically sterile or postmenopausal are 
exempt from this requirement. 
15. Willing to provide blood samples for research purposes (Section 11.2). 
Exclusion Criteria: 
1. Received glembatumumab vedotin (CR011-vcMMAE; CDX-011) or other MMAE-
containing agents previously. 
2. Chemotherapy within 21 days or at least 5 half-lives (whichever is shorter) prior 
to the planned start of study treatment; radiation outside the thorax within 14 days 
prior to the planned start of study treatment or thoracic radiation; antibody based 
therapy or investigational therapy within 28 days prior to the planned start of study 
treatment. 
3. Neuropathy >NCI-CTCAE Grade 1. 
4. 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. 


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5. Known brain metastases, unless previously treated and patients are 
neurologically returned to baseline except for residual signs and symptoms 
related to Central Nervous System (CNS) treatment and CNS lesions are not 
progressive in size and number for 4 weeks. 
6. Significant 
cardiovascular 
disease 
including 
unstable 
angina 
pectoris, 
uncontrolled hypertension, and congestive heart failure (New York Heart 
Association (NYHA) Class 3 or 4 [Appendix 5]) related to primary cardiac disease, 
a history of a serious uncontrollable arrhythmia despite treatment, ischemic or 
severe valvular heart disease, or a myocardial infarction within 6 months prior to 
the trial entry. 
7. 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, a negative urine culture is required prior to 
enrollment. 
8. Subjects 
on 
immunosuppressive 
medications 
such 
as 
azathioprine, 
mycophenolate mofetil, cyclosporine or require chronic corticosteroid use 
(defined as ≥ 3 months of prednisone dose equivalent of ≥ 10 mg). 
9. The MMAE component of glembatumumab vedotin is primarily metabolized by 
CYP3A. Patients taking strong CYP3A inhibitor and inducers are excluded in 
Phase I (the dose escalation portion), to minimize the effect of these modulators 
on exposure, tolerability and dose selection (http://medicine.iupui.edu/ 
clinpharm/ddis/main-table/). 
10. History of other malignancy except for adequately treated basal or squamous cell 
skin cancer, curatively treated in situ disease, or any other cancer from which the 
patient has been disease-free for ≥ 2 years. 
11. Pregnant or breast-feeding women. 
12. Subjects must not be on home oxygen therapy (intermittent or continuous). 
13. Any underlying medical condition that, in the Investigator’s opinion, will make the 
administration of study treatment hazardous to the patient, or would obscure the 
interpretation of adverse events. 
Criteria for 
Evaluation 
Safety Evaluations: 
Safety will be assessed by vital sign measurements, clinical laboratory tests, ECGs, 
physical examinations and the incidence and severity of adverse events (graded 
according to NCI-CTCAE V4.0.). 
Anti-Tumor Activity Evaluations: 
Anti-tumor activity will be assessed based on ORR, DOR, PFS and OS. Tumor 
response and progression will be defined by the investigator, according to RECIST 
1.1 criteria. 
Immunogenicity: 
Patients will be monitored for the development of anti-glembatumumab vedotin and 
anti-CR011 antibodies, and whether these antibodies are neutralizing. 
Pharmacokinetics (PKs): 
Concentration of the antibody-drug conjugate (ADC), total antibody (TA) and free 
MMAE 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 on 
pharmacokinetic parameters may also be examined. 
 


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Pharmacodynamics: 
Pharmacodynamic parameters will be evaluated via assessment of post-treatment 
tumor tissue obtained via voluntary biopsy or resection and/or blood samples. 
Parameters evaluated may include localization of glembatumumab vedotin, CR011 
or MMAE at the tumor site and/or gpNMB levels on cells in blood and tumor tissue, 
as well as evaluation of tumor infiltrating and peripheral leukocytes, circulating tumor 
cells and other immune response cells of interest. Soluble gpNMB levels in circulation 
may also be examined. 
Statistical 
Methods 
Sample Size Considerations: 
Escalation Phase: 
Refer to Section 5.1.1 for details. 
Three to 6 patients will be enrolled in each dose cohort based on Phase I dose 
escalation scheme as described above in the Overview of Study Design Section. 
(Dose Level 1 will enroll up to 15 patients as noted above and in Section 5.1.1). Each 
patient will participate in only 1 dose cohort. The total number of patients to be enrolled 
in the dose escalation phase is dependent upon the observed safety profile after 2 
cycles, which will determine the number of patients per dose cohort, as well as the 
number of dose escalations required to achieve the maximum tolerated dose (MTD). 
A starting sample size of 3 patients per dose cohort, expanding to 6 patients in the 
event of a marginal dose-limiting toxicity (DLT) rate (33%) was deemed to be a safe 
and conventional approach in the dose escalation of a novel oncologic agent. 
Assuming a true DLT rate of 5% or less, there would be a 3% chance that dose 
escalation would be halted in a given cohort (i.e., observing 2 or more patients with 
DLT). If a true DLT rate of 50% is assumed, then there would be an 83% chance that 
dose escalation would be halted in a given cohort. 
Phase II Study Portion: 
In the Phase II study portion, the safety and preliminary antitumor activity of 
glembatumumab vedotin at the selected dose will be explored. Up to 35 eligible, 
treated patients may be enrolled according to a single-arm Phase II trial design with 
ORR as the primary endpoint. 
The Phase II study portion will be carried out in 2 stages so that enrollment can 
terminate early in the event that glembatumumab vedotin is not sufficiently active in 
this patient population. A true ORR of 20% is hypothesized. A response rate of less 
than 5% is not considered clinically meaningful. The number of patients evaluated in 
each stage and the minimum number of responders needed to continue to the next 
stage were determined based on Simon’s 2-stage design, with 90% power and 1-
sided significance level of less than 10%. Based on the above considerations, 20 
eligible, treated patients will be enrolled (first stage): if ≤ 1 patient achieves a CR or 
(PR), then the trial will stop for futility; otherwise, 15 additional eligible, treated patients 
will be enrolled in the second stage, for a total of 35 eligible, treated patients. The 
regimen will be considered worthy of further study if 4 or more responses are 
observed among 35 eligible, treated patients. To assure sufficient eligible, treated 
patients, up to 2 additional patients may be enrolled (total of 37 patients). 
The primary endpoint of ORR will be estimated by the crude proportion of eligible, 
treated patients with best overall response of confirmed CR or PR, along with a 2-
sided 90% Confidence Interval (CI) if the study stops early; if the study proceeds to a 
second stage then the CI will be computed using the methodology of Atkinson and 
Brown. Secondarily, ORR, inclusive of confirmed and unconfirmed PR and CR, will 
also be estimated. 
 


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DOR will be calculated for patients who achieve a confirmed CR or PR. DOR is 
defined as the time from the start date of the confirmed response to the first date that 
recurrent or progressive disease or death is objectively documented. 
PFS is defined as the time from the date of the first dose of study drug to the earliest 
of documented disease progression or death without prior progression. Patients not 
experiencing an event will be censored at their last adequate disease assessment 
date. 
OS is defined as the time from the date of the first dose of study drug to the date of 
death (whatever the cause). Patients not experiencing an event will be censored at 
the last follow-up date. 
DOR, PFS, and OS will be summarized descriptively using the Kaplan-Meier method 
with 90% confidence intervals (CIs) calculated using Greenwood’s formula. Median 
follow-up for each endpoint will be estimated according to the Kaplan-Meier estimate 
of potential follow-up. PFS rate and OS rate at selected landmarks and corresponding 
90% CIs will be estimated using the Kaplan-Meier method. Greenwood’s formula will 
be used to calculate the standard errors of the Kaplan-Meier estimate and upper and 
lower limits of the 90% CI. 
Waterfall plots will be used to depict graphically the maximum decrease from baseline 
of target lesions. The correlation between gpNMB expression and clinical outcomes 
will be explored. 
The analysis of tumor response and PFS will be based on tumor response 
assessments performed by the investigator according to standardized, objective 
response criteria (RECIST 1.1). In addition, in the event of a positive study outcome, 
an additional assessment of tumor response and progression may be performed by 
an independent review committee (IRC), blinded to investigator assessments. 


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2. SCHEDULE OF ASSESSMENTS 
Table 1. Schedule of Assessments1 
Visit 
Screening2 
 
Treatment Visits3 
Disease 
Assessment 
Visit6 
Survival 
Assessment7 
Cycle 1/ 
Day 1 
Cycle 1/ 
Day 84 
Cycle 1/ 
Day 154 
Cycle 2/ 
Day 1 
Cycle 3 
onward/Day 1 
End of 
Treatment5 
Visit Window 
Day -28 to 
Day -1 
 
+/-1 
days 
+/-1 
days 
+/-3 
days 
+/-3 days 
Within 28 
days post-
dosing 
Every 6 (±1) weeks 
for 6 months then 
every 9 (±2) weeks 
thereafter 
Every 12 (±2) 
weeks until study 
closure 
Informed Consent/HIPAA 
X 
 
 
 
 
 
 
 
 
Tumor Tissue8 
X9 
 
 
 
 
 
X10 
 
 
Medical/Surgical History11 
X 
X 
 
 
 
 
 
 
 
Physical Examination12 
X 
X13 
X 
X 
X 
X 
X 
 
 
Vital Signs14 
X 
X13 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status 
X 
X13 
 
 
X 
X 
X 
 
 
Electrocardiogram (ECG) 
X 
 
 
 
 
 
X 
 
 
Pregnancy Test15 
X 
X13 
 
 
 
 
 
 
 
Hematology16 
X 
X13 
X 
X 
X 
X 
X 
 
 
Blood Chemistry16 
X 
X13 
X 
X 
X 
X 
X 
 
 
Urinalysis16 
X 
X13 
 
 
X 
X 
X 
 
 
Immunogenicity17,18 
 
X 
 
 
 
X17 
X17 
 
 
PBMC Collection18,19 
 
X 
 
 
X 
 
X 
 
 
Routine PK Sample 
Collection18,20 
 
X20 
X 
X 
X20 
X20 
X 
 
 
Disease Assessment21 
X 
 
 
 
 
 
 
X 
 
Administration of Study 
Treatment22 
 
X 
 
 
X 
X 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
X 
Concomitant Medication 
Review23 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Event Monitoring24 
 
X 
X 
X 
X 
X 
X 
 
X25 
(footnotes on next page) 


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Table 1 - Footnotes: 
1. 
A delay in study treatment or performance of study assessments due to holidays, weekends, inclement weather or other unforeseen circumstances will be 
permitted and not considered a protocol violation. However, such cases should be discussed with PrECOG to reach consensus on subsequent scheduling. 
2. 
Phase I: Prior to discussing protocol entry with the patient, call the assigned PrECOG Project Manager to ensure that a place on the protocol is open 
to the patient (Section 5.2.4). Eligibility Criteria Checklist must be sent to the PrECOG PM/designee for review and approval prior to subject 
registration. Site will receive a confirmation of approval. Once confirmation of approval is received subject can be registered. No study 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 glembatumumab vedotin (on a three-week cycle) until intolerance, progression of disease, or any of the other criteria for discontinuation of 
study treatment (Section 5.2.6) are met. 
4. 
The Cycle 1/Day 8 and Cycle 1/Day 15 visit is only required for patients treated in the Phase I, dose-escalation phase. 
5. 
The End of Treatment Visit should be performed within 28 days after last dose of study treatment and prior to initiation of alternate therapies. 
6. 
Disease assessments will be performed every 6 weeks (±1 week) for 6 months and every 9 weeks (±2 week) thereafter, until documented progression of disease 
or initiation of alternate anticancer therapies. If a partial or complete response is noted, a follow-up radiographic 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 will have glembatumumab vedotin temporarily withheld during treatment and for at least 21 days after completion of surgical resection or radiation 
treatment or until patient has recovered from any adverse events resulting from the surgical or radiation intervention before restarting treatment with 
glembatumumab vedotin. Patients may continue to receive study treatment until remaining lesions meet criteria for progression of disease. 
7. 
Subsequent to the End of Treatment Visit, all patients with disease progression 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. For patients who continue to be seen for disease assessments, the survival contact may occur at these visits (i.e., at a 6 or 9 week interval, as 
applicable). Otherwise, these visits may be performed by telephone. 
8. 
Assessment of gpNMB expression (by IHC) at a central laboratory (approximately 5 working day turnaround); additional analyses to be performed may also 
include 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, and localization of glembatumumab vedotin, CR011 or MMAE at the tumor site in post-treatment samples 
(Section 11.1). Sample collection, processing and shipping instructions will be provided. 
9. 
Tumor specimen(s) used to determine gpNMB status and eligibility may be obtained at any point in the course of disease; preferred tumor specimens are those 
obtained in the setting of advanced (recurrent, locally advanced or metastatic) disease and subsequent to the last anti-cancer regimen received.. Formalin-fixed 
paraffin-embedded (FFPE) diagnostic tumor tissue block(s) or 10-20 FFPE slides plus H&E slide from a tumor tissue block will be required (Section 11.1). 
NOTE: Additional samples from previous collection dates should also be submitted when feasible. Submitted cytology samples such as pleural effusions, 
bronchial washings or fine needle aspirates (FNA) will be used to evaluate feasibility of gpNMB expression analysis and to investigate correlations with other 
samples for the patient, but they will not be used for determination of study eligibility. Samples may be submitted and tested at any time prior to or during the 
28-day window for screening, provided that the patient has signed an appropriate consent (either a tumor tissue-specific consent or full study consent). Samples 
may be submitted for patients who are not yet fully eligible for the study at the investigators discretion. 
10. In the event of tumor resection, biopsy, or cytological sample collection anytime during treatment or following tumor progression, submission of these tissue 
samples for central analysis is strongly encouraged. 
 


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11. Medical/Surgical history includes demography, race, ethnicity, cancer history, previous therapy, and pre-existing diseases. At Cycle 1, Day 1, history is updated 
with any adverse events occurring prior to administration of study drug. 
12. Complete physical exam should be performed at screening; thereafter, symptom-directed exams are acceptable. 
13. Assessments do not need to be repeated if completed within the previous 72 hours as part of the screening assessment. NOTE: Microscopic examination of 
urinalysis is required during screening. If urinary infection is suspected, a negative urine culture is required prior to enrollment. 
14. Vital signs to include height (at screening only), weight, respiration, pulse, temperature, and resting systolic and diastolic blood pressure. On glembatumumab 
vedotin dosing days, vital signs should be assessed pre-infusion, at 45 (±15) minutes during the infusion, and within one-half hour following completion of the 
infusion. (Note: Weight is only assessed once per visit.) 
15. Serum or urine pregnancy test only for women of childbearing potential. Patients of non-childbearing potential include those who are surgically sterilized or post-
menopausal 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 follicle-stimulating hormone (FSH) and/or estradiol) are available to ensure postmenopausal status. 
16. 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 
RBC (Red Blood Count) 
Glucose (nonfasting)  
Specific gravity 
WBC (White Blood Count) 
Blood urea nitrogen (BUN) 
Blood 
Platelets 
Creatinine 
 
Differential:  
Calcium 
 
Neutrophils  
Phosphate 
 
Lymphocytes 
Alkaline phosphatase 
Microscopic 
examination 
must 
be 
performed at baseline and, if clinically 
indicated, at subsequent visits. 
Monocytes 
Alanine transaminase (ALT/SGPT) 
Eosinophils 
Aspartate transaminase (AST/SGOT) 
Basophils 
Total protein 
Differential should be reported consistently 
throughout the study as either an absolute 
count (preferred) or as a percentage. 
Albumin 
Lactate Dehydrogenase (LDH) 
Total Bilirubin 
17. 6 mL blood sample (red top tube) for serum for immunogenicity will be collected prior to dosing on Day 1 of “odd” cycles (i.e., Cycles 3, 5, 7, etc.) and End of 
Treatment. Analysis may also include circulating soluble gpNMB levels or other soluble molecules (Section 11.2). 
18. Analyses will be performed centrally. Sample collection, processing and shipping instructions will be provided. 
19. 6 mL blood sample (red top tube) for serum and 20 mL blood sample (green top tubes) for peripheral blood mononuclear cell (PBMC) will be collected on Day 
1 of Cycle 1 and 2, prior to dosing and at End of Treatment. 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 (Section 
11.2). Details on sample collection and handling will be provided. 
20. 6 mL blood sample (red top tube) for Pharmacokinetic (PK) samples will be collected (Details on sample collection and handling will be provided.): 
• 
Phase I: Day 1 of Cycles 1 and 2, prior to dosing and at end of infusion (at or within 10 minutes after completion of infusion) and 4-5 hours after the end of 
infusion. A PK sample will also be collected at Cycle 1, Days 8 and 15. Additional PK samples will be collected on Day 1 of Cycles 3 and 5 prior to dosing 
and at end of infusion (at or within 10 minutes after completion of infusion) and at End of Treatment visit. 
• 
Phase II: Day 1 of Cycle 1, 2, and 5, prior to dosing and at end of infusion (at or within 10 minutes after completion of infusion) and at End of Treatment 
visit. 


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21. 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. 
22. Unless otherwise specified, all study assessments should be performed prior to administration of study treatment, and may be performed up to 72 hours prior 
to treatment administration if assessments remain within the specified visit window. 
23. All concomitant medication will be reviewed 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 concomitant medications taken to treat glembatumumab vedotin-related serious 
adverse events (SAEs) should be recorded in the electronic Case Report Form (eCRF) throughout the duration of the study/follow-up. 
24. For patients who develop Grade 3 treatment-related rash and who provide appropriate consent, optional punch biopsies of the rash site and optional photographs 
of the rash site, as well as uninvolved skin, are strongly encouraged. Samples may be submitted for central analyses including quantification of gpNMB 
expression; in these cases, collection, processing and shipping instructions will be provided. 
25. Events occurring >28 days after discontinuation of study treatment are only reportable if both serious (SAE) and potentially treatment-related. 


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3. BACKGROUND/RATIONALE 
3.1. Squamous Cell Lung Cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2. NSCLC Clinical Trial Outcomes for Patients with Squamous Cell Histology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.2. gpNMB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.3. Glembatumumab Vedotin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 3. Study CR011-CLN-20: Activity Data in Patients with Advanced Breast Cancer 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 4. Study CDX011-03 (“EMERGE”): Response Data for Patients with Advanced gpNMB-Expressing Breast Cancer 
 
*
 






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3.4. Study Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4. STUDY OBJECTIVES 
4.1. Primary Objective 
Phase I 
The primary objective of the Phase I portion of the study is to evaluate the safety and tolerability and to 
determine the Maximum Tolerated Dose (MTD) of glembatumumab vedotin in patients with advanced 
gpNMB-expressing SCC of the lung. 
Phase II 
The primary objective of the Phase II portion of the study is to determine the anti-tumor activity, as assessed 
by objective response rate (ORR) in accordance with RECIST 1.1, of the MTD of glembatumumab vedotin 
in patients with advanced gpNMB-expressing SCC of the lung. 
4.2. Phase I & II Secondary Objectives 
Secondary objectives are: 
• 
To further characterize the safety of glembatumumab vedotin in advanced gpNMB-expressing SCC of 
the lung. 
• 
To further evaluate the anti-cancer activity of glembatumumab vedotin in advanced gpNMB-expressing 
SCC of the lung, as measured by duration of objective response (DOR), progression-free survival 
(PFS), and overall survival (OS). 
4.3. Phase I & II Exploratory Objectives 
Exploratory objectives are: 
• 
To investigate if the anti-cancer activity of glembatumumab vedotin in advanced gpNMB-expressing 
SCC of the lung is dependent upon the degree of gpNMB expression in tumor tissue. 
• 
To examine pharmacodynamic effects of treatment, including tumor immune cell infiltrate type and 
number; localization of glembatumumab vedotin, CR011 or Monomethylauristatin E (MMAE) at the 
tumor site; soluble mediators and/or gpNMB expression levels in tumor tissue; and analysis of 
peripheral blood cell subsets. 
• 
To further characterize the pharmacokinetics and immunogenicity of glembatumumab vedotin in this 
patient population. 
 
 


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5. INVESTIGATIONAL PLAN 
5.1. Overall Design and Plan of the Study 
This is an open-label, single arm study of glembatumumab vedotin in patients with Stage IIIB or IV gpNMB-
expressing SCC of the lung who have failed a prior platinum-based chemotherapy regimen. This study will 
include a dose-escalation phase followed by a 2-stage Phase II expansion, as follows: 
Study Phase 
Dose Level/ 
Cohort 
Glembatumumab Vedotin 
Dose (mg/kg) 
Patients (n) 
Phase I 
Dose-Escalation 
-1,2 
1.3 
3 
11,3 
1.9 
9 enrolled previously; 
to add 3-6 more 
 
 
 
Phase II 
Stage 1 
MTD* 
20 
Stage 2 
MTD* 
15 
1 Amendment 2: A maximum of three additional patients were treated on Dose Level/Cohort 1 (1.9 mg/kg) 
for 9 patients at this dose level to verify the safety of this dosage regimen (Section 5.1.1 for details). 
2 Three patients completed treatment on Dose Level/Cohort -1 with no DLTs. 
3 We will re-escalate to Dose Level/Cohort 1. An additional 3-6 patients will be treated on Dose Level 1 (up 
to 15 total). 
* MTD as determined during the dose-escalation phase 
All patients will be seen in the clinic at scheduled intervals during the treatment phase of the study. Patients 
will not be permitted to have concurrent chemotherapy, immunotherapy or other experimental therapies 
during study treatment. 
Patients will receive glembatumumab vedotin in an open-label fashion, once every three weeks (q3w) by 
90-minute intravenous (IV) infusion, until disease progression or intolerance. Tumor assessments will be 
performed every six (±1) weeks for six months, and every nine (±2) weeks thereafter, until progression. 
Tumor response will be assessed by the investigator in accordance with Response Evaluation Criteria for 
Solid Tumors (RECIST) 1.1 guidelines (Eisenhauer, Therasse et al. 2009). Patients who discontinue 
treatment in the absence of progression, including those who discontinue treatment for adverse events, will 
continue to have tumor assessments until documented progression or initiation of alternate anti-cancer 
therapies. 
5.1.1. Dose-Escalation Phase 
For the dose-escalation phase, the starting dose of glembatumumab vedotin will be 1.9 mg/kg q3w (Cohort 
1). This dose level is based upon the previously identified therapeutic dose of 1.88 mg/kg q3w, with rounding 
to 1.9 mg/kg for reasons of practicality and feasibility in preparation of the infusion.
 
 
 
Given the fact that one 
of the previously reported DLTs at 1.9 mg/kg in this study was complicated by the patient have progressive 
disease at the same time, and the other (pruritus) is a known and generally manageable adverse event 
associated with glembatumumab vedotin, it is reasonable to re-escalate, and re-explore the safety of the 
1.9 mg/kg cohort. 
Original Plan: 
Initially, three patients will be enrolled to Cohort 1. In the event of 1 dose-limiting toxicity (DLT), the cohort 
will be expanded to 6 patients. In the event of ≥ 2 DLTs, the cohort will have exceeded the MTD, and the 
dose will de-escalate. In this case, 3 patients will be enrolled to Cohort -1 and the same DLT evaluation 


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rules will apply, such that 1 DLT will require expansion to 6 patients; this dose level will be deemed the 
MTD if DLT occur in 0/3 or ≤ 1/6 patients; and the study will cease if ≥ 2 DLTs occur at dose level -1. 
Dose escalation from Cohort 1 to Cohort 2 may proceed if three patients in Cohort 1 complete the DLT 
observation period with 0 DLTs, or if six patients in Cohort 1 complete the DLT observation period with 0 or 
1 DLTs. The MTD for the dose-escalation phase will be the highest dose-level where 0/3, or ≤ 1/6 patients 
in a cohort experienced a DLT. 
Amendment 2.0: 
As of February 14, 2017; six patients have been enrolled to dose level 1 (1.9 mg/kg) with reporting of one 
dose limiting toxicity (DLT). Two deaths have occurred on study. One patient had a Grade 5 respiratory 
failure deemed unrelated to study drug and likely related to disease under study by the site and Sponsor. 
A second patient also had a Grade 5 respiratory failure deemed as possibly related to study drug by the 
site as it could not be ruled out. This qualified as a DLT per protocol. Review of documents obtained from 
the site demonstrated the patient had serious medical conditions including a previous respiratory failure 
intensive care unit admission in August 2016. The patient’s disease complicates the issue of assessing 
safety of the drug, and the events that transpired with this patient do not seem consistent with the drug 
toxicity profile of Glembatumumab Vedotin. The Sponsor assessed the respiratory failure as recurrent since 
the patient experienced respiratory failure previously in August 2016. It is the Sponsor’s assessment that 
the DLT event for this patient is ‘Grade 3 or higher neutropenia with associated fever greater than 38.1.’ 
Out of the six patients whom were enrolled on dose level 1 (1.9 mg/kg), 1 DLT has been identified as noted 
above. 
Dose escalation to Cohort 2 seemed premature. To further assess the safety signal and not put either 
subjects or the drug in jeopardy, it was PrECOG’s decision to modify the Phase I portion and treat a 
maximum of 3 additional patients on Cohort 1 (1.9 mg/kg) for up to 9 patients at this dose level to verify the 
safety of this dosage regimen. If any of the 3 additional patients experience a DLT, the dose will de-escalate 
to Cohort -1. If none of the additional 3 patients experience a DLT, dose escalation may proceed form 
Cohort 1 to Cohort 2. The same DLT evaluation rules will apply as noted above. 
A second DLT was observed on Cohort 1. Patient experienced treatment- related Grade 3 pruritus requiring 
hospital admission. Although a vital organ was not involved, due to the extent and intensity of the treatment 
required for pruritus, it was considered a DLT. Dose was de-escalated to Dose Level -1. 
Amendment 3.0: 
Three patients were enrolled to Dose Level -1 with no DLTs during the 42 day assessment period. 
Given the fact one of the previously reported DLTs at 1.9 mg/kg was complicated by the patient have 
progressive disease at the same time, and the other (pruritus) is a known and generally manageable 
adverse event associated with glembatumumab vedotin, it is reasonable to re-escalate, and re-explore the 
safety of the 1.9 mg/kg cohort. 
The protocol is being amended to include a plan to re-escalate to Dose Level 1. Upon re-escalation to Dose 
Level 1, 3 patients will be treated. This dose level will be deemed unsafe if at least 2 patients among the 
first 3 patients enrolled experiences a DLT, and Dose Level -1 will be deemed the MTD. If no DLTs are 
observed among the first 3 patients or if 1/3 patients experiences a DLT then we will enroll 3 more patients. 
This dose level will be determined to be the MTD in the event that <2/6 patients treated at Dose Level 1 
experience DLT. If ≥ 2/6 patients experience DLT at Level 1, then Dose Level -1 will be declared the MTD. 
Note that Dose Level 2 is no longer part of the study effective with this amendment. 
The DLT evaluation period for determination of the appropriateness of dose-escalation will be through the 
end of the second treatment cycle (Section 6.1.7). Patients who discontinue safety follow-up before day 42 
(±3 days) for reasons other than DLT will be replaced (Section 6.1.7 for DLT definition). 
Any DLT at any time point during the study must be reported to PrECOG (or designee) as soon as possible, 
but no later than 24 hours following the site becoming aware of the event, and PrECOG will distribute such 
notification to all participating sites within 24 hours of notification. Site teleconferences between PrECOG 


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and all participating sites will be held at frequent intervals and prior to dose-escalation to each cohort during 
the dose-escalation phase. PrECOG study personnel, including but not limited to the Study Chair(s), 
statistician, medical monitor and participating investigators, as applicable, will review toxicities from the 
current cohort during the site teleconferences before initiating enrollment into the next planned dose cohort. 
5.1.2. Phase II Phase 
Following determination of the MTD, a Phase II study portion will enroll up to 35 eligible, treated patients to 
further assess the safety and efficacy of glembatumumab vedotin. Patients who discontinue study for 
reasons other than symptomatic deterioration or death prior to the first radiographic assessment will be 
considered unevaluable and will be replaced. 
Enrollment to the Phase II study portion will proceed according to a two-stage trial design (Simon 1989), so 
that enrollment may terminate early if the results are not sufficiently promising to warrant further study. In 
Stage 1, approximately 20 eligible, treated patients will be enrolled. If ≥ 2 patients achieve a tumor response 
(Partial Response [PR] or Complete Response [CR]); an additional 15 eligible, treated patients will be 
enrolled in Stage 2, for a maximum total of 35 eligible, treated patients. To assure sufficient eligible, treated 
patients, up to 2 additional patients may be enrolled. 
Additionally, we will monitor for the incidence of Grade 5 events. In particular, we will monitor the Grade 5 
event rate among the first stage accrual of 20 patients. All Grade 5 events deemed at least possibly related 
to treatment as well as any Grade 5 events occurring within 3 weeks of the first dose (Cycle 1) regardless 
of attribution are included as ‘events’ for the purpose of monitoring. See Section 10.2.2.1 for details. 
5.2. Selection of Study Population 
Each of the inclusion and exclusion criteria must be met in order for a patient to be considered eligible for 
this study. An eligibility checklist is provided in Appendix 1 to confirm a patient’s eligibility. For each patient, 
this checklist must be photocopied, completed and maintained in the patient’s chart. 
*Phase I Only: Eligibility Criteria Checklist must be sent via fax (215-557-7169) or email 
(candrews@precogllc.org) to the PrECOG PM/designee for review and approval prior to subject 
registration. Site will receive a confirmation of approval. Once confirmation of approval is received 
subject can be registered. 
PrECOG will not grant any exceptions or waivers to protocol eligibility criteria. 
In calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later would be considered 
Day 28. 
NOTE: All questions regarding eligibility should be directed to the PrECOG Project Manager. Questions 
will be further discussed with the medical leads for the trial as deemed appropriate (e.g., medical monitor, 
study chair). 
5.2.1. Number of Patients 
Approximately 55 patients will be enrolled. Enrollment will be on a first-come basis, with no pre-defined 
maximum enrollment per clinical site. 
5.2.2. Subject Eligibility 
5.2.2.1. Inclusion Criteria 
1. Read, understood, and provided written informed consent and 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. Male or female patients with metastatic, histologically- or cytologically-confirmed Stage IIIB or IV non-
small cell lung cancer (NSCLC) of squamous histology (Staging per American Joint Committee on 
Cancer [AJCC], Edition 7). Mixed histology adenosquamous NSCLC will also be permitted. 


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3. Experienced progression/recurrence of disease during or subsequent to the most recent anti-cancer 
regimen. 
4. Any number of prior lines of systemic therapy may have been received for advanced (recurrent, locally 
advanced, or metastatic) SCC of the lung, but at least one must have been a platinum-based 
chemotherapy regimen. Platinum therapy may be given on-label or as part of a clinical trial. 
5. Lung cancer confirmed to express gpNMB, as assessed by immunohistochemistry at a central lab 
(using expression in ≥ 5% of tumor epithelial cells as a cut-off for positivity). This can be tested on 
archived tissue if available, although preferred tumor specimen is a biopsy after the most recent 
therapy. 
NOTE: Additional samples from previous collection dates should also be submitted when feasible. 
Submitted cytology samples such as pleural effusions, bronchial washings or fine needle aspirates 
(FNA) will be used to evaluate feasibility of gpNMB expression analysis and to investigate correlations 
with other samples for the patient, but they will not be used for determination of study eligibility. For 
patients with multiple samples submitted, eligibility will be based on the most recently obtained sample, 
or, if obtained on the same date, the sample with the highest level of gpNMB expression. However, in 
the event that disparate results are obtained for samples received within a similar timeframe (i.e., within 
a 6-month period), the medical monitor may be consulted for determination of eligibility. 
6. Age ≥ 18 years. 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1 (Appendix 2). 
8. Measurable disease by RECIST 1.1 criteria (Eisenhauer, Therasse et al. 2009) [Appendix 3]. Target 
lesions selected for tumor measurements should be those where surgical resection or radiation are not 
indicated or anticipated. 
9. Resolution of all toxicities related to prior therapies to ≤ NCI-CTCAE Grade 1 severity or back to 
baseline, except for alopecia, vitiligo, or endocrinopathies on replacement therapy. 
10. Adequate bone marrow function as assessed by absolute neutrophil count (ANC) ≥ 1500/mm3; 
hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100,000/mm3. 
11. Adequate renal function as assessed by serum creatinine ≤ 2.0 mg/dL; or calculated (Cockcroft and 
Gault Formula; Appendix 4) or 24-hour urine creatinine clearance >40 mL/min. 
12. Serum albumin≥ 3 g/dL. 
13. Adequate liver function as assessed by total bilirubin ≤ 1.5x upper limit of normal (ULN), and alanine 
transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5x ULN (≤ 5.0x ULN in the case of liver 
metastases). Patients with known Gilbert’s syndrome may be enrolled with total bilirubin ≤ 3.0 mg/dL. 
NOTE: The liver is a route of clearance for MMAE. Patients with mild hepatic impairment are excluded 
from Phase I (the dose escalation portion) to minimize the influence of hepatic impairment on tolerability 
and dose selection because a lower dose is recommended for other ADCs with a vc-MMAE moiety. 
See the acceptable liver function parameters for Phase I defined above. In Phase II (the dose 
expansion portion), a lower starting dose for patients with mild hepatic impairment will be determined 
based on the MTD recommended from the Phase I portion of this trial. The acceptable liver function 
parameters will be redefined for Phase II. 
14. Both male and female patients of childbearing potential enrolled in this trial must use adequate birth 
control measures during the course of the trial and for at least one month after discontinuing study drug. 
Adequate birth control measures are defined as double barrier contraception (e.g., condom plus 
spermicide in combination with a female condom, diaphragm, cervical cap, or intrauterine device), 
implants, injectables, combined oral contraceptives, sexual abstinence (abstinence from intercourse 
during the ovulation period), or vasectomized partner. Patients and/or partners who are surgically sterile 
or postmenopausal are exempt from this requirement. 
15. Willing to provide blood samples for research purposes (Section 11.2). 
5.2.2.2. Exclusion Criteria 
1. Received glembatumumab vedotin (CR011-vcMMAE; CDX-011) or other MMAE-containing agents 
previously. 


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2. Chemotherapy within 21 days or at least 5 half-lives (whichever is shorter) prior to the planned start of 
study treatment; radiation outside the thorax within 14 days prior to the planned start of study treatment 
or thoracic radiation; antibody based therapy or investigational therapy within 28 days prior to the 
planned start of study treatment. 
3. Neuropathy >NCI-CTCAE Grade 1. 
4. 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. 
5. Known brain metastases, unless previously treated and patients are neurologically returned to baseline 
except for residual signs and symptoms related to Central Nervous System (CNS) treatment and CNS 
lesions are not progressive in size and number for 4 weeks. 
6. Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, and 
congestive heart failure (New York Heart Association (NYHA) Class 3 or 4 [Appendix 5]) related to 
primary cardiac disease, a history of a serious uncontrollable arrhythmia despite treatment, ischemic 
or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry. 
7. 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, a negative urine culture is required prior to enrollment. 
8. Subjects on immunosuppressive medications such as azathioprine, mycophenolate mofetil, 
cyclosporine or require chronic corticosteroid use (defined as ≥ 3 months of prednisone dose equivalent 
of ≥ 10 mg). 
9. The MMAE component of glembatumumab vedotin is primarily metabolized by CYP3A. Patients taking 
strong CYP3A inhibitors and inducers are excluded in Phase I (the dose escalation portion) to minimize 
the 
effect 
of 
these 
modulators 
on 
exposure, 
tolerability 
and 
dose 
selection 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/). 
10. History of other malignancy except for adequately treated basal or squamous cell skin cancer, curatively 
treated in situ disease, or any other cancer from which the patient has been disease-free for ≥ 2 years. 
11. Pregnant or breast-feeding women. 
12. Subjects must not be on home oxygen therapy (intermittent or continuous). 
13. Any underlying medical condition that, in the Investigator’s opinion, will make the administration of study 
treatment hazardous to the patient, or would obscure the interpretation of adverse events. 
5.2.3. Regulatory Requirements 
Before a site may enter patients, protocol-specific regulatory and other documents must be submitted to 
PrECOG as noted in study materials. Detailed information regarding document submission and control is 
provided to each site in separate study materials. 
Required documents will be reviewed, and approved by PrECOG or their representative. Any changes to 
site regulatory documents must be submitted by the investigator to the responsible party in a timely manner. 
Initial study drug shipment will not occur until the regulatory packet is complete. No patients will begin 
protocol therapy without formal registration as per the process below. 
5.2.4. Patient Registration 
Phase I Registration: Prior to discussing protocol entry with the patient AND prior to registering in the 
electronic data capture (eDC) system, call the assigned PrECOG Project Manager to ensure that a place 
on the protocol is open to the patient. 
 


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*Phase I Only: Eligibility Criteria Checklist must be sent via fax (215-557-7169) or email 
(candrews@precogllc.org) to the PrECOG PM/designee for review and approval prior to subject 
registration. Site will receive a confirmation of approval. Once confirmation of approval is received 
subject can be registered. 
The Phase II portion will be conducted using the dose and schedule selected from the Phase I portion of 
the study. Patients that participate in Phase I will not be eligible to participate in Phase II. 
Phase II Registration: Prior approval of patient registration is not required. 
Patients must not start protocol treatment prior to registration. 
Patients must meet all of the eligibility requirements listed in Section 5.2.2.1 and 5.2.2.2 prior to registration. 
Treatment should begin ≤ 10 working days from study entry (date of registration). 
An eligibility checklist is included in Appendix 1 and the Study Reference Manual (SRM). A confirmation of 
eligibility assessment by the investigator and/or site will be performed during the registration process. 
Upon determination that a subject meets eligibility criteria, the subject will be registered in the study by site 
personnel via the eDC system. Confirmation of registration will be displayed in the eDC system once the 
site personnel have verified the subject’s eligibility status. 
Full information regarding registration procedures and guidelines can be found in the SRM provided to sites. 
All correspondence regarding patient registration must be kept in the study records. 
5.2.5. Measures to Minimize Bias 
This is non-randomized open-label study. The analysis of tumor response and PFS will be based on tumor 
response assessments performed by the investigator according to standardized, objective response criteria 
(RECIST 1.1). In addition, in the event of a positive study outcome, an additional assessment of tumor 
response and progression may be performed by an Independent Review Committee (IRC), blinded to 
investigator assessments. 
5.2.6. Withdrawals and Replacement of Patients 
Every effort should be made within the bounds of safety and patient choice to have each patient complete 
the study. An explanation will be recorded for each patient taken off study treatment or discontinuing the 
study. 
In the dose-escalation phase, patients who discontinue safety follow-up before day 42 (±3 days) for reasons 
other than DLT will be considered unevaluable for DLT assessment and will be replaced. 
5.2.6.1. Discontinuation of Study Treatment 
Reasons for discontinuation of study treatment include: 
1. Progressive disease, as assessed by the treating investigator in accordance with RECIST 1.1 criteria 
(Appendix 3); 
2. Symptomatic deterioration (clinical progression); 
o 
Note: This category is applicable to patients with a global deterioration of health status requiring 
discontinuation of treatment. However, per RECIST 1.1 (Appendix 3), symptomatic deterioration is 
not a descriptor of an objective response; it is a reason for stopping study therapy. Thus, every 
effort should be made to continue disease assessments per protocol until documented objective 
progression or initiation of alternate therapy. 
3. Receipt of alternate anti-cancer treatments; 
o 
Note: Patients who undergo surgical resection or radiation in the absence of progression will have 
glembatumumab vedotin temporarily withheld during treatment and for at least 21 days after 
completion of surgical resection or radiation treatment or until patient has recovered from any 
adverse events resulting from the surgical or radiation intervention before restarting treatment with 


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glembatumumab vedotin. Patients may remain on the study and continue to receive study 
treatment until remaining lesions meet criteria for progression of disease. 
4. Intercurrent illness that prevents further administration of treatment per investigator discretion; 
5. Withdrawal request by the patient or the patient’s legal representative; 
o 
Note: Withdrawal of consent for continued treatment should be differentiated from withdrawal of 
consent for study follow-up, and every effort should be made within the bounds of safety and patient 
choice to have each patient complete the study follow-up. 
6. Unacceptable adverse event, including the development of DLT (Section 6.1.7); 
7. Physician Decision; 
8. Non-compliance of the patient; 
9. Pregnancy; 
10. Death, otherwise not explainable by the above options; 
11. Patient lost to follow-up. (see below). 
Patients who discontinue glembatumumab vedotin should be seen for an End of Treatment Visit. Patients 
who discontinue treatment in the absence of progression, including for adverse events, will continue to have 
tumor assessments until documented progression or initiation of alternate anti-cancer therapies (Table 1). 
5.2.6.2. Discontinuation from Study 
Reasons for patient removal from the study include: 
1. Request of the patient or the patient’s legal representative (withdrawal of consent for the study follow-
up); 
2. Patient lost to follow-up. A subject should be considered lost to follow up only after multiple efforts have 
been made to contact the subject to assess his/her health status after failure of the subject to attend 
scheduled visits. If after 2 documented phone calls the investigative site is still unable to contact the 
subject, a certified letter should be sent to his/her home for immediate response. If there is still no 
response, the subject is to be considered lost to follow up. A record of the subject being lost to follow 
up should be noted in the source documents along with the phone contacts and the returned certified 
mail (if sent back). 
5.2.7. Completion of Study 
It is anticipated that the enrollment period will be approximately 30 months (Phase I: 12 months and Phase 
II: 18 months). All patients will be followed with regard to survival until death, discontinuation from study 
follow-up, or termination/completion of study. Patients who die or complete the study follow-up through 
study closure will be considered to have “completed” the study. The study will be declared complete when 
sufficient data is obtained to conclude the study; this is estimated at 15 months from the date when the last 
patient in the study discontinues study treatment. 
Premature termination of this study may occur because of a regulatory authority decision, drug safety 
issues, or at the discretion of PrECOG. In addition, Celldex Therapeutics, Inc., the manufacturer of the 
study drug, retains the right to discontinue development of glembatumumab vedotin at any time. 
 
 


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6. STUDY TREATMENT 
6.1. Glembatumumab Vedotin 
6.1.1. Description, Packaging and Labeling 
 
 
 
 
 
 
 
 
 
6.1.2. Accountability 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.3. Compliance 
 
6.1.4. Storage 
 
 
 
 
 
 
 
 
 


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6.1.5. Preparation and Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.5.1. Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.1.6. Dose Modifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.7. DLT definition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.1.8. Potential Toxicity and Management of Toxicity 
6.1.8.1. Previously Observed Toxicities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.8.2. Management of Toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.1.9. Additional Warnings and Precautions 
6.1.9.1. Toxicity Associated with Similar Products 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.9.2. Drug-Drug Interactions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.1.9.3. Hypersensitivity, Infusion Reaction 
 
 
 
 
 
 
 
 
6.1.9.4. Infusion Site Extravasation 
 
 
 
 
 
 
 
 
6.1.9.5. Antagonism of gpNMB 
 
 
 
 
6.1.9.6. Exposure to Free MMAE 
 
 
 
6.1.9.7. Renal Impairment 
 
 
 
 
 
6.1.9.8. Hepatic Impairment 
 
 


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6.1.9.9. Pregnancy 
 
 
 
 
 
 
 


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7. CONCOMITANT THERAPY 
While on study, when clinically appropriate, patients should strictly follow the study-prescribed treatment 
regimen. Therefore, patients should not receive additional investigational agents or anti-cancer therapies, 
unless recurrence/progression of disease warrants discontinuation of study treatment and commencement 
of alternate therapies. 
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 (Section 6.1.9.2). A table listing P450 enzyme-drug interactions is available at:  
http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
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 for chemotherapy premedication 
are also permitted. Efforts should be made to maintain stable doses of concomitant medications during the 
course of treatment with glembatumumab vedotin. 
Prolonged use of systemic corticosteroids above the physiologic dose (5 mg prednisone or equivalent) 
should be avoided, if possible, during the study do to a potential increase in risk of infections. Patients who 
receive prolonged or high dose steroids should be monitored closely for signs of infection. 
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 will have glembatumumab 
vedotin temporarily withheld during treatment and for at least 21 days after completion of surgical resection 
or radiation treatment or until patient has recovered from any adverse events resulting from the surgical or 
radiation intervention before restarting treatment with glembatumumab vedotin. Patients may continue to 
receive study treatment until remaining lesions meet criteria for progression of disease. 
All concomitant medication will be reviewed 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 and concomitant medications taken to treat 
glembatumumab vedotin-related SAEs should be recorded in the eCRF throughout the duration of 
study/follow-up. 
 
 


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8. STUDY PROCEDURES 
8.1. Schedule of Investigations and Data Collection 
The study is divided into phases with associated evaluations and procedures that must be performed at 
specific time points, as described in the following sections. The Schedule of Assessments (Table 1) 
summarizes the frequency and timing of various activity, safety, and other measurements. 
8.1.1. Screening Period 
Prior to the performance of any study-specific procedures, the patient will have the nature of the study 
explained to them, and will be asked to give written informed consent and HIPAA authorization. Informed 
consent/HIPAA authorization must be obtained prior to any study-specific procedures that do not form a 
part of the patient’s normal care. 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. 
The assessments outlined for the Screening Visit in the Schedule of Assessments (Table 1) will be 
completed for each patient prior to inclusion in the study, and results will be evaluated to verify entry criteria 
prior to study treatment assignment. 
8.1.2. Study Enrollment/Treatment Assignment 
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 only after confirming all inclusion criteria and none of the exclusion criteria have 
been met. 
For patients who are registered but do not receive any protocol therapy, baseline and follow-up information 
per Schedule of Assessments (Table 1) will be collected. 
8.1.3. Treatment Phase 
Specific procedures to be performed at each visit during the treatment phase are illustrated in the Schedule 
of Assessments (Table 1). 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 8.2.2.3, 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. 
8.1.4. Disease Assessment Visits 
Disease assessments will be performed every 6 (±1) weeks for 6 months and every 9 (±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. 
8.1.5. Survival Follow-Up 
Subsequent to progression of disease, all patients will be followed at 12 (±2) week intervals until study 
closure, as described in Table 1, Footnote 7. 
 


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8.2. Methods of Assessment 
8.2.1. Activity 
8.2.1.1. Anti-Tumor Activity 
Anti-tumor activity will be assessed via ORR, DOR, PFS, 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. 
8.2.1.2. Immunogenicity 
Patients will be monitored for the development of anti-glembatumumab vedotin and anti-CR011 antibodies, 
and whether these antibodies are neutralizing. 
8.2.1.3. Pharmacokinetic Evaluations 
Concentration of the antibody-drug conjugate (ADC), total antibody (TA) and free MMAE 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 
on pharmacokinetic parameters may also be examined. 
8.2.1.4. Pharmacodynamics 
Pharmacodynamic parameters will be evaluated via assessment of post-treatment tumor tissue obtained 
via voluntary biopsy or resection and/or blood samples. Parameters evaluated may include localization of 
glembatumumab vedotin, CR011 or MMAE at the tumor site and/or gpNMB levels on cells in blood and 
tumor tissue, as well as evaluation of tumor infiltrating and peripheral leukocytes, circulating tumor cells 
and other immune response cells of interest. Soluble gpNMB levels in circulation may also be examined. 
8.2.2. Safety Variables 
8.2.2.1. Adverse Events (AEs): Definition 
An adverse event is any untoward medical occurrence in a patient administered a study treatment. An 
adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a study treatment, whether 
or not related to the study treatment. All observed or volunteered adverse events regardless of suspected 
causal relationship to the study treatment will be reported as described in the following sections. For the 
purposes of this current study, “study treatment” is defined as glembatumumab vedotin. 
After informed consent, but prior to initiation of study treatment (glembatumumab vedotin), only AEs/SAEs 
caused by a protocol-mandated intervention will be collected (e.g., SAEs related to invasive procedures 
such as biopsies). After the initiation of study treatment, all identified AEs and SAEs must be recorded and 
described on the appropriate page of the electronic Case Report Form (eCRF). 
For all adverse events, the investigator is responsible for obtaining information adequate to determine: 
– 
Appropriate descriptive term: Adverse events should be reported using concise medical terminology, 
preferably referring to the syndrome/diagnosis rather than symptoms, when possible. 
– 
Severity: Adverse event severity will be primarily assessed using NCI Common Terminology Criteria 
for Adverse Events V4.0. (NCI-CTCAE), Version 4.0, Division of Cancer Treatment and Diagnosis 
(DCTD), National Cancer Institute (NCI), National Institute of Health (NIH), Department of Health and 
Human Services (DHHS): 
http://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 


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– 
Onset/resolution dates and outcome 
– 
Causality: The relationship of each adverse event to study drug will be defined as “unrelated” or 
“related” to study treatment: 
o 
Unrelated: There is little or no possibility that the study drug caused the reported adverse event; 
and other factor(s) including concurrent illnesses, progression and expression of the disease state, 
concurrent medications, or a reaction to concurrent medications appear to explain the adverse 
event. 
o 
Related: There exists at least a reasonable possibility that the study treatments caused or 
contributed to the adverse event; an inability to identify an alternate etiology for an adverse event 
should not, by itself, justify a “related” attribution. 
– 
whether it meets the criteria for classification as a serious adverse event (Section 8.2.2.2) 
The following study-specific points of clarification should be noted when considering AE reporting and 
recording: 
– 
Progression of neoplasia should not be reported as an AE or SAE. Findings that are clearly consistent 
with the expected progression of the underlying cancer should not be reported as an AE, and 
hospitalizations due to the progression of cancer do not necessarily qualify for a SAE. If there is any 
uncertainty about a finding or event being due solely to progression of neoplasia, the finding or event 
should be reported as an AE or SAE as appropriate. Death due to disease progression occurring within 
28 days of study treatment should be reported to PrECOG within 24 hours of the site’s awareness of 
the event; however, these events should not be documented as AEs or SAEs. If there is any uncertainty 
about the cause of death, the event should be reported as a SAE. 
– 
Withdrawal due to an AE should be distinguished from withdrawal due to insufficient response, and 
recorded. For example, if an AE due to recurrence/progression of disease necessitates discontinuation 
from the study, the primary reason for study discontinuation should be recorded as 
“Recurrence/Progression of Disease” (not AE). 
– 
Abnormal objective test findings should be reported as AEs if the findings are associated with 
accompanying symptoms, require additional diagnostic testing or medical/surgical intervention, lead to 
dose modification/discontinuation of study treatment and/or are considered otherwise clinically 
significant. 
– 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should be 
reported if it meets the definition of an AE. For example, an acute appendicitis that begins during the 
AE reporting period should be reported as the AE, and the resulting appendectomy should be recorded 
as treatment of the AE. 
– 
Any AEs/SAEs resulting in death should be recorded with an end date equal to the death date, while 
other events ongoing at the time of death should be recorded with an outcome of “continuing”. If 
requested, a summary of available autopsy findings should be submitted as soon as possible to 
PrECOG. 
8.2.2.2. Serious Adverse Events (SAEs): Definition 
An SAE is any adverse event from this study that results in one of the following outcomes: 
– 
Death (any AE that has a fatal outcome must be assigned NCI-CTCAE Grade 5) 
– 
Requires initial or prolonged inpatient hospitalization (This criterion would exclude hospitalization in the 
absence of a precipitating AE, such as admission for treatment of a preexisting condition not associated 
with a new/worsening AE, or admission for elective surgery. As well, admission to 
rehabilitation/hospice/nursing facilities and outpatient admission for same-day surgeries are not 
considered “hospitalizations” for the purpose of this criterion.) 


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– 
Is life-threatening (defined as an event in which the study patient was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more severe) 
– 
Is a persistent or significant disability/incapacity 
– 
Congenital anomaly/birth defect 
– 
Other significant medical hazard (Medical and scientific judgment should be exercised in determining 
whether an event is an important medical event. An important medical event may not be immediately 
life-threatening and/or result in death or hospitalization. However, if it is determined that the event may 
jeopardize the subject and/or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.) 
The following study-specific points of clarification should be noted when considering SAE reporting and 
recording: 
– 
Progression of neoplasia should not be reported as an AE or SAE. Findings that are clearly consistent 
with the expected progression of the underlying cancer should not be reported as an AE, and 
hospitalizations due to the progression of cancer do not necessarily qualify for a SAE. If there is any 
uncertainty about a finding being due solely to progression of neoplasia, the finding should be reported 
as an AE or SAE as appropriate. Death due to disease progression occurring within 28 days of study 
treatment should be reported to PrECOG within 24 hours of the site’s awareness of the event; however, 
these events should not be documented as AEs or SAEs. If there is any uncertainty about the cause of 
death, the event should be reported as a SAE. 
– 
The following, although not necessarily meeting criteria for an SAE, should also be reported to PrECOG 
according to SAE reporting processes: 
o 
New primary cancers that occur during protocol treatment or protocol-mandated follow-up must be 
reported within 30 days of diagnosis, regardless of relationship to protocol treatment. A copy of the 
pathology report, if applicable, should be sent, if available. 
o 
If a female becomes, or is found to be, pregnant within 6 months of exposure to the study treatments 
(maternal exposure) or if a male has been exposed to the study treatments within 6 months prior 
to conception (paternal exposure). 
o 
Any follow-up to the above-referenced events, including outcome of pregnancy. Further follow-up 
of birth outcomes will be handled on a case-by-case basis. In the case of paternal exposure, the 
investigator must obtain permission from the subject’s partner in order to conduct any follow-up or 
collect any information. 
8.2.2.3. AE/SAE Reporting 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the study 
subject. In addition, each study subject will be questioned about AEs. 
AEs and SAEs should be recorded from the time the subject has taken at least one dose of study treatment 
through (whichever occurs first) either a) 28 calendar days after the last administration of study treatment, 
or b) initiation of alternate anticancer therapy. 
However: 
– 
Any SAE occurring any time after the reporting period must be promptly reported if a causal relationship 
to study treatment is suspected. 
– 
For AEs or SAEs with a causal relationship to the investigational product, follow-up by the investigator 
is required until the event or its sequelae resolve to ≤ Grade 1, or stabilize for at least three months 
after the last administration of study treatment (whichever is sooner). 


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All AEs will be reported. All SAEs will also be reported in an expedited fashion using the Serious Adverse 
Event Report. The AEs entered in the eCRF and SAE Reports must be completed in a consistent manner; 
for example, the same adverse event term, causality, severity, and onset/resolution dates should be used 
on both forms. 
The investigator should inform PrECOG of any SAE within 24 hours of being aware of the event. The date 
of awareness should be noted on the report. This must be documented on the PrECOG SAE form. This 
form must be completed and supplied to PrECOG within 24 hours/1 business day at the latest on the 
following working day. The initial report must be as complete as possible, including details of the current 
illness and (serious) adverse event, and an assessment of the causal relationship between the event and 
the investigational product(s). Information not available at the time of the initial report (e.g., an end date for 
the adverse event or laboratory values received after the report) must be documented on a follow-up 
PrECOG SAE report form. A final report to document resolution of the SAE is required. A copy of the fax 
transmission confirmation of the SAE report to PrECOG should be attached to the SAE and retained with 
the patient records. 
All SAEs should be faxed to 888-731-8999 or scanned and emailed to pre0504@qdservices.com as 
per the instructions found in study materials provided to the investigator site. 
 
Medical Monitor 
During normal business hours  
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Phone: 484-574-2367 
 
Manager, Clinical Safety 
During normal business hours  
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Cell: 484-574-2367 
PrECOG will notify Celldex Therapeutics, Inc. of all SAE’s within 24 hours of PrECOG’s Awareness Date 
as discussed above. Relevant follow-up information will be provided to Celldex Therapeutics, Inc. as soon 
as it becomes available. 
Investigators should also report event(s) to their Institutional Review Board (IRB) as required. 
Collection of complete information concerning SAEs is extremely important. Full descriptions of each event 
will be followed. Thus, follow-up information which becomes available as the SAE evolves, as well as 
supporting documentation (e.g., hospital discharge summaries and autopsy reports), should be collected 
subsequently, if not available at the time of the initial report, and immediately sent using the same procedure 
as the initial SAE report. 
All SAEs, regardless of causality, must be collected which occur within 28 days of last dose of study 
treatment. This includes all deaths within 28 days of last dose of glembatumumab vedotin regardless of 
attribution. In addition, the Investigator should notify PrECOG or designee of any SAE that may occur after 
this time period which they believe to be definitely, probably or possibly related to investigational product. 
Serious adverse event reporting to regulatory authorities and all participating investigators will be conducted 
by PrECOG (or designee) in accordance with 21CFR312.32 and international regulations, as appropriate. 
8.2.2.4. Laboratory Safety Data 
The following clinical laboratory tests will be performed during this study to assess safety (Schedule of 
Assessments Table 1 for specific tests): 
▪ 
Hematology 
▪ 
Serum Chemistries 
▪ 
Urinalysis 


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Investigators must document their review of each laboratory report by signing or initialing and dating each 
report, as well as addressing the clinical significance and causality (for significant abnormalities). Section 
8.2.2.1 provides further guidance as to when abnormal laboratory results are to be reported as adverse 
events. 
8.2.2.5. Other Safety Data 
The following evaluations will also be performed during the study to measure the safety and tolerability of 
glembatumumab vedotin: 
▪ 
Vital sign measurements 
▪ 
Physical examination 
▪ 
ECGs 
▪ 
ECOG performance status (Appendix 2) 
 
 
 


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9. DATA SAFETY MONITORING BOARD (DSMB) 
The PrECOG data safety monitoring board (DSMB) will review cumulative data on an interim basis. The 
interim data reviews may include but are not limited to objectives and summaries of adverse events. The 
DSMB will conduct reviews approximately every 6 months, or as frequently as deemed necessary by the 
DSMB. If a safety concern is identified, the DSMB may recommend halting or permanently stopping the 
trial at any time. 
 
 


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10. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this trial will be 
documented in a Statistical Analysis Plan (SAP), which will be dated and maintained by PrECOG. 
This documentation may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol amendment. 
10.1. Analysis Endpoints 
Primary 
• 
Phase I: Safety and determination of the MTD 
• 
Phase II: Objective response rate (ORR) 
Secondary 
• 
Duration of objective response (DOR) 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
Correlative: 
• 
Concentration of ADC, TA and free MMAE 
• 
Pharmacodynamic parameters, including gpNMB expression levels in serum 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; and circulating soluble gpNMB. 
Safety 
• 
Incidence of adverse events 
• 
Deaths on study 
• 
Discontinuations of study drug due to adverse events 
• 
Changes in hematology, chemistry, and other laboratory parameters 
• 
Changes in vital sign parameters 
• 
Changes in ECGs parameters 
10.2. Sample Size and Power Calculation 
10.2.1. Phase I Escalation Phase 
Original Plan: 
Three to 6 patients will be enrolled in each dose cohort based on a standard Phase I dose escalation 
scheme (Dose Level 1 will enroll up to 9 patients as noted in Section 5.1.1). Each patient will participate in 
only 1 dose cohort. The total number of patients to be enrolled in the dose escalation phase is dependent 
upon the observed safety profile after 2 cycles, which will determine the number of patients per dose cohort, 
as well as the number of dose escalations required to achieve the MTD up to the second dose cohort of 
2.2 mg/kg. 
A starting sample size of 3 patients per dose cohort, expanding to 6 patients in the event of a marginal DLT 
rate (33%) was deemed to be a safe and conventional approach in the dose escalation of a novel oncologic 
agent. Assuming a true DLT rate of 5% or less, there would be a 3% chance that dose escalation would be 


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halted in a given cohort (i.e., observing 2 or more patients with DLT). If a true DLT rate of 50% is assumed, 
then there would be an 83% chance that dose escalation would be halted in a given cohort. 
Amendment 2.0: 
As of February 14, 2017; six patients have been enrolled to dose level 1 (1.9 mg/kg) with reporting of one 
dose limiting toxicity (DLT). Two deaths have occurred on study. One patient had a Grade 5 respiratory 
failure deemed unrelated to study drug and likely related to disease under study by the site and Sponsor. 
A second patient also had a Grade 5 respiratory failure deemed as possibly related to study drug by the 
site as it could not be ruled out. This qualified as a DLT per protocol. Review of documents obtained from 
the site demonstrated the patient had serious medical conditions including a previous respiratory failure 
intensive care unit admission in August 2016. The patient’s disease complicates the issue of assessing 
safety of the drug, and the events that transpired with this patient do not seem consistent with the drug 
toxicity profile of Glembatumumab Vedotin. The Sponsor assessed the respiratory failure as recurrent since 
the patient experienced respiratory failure previously in August 2016. It is the Sponsor’s assessment that 
the DLT event for this patient is ‘Grade 3 or higher neutropenia with associated fever greater than 38.1.’ 
Out of the six patients whom were enrolled on dose level 1 (1.9 mg/kg), 1 DLT has been identified as noted 
above. 
Dose escalation to Cohort 2 seemed premature. To further assess the safety signal and not put either 
subjects or the drug in jeopardy, it was PrECOG’s decision to modify the Phase I portion and treat a 
maximum of 3 additional patients on Cohort 1 (1.9 mg/kg) for up to 9 patients at this dose level to verify the 
safety of this dosage regimen. If any of the 3 additional patients experience a DLT, the dose will de-escalate 
to Cohort -1. If none of the additional 3 patients experience a DLT, dose escalation may proceed form 
Cohort 1 to Cohort 2. The same DLT evaluation rules will apply as noted above. 
A second DLT was observed on Cohort 1. Patient experienced treatment- related Grade 3 pruritus requiring 
hospital admission. Although a vital organ was not involved, due to the extent and intensity of the treatment 
required for pruritus, it was considered a DLT. Dose was de-escalated to Dose Level -1. 
Amendment 3.0: 
Three patients were enrolled to Dose Level -1 with no DLTs during the 42 day assessment period. 
Given the fact one of the previously reported DLTs at 1.9 mg/kg was complicated by the patient have 
progressive disease at the same time, and the other (pruritus) is a known and generally manageable 
adverse event associated with glembatumumab vedotin, it is reasonable to re-escalate, and re-explore the 
safety of the 1.9 mg/kg cohort. 
The protocol is being amended to include a plan to re-escalate to Dose Level 1. Upon re-escalation to Dose 
Level 1, 3 patients will be treated. This dose level will be deemed unsafe if at least 2 patients among the 
first 3 patients enrolled experiences a DLT, and Dose Level -1 will be deemed the MTD. If no DLTs are 
observed among the first 3 patients or if 1/3 patients experiences a DLT then we will enroll 3 more patients. 
This dose level will be determined to be the MTD in the event that <2/6 patients treated at Dose Level 1 
experience DLT. If ≥ 2/6 patients experience DLT at Level 1, then Dose Level -1 will be declared the MTD. 
Note that Dose Level 2 is no longer part of the study effective with this amendment. 
10.2.2. Phase II Study Portion 
In the Phase II study portion, the safety and preliminary antitumor activity of glembatumumab vedotin at the 
selected dose will be explored. Up to 35 eligible, treated patients may be enrolled according to a single-
arm Phase II trial design with ORR as the primary endpoint. 
The Phase II study portion will be carried out in 2 stages so that enrollment can terminate early in the event 
that glembatumumab vedotin is not sufficiently active in this patient population. A true ORR of 20% is 
hypothesized. A response rate of less than 5% is not considered clinically meaningful. The number of 
patients evaluated in each stage and the minimum number of responders needed to continue to the next 
stage were determined based on Simon’s 2-stage design, with 90% power and 1-sided significance level 
of less than 10%. Based on the above considerations, 20 eligible, treated patients will be enrolled (first 


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stage): if ≤1 patient achieves a complete response (CR) or partial response (PR), then enrollment will 
terminate; otherwise, 15 additional eligible, treated patients will be enrolled in the second stage, for a total 
of 35 eligible, treated patients. To assure sufficient eligible, treated patients, up to 2 additional patients may 
be enrolled (total of 37 patients). 
Upon completion of the second stage, if ≥ 4 patients out of the 35 eligible, treated patients achieve 
confirmed CR or PR, then the true response rate for glembatumumab vedotin likely exceeds 5%, the lower 
threshold of a clinically meaningful response rate. Alternatively, if <4 patients achieve an objective response 
at the end of the second stage, then the true response rate is likely 5% or lower and further evaluation of 
glembatumumab vedotin in this patient population may not be pursued. If the true ORR is less than 5%, the 
probability of terminating enrollment at the end of the first stage is equal to 74%. 
Safety will be assessed for all patients enrolled in an ongoing fashion based on the incidence of AEs, SAEs, 
and treatment discontinuations due to AE. No formal safety stopping rules are specified. However, if any 
significant safety issues arise, a decision to modify or terminate the trial will be made. 
An interim analysis will be performed for the Phase II study portion to determine if enrollment in the second 
stage will commence based on the criteria described in Section 10.2. 
10.2.2.1. Toxicity Monitoring 
This study will be monitored for the incidence of Grade 5 events. In particular, we will monitor the Grade 5 
event rate among the first stage accrual of 20 patients. All Grade 5 events deemed at least possibly related 
to treatment as well as any Grade 5 events occurring within 3 weeks of the first dose (Cycle 1) regardless 
of attribution are included as ‘events’ for the purpose of monitoring. The expected Grade 5 event rate is 
considered excessive if it exceeds 25%; therefore, we will call for immediate safety review in the event that 
the one-sided upper 90% exact binomial CI for the Grade 5 event rate, where the events are defined as 
above, exceeds 25%. Accrual to the study will be suspended immediately for the safety review and 
consideration of early study termination will be made. The one-sided upper 90% exact CI for the Grade 5 
event rate will exceed 25% if 3 or more patients experience a Grade 5 event as defined above. Therefore, 
observation of a third Grade 5 event meeting the above criteria will immediately trigger the stopping rule; 
full accrual of 20 patients to the first stage need not happen in order for the safety review to take place. 
10.2.3. Analysis Populations 
10.2.3.1. Safety Population 
The safety population will be used primarily for the analysis of safety data and will consist of all enrolled 
patients who receive 1 or more doses of glembatumumab vedotin (study drug). 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. 
10.2.4. Efficacy Analysis 
The eligible, treated population will be the basis for the primary analysis of efficacy in this study. Patients 
who discontinue study for reasons other than symptomatic deterioration or death prior to the first 
radiographic assessment will be considered unevaluable but will be included in the denominator when 
calculating the response rate. Every effort will be made to ascertain outcomes for all enrolled patients, 
irrespective of early discontinuation of protocol therapy. 
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. 


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10.3. Statistical Methods 
10.3.1. Safety Analysis 
Safety will be assessed by clinical review of all relevant parameters including adverse events, serious 
adverse events, laboratory values, vital signs, and ECGs results. Unless specified otherwise, the safety 
analyses will be conducted for the safety population defined in Section 10.2.3.1. The results of these 
analyses will be presented by study phase. For the escalation phase, tabulations will be provided by dose 
cohort and overall. Some safety analyses may be performed based on the dose escalation phase and 
Phase II study portion combined. 
Summary tables and listings will be provided for all reported treatment emergent adverse events (TEAEs), 
defined as: 1) adverse events that start on or after the first administration of study drug; 2) pre-existing 
signs/symptoms that worsen after the first administration of study drug; 3) any AEs occurring within 28 days 
of last dose of study drug; and 4) SAEs related to study drug regardless of when the SAE started. The 
reported adverse event term will be assigned a standardized preferred term using the current version of the 
Medical Dictionary for Regulatory Activities (MedDRA). 
TEAEs will be summarized based on the number and percentage of subjects experiencing the event by 
MedDRA System Organ Class and Preferred Term. The causal relationship between the occurrence of an 
adverse event and study drug will be judged by the Investigator based on the conventions described in 
Section 8.2.2.1. In the event a patient experiences repeat episodes of the same adverse event, then the 
event with the highest severity grade and strongest causal relationship to study drug will be used for 
purposes of incidence tabulations. 
Tabular summaries will be provided for: 
• 
all TEAEs 
• 
TEAEs by relationship (yes, no) to study drug and maximum severity grade 
• 
TEAEs with action of study drug delayed/interrupted or treatment reduced 
• 
TEAEs with action of study drug discontinued 
• 
serious adverse events 
For the escalation phase, the observed DLT rate in each dose cohort will be calculated by the crude 
proportion of patients in the escalation-evaluable population who experience DLT. The escalation-evaluable 
population includes patients who receive at least one dose of study drug and excludes patients who 
discontinue safety follow-up before day 42 (±3 days) for reasons other than DLT. Multiple concurrent 
adverse events leading to DLT will be considered a single DLT. The estimate of the DLT rate will be 
accompanied by a 2-sided 95% exact binomial confidence interval (CI). The relationship between the dose 
of study drug and the probability of DLT may be assessed in an exploratory manner by fitting various 
regression models such as Emax, logistic, and exponential model shapes. 
All deaths that occur on study (defined as during treatment or within 28 days of treatment discontinuation) 
will be reported in a patient listing, which will include the primary cause of death and the number of days 
between the date of the last dose of study drug and death. 
Hematology and serum chemistries will be summarized in a descriptive manner by calculating the mean, 
standard deviation, median, and range as follows: 
• 
Baseline value 
• 
Minimum post-baseline value 
• 
Maximum post-baseline value 
• 
Average post-baseline value 
• 
Last post-baseline value 


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Laboratory values will be assigned toxicity grades when available using the NCI-CTCAE scale. Directional 
shifts in laboratory toxicity grades (comparing baseline grade with worst post-baseline grade) will be 
analyzed using standard shift tables, presenting number and proportion of patients and their maximum 
grade shift. For analytes without a toxicity grading scale, the shift table will present directional shifts from 
baseline to above or below the laboratory standard normal range using the maximum increase and/or 
decrease observed throughout the course of treatment/observation. 
All patients will have pretreatment baseline vital signs and pre-dose measurements on Day 1 of each cycle. 
The results for each vital sign will be summarized in a descriptive manner by calculating the mean, standard 
deviation, median, and range by time point in the same manner described for laboratory values. For these 
analyses, the minimum, maximum, average, and last post-baseline value will be determined relative to the 
baseline vital sign measurements only. In addition, serial measurements will be obtained during and after 
each infusion of study drug. For each patient, the vital signs change from the pre-dose value will be 
summarized in a descriptive manner. The Wilcoxon signed rank test may be used to assist in the 
identification of any systematic changes. 
10.3.2. Efficacy Analysis 
The primary endpoint, ORR, will be estimated for eligible, treated patients enrolled in the Phase II study 
portion. The estimate of the ORR will be calculated based on the maximum likelihood estimator (i.e., crude 
proportion of patients with best overall response of confirmed CR or PR based on RECIST). The estimate 
of the ORR will be accompanied by a 2-sided exact 90% CI if the study stops early; if the study proceeds 
to a second stage then the CI will be computed using the methodology of Atkinson and Brown. 
DOR will be calculated for patients who achieve confirmed CR or PR. For such patients, DOR is defined as 
the time from the start date of confirmed CR or PR (whichever response status is observed first), to the first 
date that recurrent or progressive disease or death is objectively documented. 
PFS is defined as the time from the date of the first dose of study drug to the earliest of documented disease 
progression based on RECIST or death without prior progression. Patients not experiencing an event will 
be censored at their last adequate disease assessment date. 
OS is defined as the time from the date of the first dose of study drug to the date of death (whatever the 
cause). Patients not experiencing an event will be censored at the last follow-up date. 
DOR, PFS, and OS will be summarized descriptively using the Kaplan-Meier method with 90% CIs 
calculated using Greenwood’s formula. Median follow-up for each endpoint will be estimated according to 
the Kaplan-Meier estimate of potential follow-up (Schemper and Smith 1996). The PFS rate and OS rate 
at selected landmarks and corresponding 90% CIs will be estimated using the Kaplan-Meier method. 
Greenwood’s formula will be used to calculate the standard errors of the Kaplan-Meier estimate and upper 
and lower limits of the 90% CI. 
For DOR and PFS, patients who meet one or more of the following conditions will be right-censored as 
follows: 
• 
Patients with no baseline or post-baseline disease assessments unless death occurred prior to the first 
planned assessment (in which case the death will be considered a PFS event). 
• 
Patients who initiate subsequent anticancer therapy in the absence of documented progression. 
• 
Patients who die or have disease progression after missing 2 or more consecutively scheduled disease 
assessment visits. 
• 
Patients who are last known to be alive and progression-free on or before the data cut-off date. 
For such patients, the progression or censoring date will be determined based on described conventions 
(FDA 2007). 
For OS, patients who are alive or lost to follow-up as of the data analysis cutoff date will be right-censored. 
The censoring date will be determined from the patients’ date of last contact. 


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Waterfall plots will be used to depict graphically the maximum decrease from baseline in the sum of longest 
diameters of target lesions. Exploratory analysis will be performed for the correlation between gpNMB 
expression and clinical outcomes. 
 


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11. LABORATORY AND PATHOLOGY CORRELATIVE STUDIES 
11.1. Tumor Tissue Samples 
11.1.1. gpNMB Expression (Mandatory) 
Procurement of archived tumor tissue samples is mandatory to test for expression of gpNMB, by 
immunohistochemistry (IHC) at a central lab (approximately 5 working day turnaround). Archived tumor 
specimens obtained at any point in the course of disease are acceptable, but tumor specimens obtained in 
the setting of advanced (recurrent, locally advanced or metastatic) disease and subsequent to the last anti-
cancer regimen received are preferred. Formalin-fixed paraffin-embedded (FFPE) diagnostic tumor tissue 
block(s) or 10-20 FFPE unstained, positively charged slides plus H&E slide from a tumor tissue block and 
copy of pathology report will be required. 
Additional samples with pathology reports from previous collection dates should also be submitted when 
feasible. Submitted cytology samples such as pleural effusions, bronchial washings or fine needle aspirates 
(FNA) will be used to evaluate feasibility of gpNMB expression analysis and to investigate correlations with 
other samples for the patient, but they will not be used to determine study eligibility. 
Any left-over samples will be banked for future research (optional). 
11.1.2. Pharmacodynamics (Optional) 
In the event of tumor resection, biopsy, or cytological sample collection anytime during treatment or 
following tumor progression, submission of these tissue samples and pathology reports is strongly 
encouraged. Analysis may include gpNMB expression by reverse transcriptase polymerase chain reaction 
(RT-PCR), examination of tumor markers using IHC or other molecular analyses, localization of 
glembatumumab vedotin, CR011 or MMAE at the tumor site and/or gpNMB expression levels in the tumor 
tissue, as well as evaluation of tumor infiltrating leukocytes and other immune response cells of interest. 
Any left-over samples will be banked for future research. 
11.1.2.1. Tumor Tissue Sample Shipping 
Samples should be shipped Monday-Friday. Samples will be shipped ambient via overnight courier. 
All samples collected will be labeled with a unique numeric identifier that will be coded for patient privacy 
protection. 
Kits and instructions for sample collection, processing, storage and shipment will also be provided. 
Please see Laboratory Manual for detailed instructions. 
11.2. Blood Samples 
11.2.1. Immunogenicity 
Peripheral blood will be obtained to monitor for the development of anti-glembatumumab vedotin and anti-
CR011 antibodies, and whether these antibodies are neutralizing. 
6 mL blood sample (red top tube) for serum will be collected prior to dosing on Day 1 of odd-numbered 
cycles (Cycle 1, Cycle 3, etc.) and at End of Treatment. 
Any left-over blood samples will be banked for future research (optional). 
 
 


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11.2.2. Pharmacokinetics (PK) 
Concentration of the antibody-drug conjugate (ADC), total antibody (TA) and free MMAE will be determined 
using GLP compliant enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem 
mass spectrometry (LC-MS/MS) methods. The impact of circulating soluble gpNMB levels or other soluble 
molecules on pharmacokinetic parameters may also be examined. 
6 mL blood sample (red top tube) for serum will be collected. 
• 
Phase I 
o 
Day 1 of Cycles 1 and 2, prior to dosing and at end of infusion (at or within 10 minutes after 
completion of infusion) and 4-5 hours after the end of infusion. 
o 
Cycle 1, Days 8 and 15. 
o 
Day 1 of Cycles 3 and 5 prior to dosing and at end of infusion (at or within 10 minutes after 
completion of infusion). 
o 
End of Treatment visit. 
• 
Phase II 
o 
Day 1 of Cycle 1, 2, and 5, prior to dosing and at end of infusion (at or within 10 minutes after 
completion of infusion). 
o 
End of Treatment visit. 
Any left-over blood samples will be banked for future research (optional). 
11.2.3. Pharmacodynamics 
Serum and peripheral blood mononuclear cells (PBMC) samples will be obtained. Analysis may include 
(but not limited to) examination of gpNMB expression levels (and/or potential binding partners for gpNMB) 
on myeloid suppressor cells, as well as evaluation of peripheral leukocytes, circulating tumor cells and other 
immune response cells of interest. Soluble gpNMB levels in circulation may also be examined. 
6 mL blood sample (red top tube) for serum and 20 mL blood sample (green top tubes) for whole blood will 
be collected prior to dosing on Cycle 1, Day 1, Cycle 2, Day 1 and at End of Treatment. 
Any left-over blood samples will be banked for future research (optional). 
11.3. Research Blood Samples Processing, Storage and Shipment 
Kits and instructions for sample collection, processing, storage and shipment will also be provided. 
Please see Laboratory Manual for detailed instructions. 
All samples collected will be labeled with a unique numeric identifier that will be coded for patient privacy 
protection. 
Red Top Tube Processing, Storage and Shipment 
Gently mix the blood sample by inversion 8 times (do not shake). Allow the sample to sit at room 
temperature for 15-30 minutes until a clot has formed. If the blood is not centrifuged immediately after the 
clotting time (15 to 30 minutes at room temperature), the tubes should be refrigerated (4ºC) for no longer 
than 4 hours. 
Once the clot has formed, the sample is ready for centrifugation. Centrifuge for 15 minutes at room 
temperature at 3000 RPM. Aliquot and store the resulting serum from each red top tube, as applicable per 
time point, into properly labeled polypropylene tubes as directed by the lab manual. Be careful to not disturb 
the clot. Store the samples in the freezer at ≤ -20°C or colder until they are shipped. 
Samples should be batched and shipped quarterly or as requested by PrECOG. Ship samples Monday-
Wednesday. Samples must be shipped on dry ice via overnight courier. Shipping labels, supplies and 
address will be provided. 


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Green Top Tube Processing and Shipment 
Gently mix the blood sample by inversion 8 times (do not shake). Maintain and ship the same day at ambient 
temperature. 
Sample collection should ONLY occur Monday-Thursday. Samples must be shipped via overnight courier. 
Shipping labels, supplies and address will be provided. 
 
 


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12. DATA HANDLING AND RECORD KEEPING 
12.1. Data Quality Assurance 
Monitoring and auditing procedures defined by PrECOG will be followed, in order to comply with Good 
Clinical Practice (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 
electronic case report forms (eCRF) for completeness and clarity, cross-checking with source documents, 
clarification of administrative matters and drug accountability. 
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. All the 
information required by the protocol should be provided; any omissions require explanation. 
PrECOG will provide eCRFs via an electronic data capture (eDC) system for the recording and collection 
of data. Entries made in the eCRF must be verifiable against source documents. Corrections to eCRFs and 
source data will be made by authorized members of the study staff. The Investigator will sign the eCRFs to 
indicate that, to his/her knowledge, they are complete and accurate. An electronic audit trail will be 
maintained. 
The Investigator will permit PrECOG direct access to source data/documents for trial-related monitoring, 
audits, review, and inspection(s). Through ongoing monitoring visits at the investigational sites, PrECOG 
will periodically check the patient data recorded in the eCRF’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 PrECOG and/or regulatory agencies at any time. If requested, the 
Investigator will provide PrECOG, applicable regulatory agencies and/or applicable ethical review boards 
with direct access to original source documents. 
12.2. Electronic Case Report Form (eCRF) Information 
Additional information regarding eCRF instructions, timelines for data entry/submission and query 
completion can be found in supplemental materials provided to the site. Sites will be expected to complete 
eCRFs as per the schedule provided and submit all relevant data as per the specified timelines. All items 
recorded on eCRFs must be found in source documents. 
The completed eCRF must be reviewed, electronically signed, and dated by the Principal Investigator. 
Instructions for management of patients who do not receive any protocol therapy: 
If a patient is registered and does not receive any assigned protocol treatment, baseline, SAE and follow-
up data will still be entered and must be submitted according to the eCRF instructions. Document the reason 
for not starting protocol treatment on the appropriate electronic off treatment form. 
12.3. Archiving of Study Documentation 
To enable evaluations and/or audits by regulatory authorities or PrECOG, the investigator agrees to keep 
records, including the identity of all participating patients (sufficient information to link records), all signed 
informed consent forms, SAE forms, source documents, and detailed records of treatment disposition, and 
adequate documentation of relevant correspondence. The duration of record retention by the investigator 
should be according to International Conference of Harmonization (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), PrECOG should be notified. The study records must be transferred to a 
designee acceptable to PrECOG, such as another investigator or another institution. The investigator must 
obtain PrECOG's written permission before disposing of any records, even if retention requirements have 
been met. 


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13. ETHICAL CONSIDERATIONS 
13.1. Institutional Review Board or Independent Ethics Committee 
ICH GCP guidelines require that all investigational drug studies be conducted under the auspices of an 
Institutional Review Board/Independent Ethics Committee (IRB/IEC). 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 PrECOG with a copy of the communication from the IRB/IEC 
to the Investigator indicating approval/favorable opinion of 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 PrECOG 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/IEC re-approval throughout the duration of the study. 
Copies of the Investigator’s periodic report to the IRB/IEC and copies of the IRB/IEC’s continuance of 
approval must be retained in the site study files and furnished to PrECOG. 
The IRB/IECs must supply to PrECOG, upon request, a list of the IRB/IEC members involved in the vote 
and a statement to confirm that the IRB/IEC 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 the sponsor and investigator abide by GCP 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/IECs 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 IRB/IEC 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 GCP Guidelines (E6) in addition to any other 
elements required by federal, state, local or institutional policy. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the consent process 
will also include written authorization by patients to release medical information to allow PrECOG and/or its 
agents, regulatory authorities, and the IRB of record at the study site for access to patient records and 
medical information relevant to the study, including the medical history. This will be documented in the 
informed consent form or other approved form obtained at the time of informed consent per institutional 
policies. This form should also be submitted to PrECOG and/or its agents for review prior to its 
implementation. 
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 


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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. 
The original or copy of the signed Informed Consent must be maintained in the institution’s records, and is 
subject to inspection by PrECOG or regulatory agencies. The patient or his/her legally authorized 
representative will also be given a copy of the signed consent form. 
The informed consent and any other information provided to patients or the patient's legally acceptable 
representative, should be revised whenever important new information becomes available that is relevant 
to the patient's consent, and should receive IRB approval prior to use. The Investigator, or a person 
designated by the Investigator should inform the patient or the patient's legally acceptable representative 
of all pertinent aspects of the study and of any new information relevant to the patient's willingness to 
continue participation in the study. This communication should be documented in the patient record. During 
a patient's participation in the trial, any updates to the consent form and any updates to the written 
information will be provided to the patient. 
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 PrECOG or the Investigator without 
agreement by each party and IRB/IEC 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 IRB/IEC/PrECOG approval/favorable opinion. The implemented deviation or change, 
the reasons for it, and if appropriate, the proposed protocol amendment, should be submitted to the IRB/IEC 
and PrECOG 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 PI to 
PrECOG. Any subsequent actions will be assessed by PrECOG and documented. 
13.5. Safety Communication 
Investigators will be notified of all AEs that are serious, unexpected, and definitely, probably, or possibly 
related to the investigational product. Upon receiving such notices, the Investigator must review and retain 
the notice with the Investigator Brochure and submit a copy of this information to the IRB/IEC according to 
local regulations. The Investigator and IRB/IEC will determine if the informed consent requires revision. The 
Investigator should also comply with the IRB/IEC procedures for reporting any other safety information. All 
revisions should be submitted to PrECOG and/or agents for review. 
13.6. 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 PrECOG. Only the patient number and patient initials will be recorded 
in the eCRF, 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 PrECOG. 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 the PrECOG, IRB/IEC, 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. 
 
 


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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. 
Wao, H., R. Mhaskar, et al. (2013). "Survival of patients with non-small cell lung cancer without treatment: 
a systematic review and meta-analysis." Systematic reviews 2: 10. 
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. 
 
 
 


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Appendix 1: PrE0504 Eligibility Checklist 
Each of the inclusion and exclusion criteria must be met in order for a patient to be considered eligible for 
this study. An eligibility checklist is provided to confirm a patient’s eligibility. For each patient, this checklist 
must be photocopied, completed and maintained in the patient’s chart. 
Phase I Only: Eligibility Criteria Checklist must be sent via fax (215-557-7169) or email 
(candrews@precogllc.org) to the PrECOG PM/designee for review and approval prior to subject 
registration. Site will receive a confirmation of approval. Once confirmation of approval is received 
subject can be registered. 
PrECOG will not grant any exceptions or waivers to protocol eligibility criteria. 
In calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later would be considered 
Day 28. 
PrECOG Patient No. 
 
 
Patient’s Initials ( F, M, L) 
 
 
Physician Signature and 
Date 
 
NOTE: All questions regarding eligibility should be directed to the PrECOG Project Manager. Questions 
will be further discussed with the medical leads for the trial as deemed appropriate (e.g., medical monitor, 
study chair). 
NOTE: Institutions may use the eligibility checklist as source documentation if it has been reviewed, signed, 
and dated prior to registration by the treating physician. 
INCLUSION CRITERIA 
1. Read, understood, and provided written informed consent and 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. Male or female patients with metastatic, histologically- or cytologically-confirmed Stage IIIB or 
IV non-small cell lung cancer (NSCLC) of squamous histology (Staging per American Joint 
Committee on Cancer [AJCC], Edition 7). Mixed histology adenosquamous NSCLC will also 
be permitted. 
3. Experienced progression/recurrence of disease during or subsequent to the most recent anti-
cancer regimen. 
4. Any number of prior lines of systemic therapy may have been received for advanced (recurrent, 
locally advanced, or metastatic) SCC of the lung, but at least one must have been a platinum-
based chemotherapy regimen. Platinum therapy may be given on-label or as part of a clinical 
trial. 
5. Lung cancer confirmed to express gpNMB, as assessed by immunohistochemistry at a central 
lab (using expression in ≥ 5% of tumor epithelial cells as a cut-off for positivity). This can be 
tested on archived tissue if available, although preferred tumor specimen is a biopsy after the 
most recent therapy. 
NOTE: Additional samples from previous collection dates should also be submitted when 
feasible. Submitted cytology samples such as pleural effusions, bronchial washings or fine 
needle aspirates (FNA) will be used to evaluate feasibility of gpNMB expression analysis and 
to investigate correlations with other samples for the patient, but they will not be used for 
determination of study eligibility. For patients with multiple samples submitted, eligibility will be 
_____ 
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based on the most recently obtained sample, or, if obtained on the same date, the sample with 
the highest level of gpNMB expression. However, in the event that disparate results are 
obtained for samples received within a similar timeframe (i.e., within a 6-month period), the 
medical monitor may be consulted for determination of eligibility. 
6. Age ≥ 18 years. 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1 (Appendix 2). 
Performance Status: ___________ Date of Assessment: ______________ 
8. Measurable disease by RECIST 1.1 criteria (Eisenhauer, Therasse et al. 2009) [Appendix 3]. 
Target lesions selected for tumor measurements should be those where surgical resection or 
radiation are not indicated or anticipated. 
9. Resolution of all toxicities related to prior therapies to ≤ NCI-CTCAE Grade 1 severity or back 
to baseline, except for alopecia, vitiligo, or endocrinopathies on replacement therapy. 
10. Adequate bone marrow function as assessed by: 
• 
Absolute Neutrophil Count (ANC) ≥ 1500/mm3 
ANC: __________________ 
Date of Test: ____________ 
• 
Hemoglobin ≥ 9.0 g/dL 
Hemoglobin: ____________ 
Date of Test: ____________ 
• 
Platelets ≥ 100,000/mm3 
Platelets: _______________ 
 
Date of Test: ____________ 
11. Adequate renal function as assessed by: 
• 
Serum Creatinine ≤ 2.0 mg/dL 
Serum Creatinine: ________ 
 
Date of Test: ____________ 
• 
Calculated (Cockcroft and Gault Formula Appendix 4) or 24-Hour Urine Creatinine 
Clearance >40 mL/min 
Creatinine Clearance: _____ 
 
Date of Test: ____________ 
12. Serum albumin ≥ 3 g/dL. 
13. Adequate liver function as assessed by: 
• 
Total Bilirubin ≤ 1.5x upper limit of normal (ULN) 
Total Bilirubin: ___________ 
ULN: ________ 
Date of Test: ___________ 
• 
Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5x ULN (≤ 5.0x ULN in 
patients with liver metastases) 
ALT: ___________________ 
ULN: ________ 
Date of Test: ___________ 
AST: ___________________ 
ULN: ________ 
Date of Test: ___________ 
NOTE: Patients with known Gilbert’s syndrome may be enrolled with total bilirubin ≤ 3.0 mg/dL. 
NOTE: The liver is a route of clearance for MMAE. Patients with mild hepatic impairment are 
excluded from Phase I (the dose escalation portion) to minimize the influence of hepatic 
impairment on tolerability and dose selection because a lower dose is recommended for other 
ADCs with a vc-MMAE moiety. See the acceptable liver function parameters for Phase I 
defined above. In Phase II (the dose expansion portion), a lower starting dose for patients with 
mild hepatic impairment will be determined based on the MTD recommended from the Phase 
_____
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I portion of this trial. The acceptable liver function parameters will be redefined for Phase 
II. 
14. Both male and female patients of childbearing potential enrolled in this trial must use adequate 
birth control measures during the course of the trial and for at least one month after 
discontinuing study drug. Adequate birth control measures are defined as double barrier 
contraception (e.g., condom plus spermicide in combination with a female condom, diaphragm, 
cervical cap, or intrauterine device), implants, injectables, combined oral contraceptives, sexual 
abstinence (abstinence from intercourse during the ovulation period), or vasectomized partner. 
Patients and/or partners who are surgically sterile or postmenopausal are exempt from this 
requirement. 
15. Willing to provide blood samples for research purposes (Section 11.2). 
EXCLUSION CRITERIA 
1. Received glembatumumab vedotin (CR011-vcMMAE; CDX-011) or other MMAE-containing 
agents previously. 
2. Chemotherapy within 21 days or at least 5 half-lives (whichever is shorter) prior to the planned 
start of study treatment; radiation outside the thorax within 14 days prior to the planned start of 
study treatment or thoracic radiation; antibody based therapy or investigational therapy within 
28 days prior to the planned start of study treatment. 
3. Neuropathy >NCI-CTCAE Grade 1. 
4. 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. 
5. Known brain metastases, unless previously treated and patients are neurologically returned to 
baseline except for residual signs and symptoms related to CNS treatment and CNS lesions 
are not progressive in size and number for 4 weeks. 
6. Significant cardiovascular disease including unstable angina pectoris, uncontrolled 
hypertension, and congestive heart failure (New York Heart Association (NYHA) Class 3 or 4 
[Appendix 5]) related to primary cardiac disease, a history of a serious uncontrollable 
arrhythmia despite treatment, ischemic or severe valvular heart disease, or a myocardial 
infarction within 6 months prior to the trial entry. 
7. 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, a negative urine culture is required prior to enrollment. 
8. Subjects on immunosuppressive medications such as azathioprine, mycophenolate mofetil, 
cyclosporine or require chronic corticosteroid use (defined as ≥ 3 months of prednisone dose 
equivalent of ≥ 10 mg). 
9. The MMAE component of glembatumumab vedotin is primarily metabolized by CYP3A. 
Patients taking strong CYP3A inhibitors and inducers are excluded in Phase I (the dose 
escalation portion) to minimize the effect of these modulators on exposure, tolerability and dose 
selection (http://medicine.iupui.edu/clinpharm/ddis/main-table/). 
10. History of other malignancy except for adequately treated basal or squamous cell skin cancer, 
curatively treated in situ disease, or any other cancer from which the patient has been disease-
free for ≥ 2 years. 
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11. Pregnant or breast-feeding women. 
Is the patient a woman of childbearing potential? _____________________ (yes/no) 
If yes, Date of Test: _______________ 
Results: ____________________________ 
12. Subjects must not be on home oxygen therapy (intermittent or continuous). 
13. Any underlying medical condition that, in the Investigator’s opinion, will make the administration 
of study treatment hazardous to the patient, or would obscure the interpretation of adverse 
events. 
 
 
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Appendix 2: ECOG Performance Status 
 
PS 0 
Fully active, able to carry on all pre-disease performance without 
restriction 
PS 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. 
PS 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. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
Source: Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 


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Appendix 3: RECIST 1.1 Criteria 
To assess objective response or future progression, it is necessary to estimate the overall tumor burden at 
baseline and use this as a comparator for subsequent measurements. All baseline evaluations should be 
performed as close as possible to the treatment start and never more than 4 weeks before the beginning 
of the treatment. 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. Imaging based evaluation should 
always be done rather than clinical examination, unless the lesion(s) being followed cannot be imaged but 
are assessable by clinical exam. (“Methods of Lesion Measurement” for further guidance.) 
Only patients with measurable disease on baseline evaluations should be included. (Measurable disease 
is defined by the presence of at least one measurable lesion; see “Measurability of Tumor at Baseline”.) At 
baseline, lesions should be identified as either “Target” or “Non-Target” as follows: 
Target Lesions: 
o 
Up to a maximum of five measurable target lesions total (with a maximum of two target lesions per 
organ) should be identified as target lesions and will be recorded and measured at baseline. (This 
means in instances where patients have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded.) 
o 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. 
o 
All target lesion measurements should be recorded in metric notation, using calipers if clinically 
assessed. 
o 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and reported as the baseline sum diameters. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the measurable dimension 
of the disease. (“Tumor Response Evaluation”) 
Non-Target Lesions: 
o 
All other measurable/non-measureable lesions (or sites of disease) including pathological lymph nodes 
should be identified as non-target lesions and should also be recorded at baseline. It is acceptable to 
record multiple non-target lesions involving the same organ as a single item on the case report form 
(e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
o 
Non-target lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. 
(“Tumor Response Evaluation”) While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively. 


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MEASURABILITY OF TUMOR AT BASELINE 
o 
Measurable: Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of: 
▪ 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
▪ 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable). 
▪ 
20 mm by chest x-ray. 
Note: To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in 
short axis when assessed by CT scan (for lymph nodes, only the short axis is measured and followed). 
o 
Non-Measurable: All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥ 10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques. 
Special considerations regarding lesion measurability: 
o 
Malignant Lymph Nodes: Lymph nodes merit special mention since they are normal anatomical 
structures which may be visible by imaging even if not involved by tumor. Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane; for MRI the plane of acquisition may be axial, saggital or coronal). The smaller 
of these measures is the short axis. At baseline and in follow-up, only the short axis will be measured 
and followed. To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). All other pathological nodes (those with short axis ≥ 10 mm but <15 mm) should be 
considered non-target lesions. Nodes that have a short axis <10 mm are considered non-pathological 
and should not be recorded or followed. 
o 
Bone Lesions: Bone scan, positron emission tomography (PET) scan or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, 
with identifiable soft tissue components, that can be evaluated by cross sectional imaging techniques 
such as CT or MRI can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above. Blastic bone lesions are non-measurable. 
o 
Cystic Lesions: Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
o 
Lesions with prior local treatment: Tumor lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 


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METHODS OF LESION MEASUREMENT 
o 
Clinical Exam: Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is suggested. 
As noted above, when lesions can be evaluated by both clinical exam and imaging, imaging evaluation 
should be undertaken since it is more objective and may also be reviewed at the end of the study. 
o 
Chest X-Ray: Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated 
lung.  
o 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). If there is concern about radiation exposure at 
CT, MRI may be used instead of CT in selected instances. 
o 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression. (“Tumor Response Evaluation”) 
o 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. 
o 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
o 
Tumor Markers: Tumor markers alone cannot be used to assess objective tumor response. If markers 
are initially above the upper normal limit, however, they must normalize for a patient to be considered 
in complete response. 
o 
Cytology, Histology: These techniques can be used to differentiate between PR and CR in rare cases 
if required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). When effusions are known to be a potential adverse effect 
of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease in order to 
differentiate between response (or stable disease) and progressive disease. 


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TUMOR RESPONSE EVALUATION 
Evaluation of Target Lesions: 
Target lesions will be assigned an overall response assessment at each evaluation time point according to 
the following definitions: 
o 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
o 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
o 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
o 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
Special notes on the assessment of target lesions: 
o 
Lymph Nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even if 
the nodes regress to below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of <10 mm. For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
o 
Target Lesions that become ‘too small to measure’: While on study, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes which are recorded 
as target lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being ‘too small to measure’. When this occurs it 
is important that a value be recorded on the eCRF. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned. 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the retroperitoneum; however, if a 
lymph node is believed to be present and is faintly seen but too small to measure, a default value of 5 
mm should be assigned in this circumstance as well). This default value is derived from the 5 mm CT 
slice thickness (but should not be changed with varying CT slice thickness). The measurement of these 
lesions is potentially non-reproducible, therefore providing this default value will prevent false 
responses or progressions based upon measurement error. To reiterate, however, if the radiologist is 
able to provide an actual measure, that should be recorded, even if it is below 5 mm. 
o 
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest diameters 
of the fragmented portions should be added together to calculate the target lesion sum. Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion. If the lesions have truly coalesced such that they are 
no longer separable, the vector of the longest diameter in this instance should be the maximal longest 
diameter for the ‘coalesced lesion’. 
 
 
 
 


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Evaluation of Non-Target Lesions: 
Non-target lesions will be assigned an overall response assessment at each evaluation time point according 
to the following definitions: 
o 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
o 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
o 
Progressive Disease (PD): Unequivocal progression (special notes below) of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also considered progression). 
Special notes on assessment of progression of non-target disease: 
o 
When the patient also has measurable disease: In this setting, to achieve ‘unequivocal progression’ on 
the basis of the non-target disease, there must be an overall level of substantial worsening in non-
target disease such that, even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy (further details below). A modest ‘increase’ in 
the size of one or more non-target lesions is usually not sufficient to quality for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare. 
o 
When the patient has only non-measurable disease: The same general concepts apply here as noted 
above, however, in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden. Because worsening in non-target 
disease cannot be easily quantified (by definition: if all lesions are truly non-measurable) a useful test 
that can be applied when assessing patients for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in non-measurable disease is comparable in magnitude 
to the increase that would be required to declare PD for measurable disease: i.e., an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase 
diameter in a measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to 
‘large’, an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to have objective 
criteria to apply to non-measurable disease, the very nature of that disease makes it impossible to do 
so, therefore the increase must be substantial. 
New Lesions: 
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important. 
o 
There are no specific criteria for the identification of new radiographic lesions; however, the finding of 
a new lesion should be unequivocal: i.e. not attributable to differences in scanning technique, change 
in imaging modality or findings thought to represent something other than tumor (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the patient’s baseline lesions show partial or complete response. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
o 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. An example of this is the patient who 
has visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals 
metastases. The patient’s brain metastases are considered to be evidence of PD even if he/she did not 
have brain imaging at baseline. 
o 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. 


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o 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. (A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.) 
b.  No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-
up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed 
to determine if there is truly progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-
existing site of disease on CT that is not progressing on the basis of the anatomic images, this is 
not PD. 
Evaluation of Overall Response: 
It is assumed that at each protocol specified time point, an overall response assessment occurs. The 
patient’s overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. 
Appendix 3 Table 1 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. When patients have non-measurable (therefore non-
target) disease only, Appendix 3 Table 2 is to be used. 
Special notes on evaluation of overall response: 
o 
Missing assessments and inevaluable designation: 
– 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable 
(NE) at that time point. 
– 
If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered NE at that time point, unless a convincing argument can be made that the contribution 
of the individual missing lesion(s) would not change the assigned time point response. This would 
be most likely to happen in the case of PD. For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and at follow-up only two lesions were assessed, but those gave a 
sum of 80 mm, the patient will have achieved PD status, regardless of the contribution of the 
missing lesion. 
o 
‘Symptomatic deterioration’: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time should be 
reported as ‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. The objective response status of such patients is to 
be determined by evaluation of target and non-target disease as shown in Appendix 3 Tables 1 & 2. 
o 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of complete response. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where 
a residual radiographic abnormality is thought to represent fibrosis or scarring. 
o 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date 
when progression was suspected. 
o 
Confirmation of response: In the event of complete or partial responses, efforts should be made to 
obtain a confirmatory scan (no sooner than 28 days later). 


PrECOG Protocol Number: PrE0504 
IND Number: 128597 
Confidential 
Date: 11/14/2017 
 
Page 84 of 89 
Appendix 3 Table 1: Overall Response: Patients with Target +/–Non-Target Disease. 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR  
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not Evaluated 
No 
PR 
PR 
Non-PD or Not All Evaluated 
No 
PR 
SD 
Non-PD or Not All Evaluated 
No 
SD 
Not All Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, and NE = inevaluable. 
 
Appendix 3 Table 2: Overall Response: Patients with Non-Target Disease Only. 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PDa 
Not All Evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease, and NE = inevaluable. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this category 
when no lesions can be measured is not advised. 


PrECOG Protocol Number: PrE0504 
IND Number: 128597 
Confidential 
Date: 11/14/2017 
 
Page 85 of 89 
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. 
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 centre to be sure that future evaluations are done with the 
baseline technique so at least SOME courses are fully evaluable. 


PrECOG Protocol Number: PrE0504 
IND Number: 128597 
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Date: 11/14/2017 
 
Page 86 of 89 
(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 retrieve the lesion 
evaluability. 
(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 being non-evaluable makes the 
overall response interpretation inevaluable 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 centre. 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 
5 mm 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. 
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) 
 
 


PrECOG Protocol Number: PrE0504 
IND Number: 128597 
Confidential 
Date: 11/14/2017 
 
Page 87 of 89 
Appendix 4: Cockroft and Gault Formula 
 
(140 - age [years]) (body wt [kg]) 
Creatinine clearance for males =  
————————————— 
(72) (serum creatinine [mg/dL]) 
 
 
Creatinine clearance for females = 0.85 x male value 
 
 




PrECOG Protocol Number: PrE0504 
IND Number: 128597 
Confidential 
Date: 11/14/2017 
 
Page 89 of 89 
Appendix 6: Investigator Signature 
1. 
I have carefully read this protocol entitled “A Phase I/II Study of Glembatumumab 
Vedotin in Patients with gpNMB-Expressing, Advanced or Metastatic Squamous Cell 
Carcinoma of the Lung”, Version 3.0 dated 11/14/2017 (Protocol Number 
PrE0504) and agree that it contains all the necessary information required to 
conduct the study. I agree to conduct the study as outlined in the protocol. 
2. 
I agree to conduct this study according to the moral, ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki, the principles of 
Good Clinical Practice (GCP) as described in 21 Code of Federal Regulations (CFR) 
and any applicable local requirements. 
3. 
I understand that this trial and any subsequent changes to the trial will not be initiated 
without approval of the appropriate Institutional Review Board, and that all 
administrative requirements of the governing body of the institution will be complied 
with fully. 
4. 
Informed written consent will be obtained from all participating patients in 
accordance with institutional and Food and Drug Administration (FDA) requirements 
as specified in Title 21, CFR, Part 50. 
5. 
I understand that my signature on the electronic Case Report Form (eCRF) indicates 
that I have carefully reviewed each page and accept full responsibility for the 
contents thereof. 
6. 
I understand that the information presented in this study protocol is confidential, and 
I hereby assure that no information based on the conduct of the study will be 
released without prior consent from PrECOG, LLC unless this requirement is 
superseded by the FDA. 
Principal Investigator (PI): 
PI Name: 
 
 
 
 
 
 
 
 
 
 
Site Name: 
 
 
 
 
 
 
 
 
 
 
Signature of PI: 
 
 
 
 
 
 
 
 
 
Date of Signature: 
 
 
\ 
 
\ 
 
 
 
 
 
 
 
MM 
 
DD 
 
YYYY 
 

SAP_001.pdf: 
PrECOG, LLC 
Protocol: PrE0504 / Phase I/II  
Statistical Analysis Plan  
 
 Version: Final 1.0 / 28Oct2016 
1 
 
Statistical Analysis Plan 
Protocol 
PrE0504 
Version 
Final 1.0 
Date 
28 October 2016 
A Phase I/II Study of Glembatumumab Vedotin in Patients with gpNMB-Expressing, 
Advanced or Metastatic Squamous Cell Carcinoma of the Lung 
 
 
 


PrECOG, LLC 
Protocol: PrE0504 / Phase I/II  
Statistical Analysis Plan  
 
 Version: Final 1.0 / 28Oct2016 
2 
 
DOCUMENT: 
 
Statistical Analysis Plan 
 
 
 
PROTOCOL 
 
 
Number: 
 
PrE0504 
 
Title: 
 
A Phase I/II Study of Glembatumumab Vedotin in Patients with 
gpNMB-Expressing, Advanced or Metastatic Squamous Cell 
Carcinoma of the Lung 
Date: 
 
23 December 2015 
 
 
 
 
 
 
SAP STATUS 
 
Final  
 
 
 
SAP VERSION AND DATE 
 
Version: Final 1.0   Date: 28 October 2016 
 
 
 
SPONSOR: 
 
PrECOG, LLC 
PREPARED BY: 
 
Quality Data Services, Inc. 
 
 
 
 
 


PrECOG, LLC 
Protocol: PrE0504 / Phase I/II  
Statistical Analysis Plan  
 
 Version: Final 1.0 / 28Oct2016 
3 
 
SIGNATURES/APPROVAL PAGE  
 
 
AUTHORS 
 
 
 
 
 
 
10/28/16 
 
 
 
Sr. Biostatistician 
Quality Data Services, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
Quality Data Services, Inc. 
 
 
 
Date 
 
 
 
 
APPROVERS 
 
 
 
 
 
11/03/2016 
 
 
  
Statistician 
 
Date 
 
 
 
 
 
 
 
 
 
 
PrECOG, LLC 
 
 
Date 
 
 
 


PrECOG, LLC 
Protocol: PrE0504 / Phase I/II  
Statistical Analysis Plan  
 
 Version: Final 1.0 / 28Oct2016 
4 
 
TABLE OF CONTENTS 
FOR  FOR  FOR TITLE PAGE .................................................................................. 1 
1. 
LIST OF ABBREVIATIONS ............................................................................. 6 
2. 
INTRODUCTION .............................................................................................. 8 
2.1. 
Objective of the Statistical Analysis Plan .................................................... 8 
3. 
STUDY OBJECTIVES ...................................................................................... 9 
3.1. 
Primary Objective ........................................................................................... 9 
3.2. 
Secondary Objective ...................................................................................... 9 
3.3. 
Exploratory Objective .................................................................................... 9 
4. 
STUDY DESIGN ............................................................................................. 10 
4.1. 
General Study Design and Treatment  Plan ............................................... 10 
4.2. 
Study Population .......................................................................................... 10 
4.3. 
Duration of Study Treatment, Follow-up and End of Study ...................... 11 
4.4. 
Criteria for discontinuation from Study Treatment ................................... 12 
5. 
GEBERAL STATISTICAL CONSIDERATIONS ........................................... 12 
5.1. 
ANALYSIS ENDPOINTS ............................................................................... 12 
5.2. 
METHODOLOGY .......................................................................................... 13 
5.3. 
HANDLE MISSING, UNSCHEDULED AND REPEATED 
MEASUREMENTS DATA........................................................................................ 13 
5.4. 
INTERIM ANALYSIS AND DATA MONITORING ....................................... 14 
6. 
STUDY POPULATION CHARACTERISTICS ............................................... 14 
6.1. 
Subject Disposition ...................................................................................... 14 
6.2. 
Protocol Deviation and Violation ................................................................ 14 
6.3. 
Demographics and Baseline Characteristics ............................................. 14 
6.4. 
Dosing and Extent of Exposure .................................................................. 15 


PrECOG, LLC 
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6.5. 
Medical History and Cancer therapy........................................................... 15 
6.6. 
Concomitant Medications ............................................................................ 15 
7. 
MEASUREMENT OF EFFECT ...................................................................... 15 
7.1. 
Efficacy  Analysis ......................................................................................... 15 
7.2. 
Primary Endpoint Assessment ................................................................... 15 
7.3. 
Secondary Endpoint Assessment............................................................... 16 
8. 
SAFETY MEASUREMENTS .......................................................................... 17 
8.1. 
Adverse Events ............................................................................................ 17 
8.2. 
Laboratory assessment ............................................................................... 18 
9. 
EXPLORATORY ENDPOINTS ASSESSMENT ............................................. 19 
9.1. 
Efficacy variables and degree of gpNMB expression ............................... 19 
9.2. 
Pharmacokinetics (PK) Analysis ................................................................. 19 
9.3. 
Pharmacodynamics (PD) Analysis.............................................................. 19 
10. 
REPORTING CONVENTIONS ...................................................................... 20 
11. 
APPENDIX: SCHEDULE OF ASSESSMENTS1 ............................................ 23 
 
 
 
 


PrECOG, LLC 
Protocol: PrE0504 / Phase I/II  
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1. LIST OF ABBREVIATIONS  
 
Abbreviation/Acronym 
Definition 
ACS  
American Cancer Society  
ADC  
Antibody-Drug Conjugate  
AE 
Adverse event 
ALK  
Anaplastic Lymphoma Receptor Tyrosine Kinase  
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)  
CFR  
Code of Federal Regulations  
CI  
Confidence Interval  
CR  
Complete Response  
CNS  
Central Nervous System  
CT  
Computed Tomography  
CTCAE  
Common Toxicity Criteria for Adverse Events  
DC-HIL  
Dendritic Cell-Heparin Integrin Ligand  
DCTD  
Division of Cancer Treatment and Diagnosis  
DHHS  
Department of Health and Human Services  
DLT  
Dose-Limiting Toxicity  
DOR  
Duration of Response  
DSMB  
Data Safety Monitoring Board  
ECG  
Electrocardiogram  
ECOG  
Eastern Cooperative Oncology Group  
eCRF  
Electronic Case Report Form  
eDC  
Electronic Data Capture  
EGFR  
Epidermal Growth Factor Receptor  
ELISA  
Enzyme-Linked Immunosorbent Assay  
EST  
Eastern  
FDA  
Food and Drug Administration  
FNA  
Fine Needle Aspirate  
FSH  
Follicle-Stimulating Hormone  


PrECOG, LLC 
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 Version: Final 1.0 / 28Oct2016 
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GCP  
Good Clinical Practice 
GLP  
Good Laboratory Practices  
gpNMB  
Glycoprotein NMB  
HGFIN  
Hematopoietic Growth Factor Inducible Neurokinin-1 type  
HIPAA  
Health Insurance Portability and Accountability Act  
IC  
Investigator’s Choice  
ICH  
International Conference on Harmonization  
IgG2  
Immunoglobulin G, Subclass 2  
IHC  
Immunohistochemistry  
IND  
Investigational New Drug  
IRB/IEC  
Institutional Review Board/Independent Ethics Committee  
IRC  
Independent Review Committee  
IV  
Intravenous  
Kg  
Kilogram  
LCMS/MS  
Liquid Chromatography-Tandem Mass Spectrometry  
LDH  
Lactate Dehydrogenase  
MCV  
Mean Corpuscular Volume  
MedDRA  
Medical Dictionary for Regulatory Activities  
mg  
Milligrams  
mL  
Milliliters  
MMAE  
Monoethylauristatin E  
MRI  
Magnetic Resonance Imaging  
MTD  
Maximum Tolerated Dose  
n  
number  
NCCN  
National Comprehensive Cancer Network  
NCI  
National Cancer Institute (of the United States)  
NE  
Inevaluable  
NIH  
National Institutes of Health  
NR  
Not Reported  
NSCLC  
Non-Small Cell Lung Carcinoma  
NYHA  
New York Heart Association  
ORR  
Objective Response Rate  
OS  
Overall Survival  
PBMC  
Peripheral Blood Mononuclear Cell 


PrECOG, LLC 
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PD  
Progressive Disease  
PET  
Positron Emission Tomography  
PFS  
Progression-Free Survival  
PI  
Principal Investigator  
PK  
Pharmacokinetics  
PR  
Partial Response  
q3w  
Every 3 Weeks  
RBC  
Red Blood Count  
RECIST  
Response Evaluation Criteria for Solid Tumors  
RNA  
Ribonucleic Acid  
ROC  
Receiver Operating Curve  
RT-PCR  
Reverse Transcriptase Polymerase Chain Reaction  
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SCC  
Squamous Cell Carcinoma  
SD  
Stable Disease  
SOPs  
Standard Operating Procedures  
SRM  
Study Reference Manual  
TA  
Total Antibody  
TEAE  
Treatment-Emergent Adverse Event  
TKI  
Tyrosine Kinase Inhibitor  
TTP  
Time to Progression  
ULN  
Upper Limit of Normal  
vc  
Valine-Citrulline  
VEGFR  
Vascular Endothelial Growth Factor Receptor  
WBC  
White Blood Count 
 
2. INTRODUCTION 
2.1. Objective of the Statistical Analysis Plan 
This statistical analysis plan (SAP) describes the planned analysis of the data collected in the Phase 
II of this study. A detailed description of the planned tables, figures and listings (TFLs) to be 


PrECOG, LLC 
Protocol: PrE0504 / Phase I/II  
Statistical Analysis Plan  
 
 Version: Final 1.0 / 28Oct2016 
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presented in the Clinical Study Report (CSR) is provided in the accompanying TFL template 
document.  
The intent of this document is to provide guidance for the analysis of data related to safety and 
efficacy of data collected in Phase II of the study and to describe any applicable statistical 
procedures. In general, the analyses come directly from the protocol, unless they have been 
modified by agreement between the Sponsor and QDS. A limited amount of information 
concerning this study (e.g., objectives, study design) is summarized to help the reader interpret the 
accompanying TFL templates. Attached signatures indicate approval of the safety and statistical 
analyses sections of the SAP. These sections must be agreed upon prior to database lock. When 
the SAP and TFL templates are agreed upon and finalized, they will serve as the template for 
generation of the TFLs that will be the basis of the safety results described in the clinical study 
report. 
Deviations from this SAP, both substantial and non-substantial, will be documented in the CSR. 
All deviations from the SAP and/or TFL templates will be documented in a running Addendum to 
the SAP document and finalized with signoff as an addendum to the SAP prior to database lock. 
3. STUDY OBJECTIVES 
3.1. Primary Objective  
• Phase I: To evaluate the safety and tolerability and determine the Maximum Tolerated Dose 
(MTD) of glembatumumab vedotin in patients with advanced gpNMB-expressing 
Squamous Cell Carcinoma (SCC) of the lung. 
• Phase II: Determine the anti-tumor activity, as assessed by objective response rate (ORR) 
in accordance with RECIST 1.1, of the MTD of glembatumumab vedotin in patients with 
advanced gpNMB-expressing SCC of the lung. 
3.2. Secondary Objective 
• To further characterize the safety of glembatumumab vedotin in advanced gpNMB-
expressing SCC of the lung.  
• To further evaluate the anti-cancer activity of glembatumumab vedotin in advanced 
gpNMB-expressing SCC of the lung, as measured by duration of objective response 
(DOR), progression-free survival (PFS), and overall survival (OS).  
3.3. Exploratory Objective 
• To investigate if the anti-cancer activity of glembatumumab vedotin in advanced gpNMB-
expressing SCC of the lung is dependent upon the degree of gpNMB expression in tumor 
tissue. 
• To examine pharmacodynamic effects of treatment, including tumor immune cell infiltrate 
type and number; localization of glembatumumab vedotin, CR011 or Monoethylauristatin 
E (MMAE) at the tumor site; soluble mediators and/or gpNMB expression levels in tumor 
tissue; and analysis of peripheral blood cell subsets. 


PrECOG, LLC 
Protocol: PrE0504 / Phase I/II  
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• To further characterize the pharmacokinetics and immunogenicity of glembatumumab 
vedotin in this patient population. 
 
4.  STUDY DESIGN 
4.1. General Study Design and Treatment  Plan  
This is an open-label, single arm study of glembatumumab vedotin in patients with unresectable, 
Stage IIIB or IV, gpNMB-expressing SCC of the lung who have failed a prior platinum-based 
chemotherapy regimen. This study will include a dose-escalation phase followed by a 2-stage 
Phase II expansion, as follows: 
Study Phase 
Dose 
Level/Cohort 
Glembatumumab Vedotin 
Dose (mg/kg) 
Patients (n) 
Phase I  
Dose-Escalation 
-1 
1.3 
3-6 
1 
1.9 
3-6 
2 
2.2 
3-6 
Phase II 
Stage 1 
MTD* 
20 
Stage 2 
MTD* 
15 
* MTD as determined during the dose-escalation phase 
Subjects will receive study drug, glembatumumab vedotin in an open-label fashion, once every 
three weeks (q3w) by 90-minute intravenous (IV) infusion, until disease progression or 
intolerance. Tumor assessments will be performed every 6 (±1) weeks for six months, and every 
9 (±2) weeks thereafter, until progression. Tumor response will be assessed by the investigator in 
accordance with RECIST 1.1 guidelines. Subjects who discontinue treatment in the absence of 
progression will continue to have tumor assessments until documented progression or initiation of 
alternate anti-cancer therapies.  
The MTD for the dose-escalation phase will be the highest dose-level where 0/3, or 1/6 subject 
experienced a Dose-Limiting Toxicity (DLT). 
4.2. Study Population 
Subjects with gpNMB-Expressing, Advanced or Metastatic SCC of the Lung, who have failed a 
prior platinum-based chemotherapy regimen. All subjects have to meet all inclusion and 
exclusion criteria in order to be eligible for participation of study. 
Subjects that participated in Phase I will not be eligible to participate in Phase II. 


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Protocol: PrE0504 / Phase I/II  
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Number of subjects: Phase I will enroll up to 12 subjects and Phase II will enroll up to 35 
subjects. There will be 20 subjects enrolled in Phase II Stage 1 initially and another 15 subjects 
will be enrolled in Stage 2. There may be additional 2 subjects needed to ensure sufficient 
eligible and treated subjects. In Phase II, subjects who discontinue study for reasons other than 
symptomatic deterioration or death prior to the first radiographic assessment will be considered 
unevaluable and will be replaced. Approximately up to 49 subjects will be enrolled. 
MTD evaluable subjects: In Phase I, subjects who discontinue safety follow-up before day 42 
(±3 days) for reasons other than DLT will be considered unevaluable for DLT assessment and 
will be replaced. 
Safety analysis population: The safety population will be used primarily for the analysis of safety 
data and will consist of all enrolled subjects who receive at least 1 study drug. It includes Phase I 
and Phase II all subjects.  
Efficacy analysis population: Phase II subjects who receive at least 1 study drug and are eligible 
will be defined as efficacy analysis population. 
Per-protocol analysis population: Subjects who are in efficacy analysis population, have a 
baseline and at least 1 follow-up measurement after study treatment, and also do not have major 
protocol deviation and violation are considered as per-protocol analysis population. PrECOG 
will provide a list of important deviations and protocol violations that will used to determine per-
protocol population before database locking. This population may use for supportive analysis for 
certain efficacy parameters. 
Pharmacokinetics (PK) analysis population: Phase I and Phase II Subjects who have adequate 
PK samples and results collected will be included in the PK analysis population.   
Pharmacodynamics (PD) analysis population: Phase I and Phase II Subjects who have adequate 
PD samples and results collected will be included in the PD analysis population.   
 
4.3. Duration of Study Treatment, Follow-up and End of Study 
 
Treatment phase: Subjects will start study treatment within 10 working days from registration until 
disease progression or intolerance. Phase I subjects have to complete DLT evaluation period, at 
the end of cycle 2 (Day 42 ± 3 days) in order for MTD determination. 
 
Survival Follow-Up: Subsequent to progression of disease, all subjects will be followed until study 
closure. 
 
Subject Complete study: subjects who die or complete the study follow-up through study closure 
will be considered to have completed the study.  
 
The study completion: the study will be declared complete when sufficient data is obtained to 
conclude the study. This is estimated at 15 months from the date when the last subject discontinues 
study treatment. 


PrECOG, LLC 
Protocol: PrE0504 / Phase I/II  
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It is anticipated that the enrollment period will be approximately 30 months (Phase I: 12 months 
and Phase II: 18 months). All subjects will be followed with regard to survival until death, 
discontinuation from study follow-up, or termination/completion of study. 
 
Premature termination of this study may occur because of a regulatory authority decision, drug 
safety issues, or at the discretion of PrECOG. 
 
4.4. Criteria for discontinuation from Study Treatment  
Subjects will receive protocol therapy unless:  
• Progressive disease, as assessed by the treating investigator in accordance with RECIST 
1.1 criteria.  
• Symptomatic deterioration (clinical progression); 
• Receipt of alternate anti-cancer treatments;  
• Intercurrent illness that prevents further administration of treatment per investigator 
discretion;  
• Withdrawal request by the subject or the subject’s legal representative;  
• Unacceptable adverse event, including the development of DLT  
• Physician Decision; 
• Non-compliance of the subject; 
• Pregnancy; 
• Death, otherwise not explainable by the above options; 
• Subject lost to follow-up. 
 
5. GEBERAL STATISTICAL CONSIDERATIONS 
Statistical analysis and programming of tables, listings and figures will be conducted by QDS, 
using SAS® Release 9.4 (SAS Institute Inc., Cary, North Carolina, USA).   
All analyses will base on the approved final version of this statistical Analysis Plan (SAP).  
The analyses described in this SAP are applicable for the planned TFLs mockup listed in 
separate documents. 
5.1. Analysis Endpoints 
Primary: 
• Phase I: Safety and determination of the MTD 
• Phase II: Objective response rate (ORR) 


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Secondary: 
• Duration of objective response (DOR) 
• Progression-free survival (PFS) 
• Overall survival (OS) 
Correlative: 
• Concentration of Antibody-Drug Conjugate (ADC), Total Antibody (TA) and free 
MMAE 
• Pharmacodynamic parameters, including gpNMB expression levels in serum 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; and circulating soluble gpNMB. 
Safety 
• Incidence of adverse events 
• Deaths on study 
• Discontinuations of study drug due to adverse events 
• Changes in hematology, chemistry, and other laboratory parameters 
• Changes in vital sign parameters 
• Changes in ECGs parameters 
5.2. Methodology 
Continuous data will be summarized with the following descriptive statistics: number of 
observations (n), mean, standard deviation (SD), median, minimum (min), and maximum (max). 
Categorical data will be summarized with frequencies and percentages. 
 
Listings will be presented by subject and all data will be presented.  Tables will be presented by 
overall subjects and only data pertaining to the specific population being analyzed will be used. 
 
5.3. Handle Missing, Unscheduled and Repeated Measurements Data 
If AE start date is missing, then the first study treatment date will be assumed. If AEs with 
missing relationship, it will be considered study drug related. 
If other data have missing or invalid values, they are treated as missing and no imputation 
needed. 
In summary statistics, if there are repeated post-baseline measures in laboratory and vital signs 
safety data, the average value will be used to represent that time point measurements for 
continuous data, and the worst value for categorical data. 
Unscheduled safety measurements will be included in the summary statistics and also will be 
displayed in data listing. Baseline will include unscheduled measure in the baseline selection 
algorism. The unscheduled efficacy variables, such as tumor assessment will be treated as the 
same as planned measurement.  
Clinical visits from CRF will be used for by-visit analysis. If the visit date outside of protocol 
defined visit window, data inquiry will be performed to confirm the data.  


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5.4. Interim Analysis and Data monitoring 
An interim analysis will be performed for the Phase II study portion to determine if enrollment in 
the second stage will commence based on the criteria described in protocol Section 10.2.  
 
At end of stage 1, after 20 eligible subjects enrolled, and treated, if ≥2 subjects achieve a 
complete response (CR) or partial response (PR), then stage 2 will open to enroll 15 additional 
eligible subjects. 
 
A group of key efficacy and safety analysis TFLs will be provided in the interim analysis.  
 
6. STUDY POPULATION CHARACTERISTICS  
6.1. Subject Disposition 
The number of subjects enrolled in the study, inevaluable subjects, completing the therapy will 
be tabulated by study phase for overall, and will be listed by subject. Subject status will be 
summarized at the end of study.  End of treatment summary will indicate number of subjects 
who completed treatment and subject status for those who discontinued early.  The percentage 
for eligible subjects and inevaluable subjects are based on enrolled subjects.   
6.2. Protocol Deviation and Violation 
Protocol deviations and violation will be summarized using descriptive statistics by protocol 
deviation classification, visit, and module for overall subjects.  
The determination of protocol violations will be made prior to clinical database lock by 
PrECOG. QDS will incorporate this information to consist of Per-protocol population in 
database. 
If any protocol violation and eligibility inclusion or exclusion exceptions occur, they will be 
listed by subject with the same inclusion/exclusion number stated in the protocol. 
If there are any subjects who were registered but not eligible and not treated, they will be 
displayed in the data listing with the reasons.    
6.3. Demographics and Baseline Characteristics 
Demographic data (age, sex, ethnicity, race, height, weight, and study phase) will be listed and 
summarized overall using descriptive statistics (mean, standard deviation, median, minimum, 
and maximum for a numerical variable, and frequency counts / percentages for categorical 
variable).  In addition to demographics, the following baseline characteristics will be 
summarized using descriptive statistics and listed by subject: Cancer diagnosis and staging, prior 
therapy, medical surgical history, ECOG performance status, and baseline tumor assessment. 


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6.4. Dosing and Extent of Exposure 
Study drug will be administered on Day 1 of each 21 day cycle. Subjects will continue to be 
dosed once every 3 weeks. Treatment may be delayed for up to 3 weeks, if more than 3 weeks is 
required, PrECOG will determine whether subject continue to be treated. If treatment delayed, 
the subsequent treatments will maintain 3-week cycle interval. 
There are 3 dose levels in Phase I and only 1 dose level, MTD dose in Phase II.   
Dose adjustments are permitted but a maximum of 2 dose reductions are allowed. Dosing below 
1.0 mg/kg will not be allowed.  
Descriptive statistics of treatment cycle and dose exposure will be provided. Data listing for 
subject treatment exposure will be produced as well. 
6.5. Medical History and Cancer therapy  
Medical, surgical history and existing symptoms will be summarized by study phase. Data will 
be also displayed in listing format. 
6.6. Concomitant Medications 
Concomitant medications are that 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. All concomitant medications will be coded by current version of 
WHO Drug Dictionary. 
Concomitant medication will be summarized by ATC classification and WHO Drug Dictionary 
preferred term. A data listing will also be presented.  
7. MEASUREMENT OF EFFECT 
7.1. Efficacy  Analysis 
Efficacy analysis include objective response rate (ORR), duration of objective response (DOR), 
progression-free survival (PFS), and overall survival (OS). 
7.2. Primary Endpoint Assessment  
ORR, the primary endpoint, will be estimated for eligible, treated subjects enrolled in the Phase 
II study portion. The estimate of the ORR will be calculated based on the maximum likelihood 
estimator (i.e., crude proportion of subjects with best overall response of confirmed CR or PR 
based on RECIST). The estimate of the ORR will be accompanied by a 2-sided exact repeated 
90% CI.  
The subject’s overall response assignment will depend on the findings of both target and non-
target disease and will also take into consideration the appearance of new lesions. 
 


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The best overall response is the best response recorded from the start of the treatment until end 
of study. The order of response from best to worst is: Complete Response (CR), Partial Response 
(PR), Stable Disease (SD), Inevaluable (NE) and Progressive Disease (PD).  It includes 
scheduled and unscheduled tumor assessments. Only confirmed CR and PR are considered as 
response for ORR analysis.  
 
The details about tumor response criteria for target, non-target and new lesions are included in 
protocol Appendix 3. 
 
7.3. Secondary Endpoint Assessment  
DOR is defined as the time from the start date of CR or PR (whichever response status is observed 
first), to the first date that recurrent or progressive disease or death is objectively documented. 
PFS is defined as the time from the date of the first dose of study drug to the earliest of 
documented disease progression based on RECIST or death without prior progression. 
OS is defined as the time from the date of the first dose of study drug to the date of death 
(whatever the cause). 
DOR, PFS, and OS will be summarized descriptively using the Kaplan-Meier method with 90% 
CIs calculated using Greenwood’s formula. Median follow-up for each endpoint will be 
estimated according to the Kaplan-Meier estimate of potential follow-up. The PFS rate and OS 
rate at selected landmarks and corresponding 90% CIs will be estimated using the Kaplan-Meier 
method. Greenwood’s formula will be used to calculate the standard errors of the Kaplan-Meier 
estimate and upper and lower limits of the 90% CI. 
For DOR and PFS, subjects who meet one or more of the following conditions will be right-
censored as follows: 
• Subjects with no baseline or post-baseline disease assessments unless death occurred prior 
to the first planned assessment (in which case the death will be considered a PFS event). 
• Subjects who initiate subsequent anticancer therapy in the absence of documented 
progression. 
• Subjects who die or have disease progression after missing 2 or more consecutively 
scheduled disease assessment visits. 
• Subjects who are last known to be alive and progression-free on or before the data cut-off 
date 
For OS, subjects who are alive or lost to follow-up as of the data analysis cutoff date will be right-
censored. The censoring date will be determined from the subjects’ date of last contact or data 
analysis cutoff date, whichever event occurs first. 


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Waterfall plots will be used to depict graphically the maximum decrease from baseline in the sum 
of longest diameters of target lesions. Exploratory analysis will be performed for the correlation 
between gpNMB expression and clinical outcomes. 
8. SAFETY MEASUREMENTS 
Safety is to be evaluated by  
• Incidence of adverse events 
• Deaths on study 
• Discontinuations of study drug due to adverse events 
• Changes in hematology, chemistry, and other laboratory parameters  
• Changes in vital sign parameters 
• Changes in ECGs parameters 
 
Safety will be assessed by clinical review of all relevant parameters including adverse events, 
serious adverse events, laboratory values, vital signs, physical exam, ECOG performance status, 
and ECGs results. Unless specified otherwise, the safety analyses will be conducted for the safety 
population. The results of these analyses will be presented by study phase. For the escalation phase, 
tabulations will be provided by dose cohort and overall. Some safety analyses may be performed 
based on the dose escalation phase and Phase II study portion combined. 
 
8.1. Adverse Events 
Treatment emergent adverse events (TEAEs) is defined as:  
1) adverse events that start on or after the first administration of study drug;  
2) pre-existing signs/symptoms that worsen after the first administration of study drug;  
3) any AEs occurring within 28 days of last dose of study drug; and  
4) SAEs related to study drug regardless of when the SAE started.  
If the AE onset date is unknown, then the date of first administration of study drug will be used. 
The reported adverse event term will be assigned a standardized preferred term using the current 
version of the Medical Dictionary for Regulatory Activities (MedDRA). 
TEAEs will be summarized based on the number and percentage of subjects experiencing the event 
by MedDRA System Organ Class and Preferred Term. The causal relationship between the 
occurrence of an adverse event and study drug will be judged by the Investigator. In the event a 
subject experiences repeat episodes of the same adverse event, then the event with the highest 
severity grade and strongest causal relationship to study drug will be used for purposes of incidence 
tabulations. 


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Tabular summaries will be provided for: 
• all TEAEs 
• TEAEs by relationship (yes, no) to study drug and maximum severity grade 
• TEAEs with action of study drug delayed/interrupted or treatment reduced 
• TEAEs with action of study drug discontinued 
• serious adverse events 
All deaths that occur on study (defined as during treatment or within 28 days of treatment 
discontinuation) will be reported in a subject listing, which will include the primary cause of death 
and the number of days between the date of the last dose of study drug and death 
AE Severity: 
CTCAE grade: The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be utilized for AE reporting.  
AE relationship to study drug 
The causal relationship between the occurrence of an adverse event and study drug will be judged 
by the Investigator and recorded in CRF page in the options of “unrelated” and “related”. AEs with 
missing relationship will be considered study drug related. 
The following by subject data listings will be prepared:  subjects with serious adverse events, 
subjects with treatment-related adverse event, adverse events leading to discontinuation of study 
treatment and subjects with Grade 5 adverse events. 
8.2. Laboratory assessment 
Laboratory values will be assigned toxicity grades when available using the NCI-CTCAE scale. 
Directional shifts in laboratory toxicity grades (comparing baseline grade with worst post-
baseline grade) will be analyzed using standard shift tables, presenting number and proportion of 
subjects and their maximum grade shift. For analytes without a toxicity grading scale, the shift 
table will present directional shifts from baseline to above or below the laboratory standard 
normal range using the maximum increase and/or decrease observed throughout the course of 
treatment/observation.  
8.3. Vital Sign 
All subjects will have pretreatment baseline vital signs and pre-dose measurements on Day 1 of 
each cycle. The results for each vital sign will be summarized in a descriptive manner by 
calculating the mean, standard deviation, median, and range by time point in the same manner 
described for laboratory values. The change from baseline at each treatment cycle will be also 
summarized.  
Baseline of vital sign is defined as the last measurement during screening period. If screening 
measurement is missing, the pre-dose measurement on Day 1 will be used for baseline.  
In addition, serial measurements will be obtained during and after each infusion of study drug. 
For each subject, the vital signs change from the pre-dose value will be summarized in a 


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descriptive manner. The Wilcoxon signed rank test may be used to assist in the identification of 
any systematic changes. 
8.4. Other safety data 
Physical examination, ECG and ECOG performance status are also performed during the study 
to measure the safety and tolerability of study drug.  
The summary statistics and change from baseline will be performed by each scheduled visit for 
these parameters. 
If any screening (baseline) safety data are repeated, the measurement taken closest to dosing will 
be used in the analysis. Baseline will be defined as the last non-missing result, including results 
from repeated and unscheduled measurements, before dosing. If there are repeated measurements 
at a time point after dosing, the average value at that time point will be used in the summary 
tables for continuous data, and worst value for categorical data. 
9. EXPLORATORY ENDPOINTS ASSESSMENT  
9.1. Efficacy variables and degree of gpNMB expression 
To investigate if the anti-cancer activity of glembatumumab vedotin in advanced gpNMB-
expressing SCC of the lung is dependent upon the degree of gpNMB expression in tumor tissue. 
9.2. Pharmacokinetics (PK) Analysis 
To further characterize the pharmacokinetics and immunogenicity of glembatumumab vedotin in 
this subject population.  
Concentration of the antibody-drug conjugate (ADC), total antibody (TA) and free MMAE will 
be determined using GLP compliant enzyme-linked immunosorbent assay (ELISA) and liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) methods. 
Descriptive statistics for the concentration of PK variables by study drug dose level will be 
provided. Concentration data listing will be displayed by subject and time points.  
9.3. Pharmacodynamics (PD) Analysis 
To examine pharmacodynamic effects of treatment, including tumor immune cell infiltrate type 
and number; localization of glembatumumab vedotin, CR011 or Monoethylauristatin E (MMAE) 
at the tumor site; soluble mediators and/or gpNMB expression levels in tumor tissue; and 
analysis of peripheral blood cell subsets. 
Serum and peripheral blood mononuclear cells (PBMC) samples will be obtained. Analysis may 
include examination of gpNMB expression levels on myeloid suppressor cells, as well as 
evaluation of peripheral leukocytes, circulating tumor cells and other immune response cells of 
interest. Soluble gpNMB levels in circulation may also be examined. 


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Descriptive statistics for gpNMB expression level, leukocytes, and circulating tumor cell by 
study drug level may be performed. Data listing will be provided. 
 
10. REPORTING CONVENTIONS 
The mean and median will be displayed to one decimal place greater than the original value, and 
the standard deviation will be displayed to two decimal places greater than the original value. All 
statistical programming and analyses will be performed using SAS® Release 9.4 (SAS Institute 
Inc., Cary, North Carolina, USA). 
The following standards will be used in the data presentation: 
• Section 14 tables and Section 16 Listings should be in landscape format with Courier New 9 
pt. font. Output should adhere to margins of: top - 1.0 in, bottom - 1.0 in, right - 1.0 in, and left 
- 1.0 in). For item 14 tables, a blank row will separate the header from the content of the table 
listing. For tables that have “n (%)”, the placement should be centered below “N=xx” in the 
column header. Frequency tables will be center justified. Descriptive statistics will be decimal 
aligned.  
• Percentages presented in in-text tables should be rounded to one decimal using the SAS 
rounding function. If “%” is part of the column heading, do not repeat the “%” sign in the body 
of the table. Unless specified otherwise, “%” should reflect the total population of the treatment 
groups. Any deviation from that should be part of the footnote. For 0 counts, the corresponding 
percentage should be indicated as 0. 
• SD should be the default for representing scale, unless standard error has been specified. 
Standard deviation should be abbreviated as “SD”, and presented below the mean value. The 
SD should have one additional decimal place beyond that of the mean (e.g., mean has one 
decimal place, SD should have two). 
• If the table or listing is too long to display on one page, the additional (treatment) columns will 
be continued on the following pages. 
• “N” will represent the entire population group being analyzed, while “n” will represent a subset 
of “N”. For tables with population designated as a row heading, “N” should be used (i.e., tables 
where all participant data is not available for every variable within a treatment group). As a 
guideline, if the number is used in a denominator, it should be presented as “N”. If the number 
is used in the numerator, it should be presented as an “n”. 
• The heading should consist of four lines. Line 1: Sponsor identifier. Line 2: Protocol identifier. 
Line 3: blank line. Line 4: Table/Appendix number Table Title – Population. The title for in-
text tables should begin with the Table/Appendix number. 
• All data listings will be sorted by Subject Number and parameter or time point (as applicable). 
• The date format for all dates is DDMMMYYYY.  


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• If no data are collected for use in the tables and listings, then a table and/or listing will be 
created stating that no data are available. 
• A solid line should appear both above and below the column headings of a table. A solid line 
should appear at the end of the table or at the bottom of each page if the table extends to 
more than one page. Footnotes should start after the bottom solid line. 
• The footnotes should contain three lines at the bottom end.  a) Program Source b) Output 
Path and c) Source Data. 


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Visit 
Screening
2 
 
Treatment Visits3 
Disease 
Assessment 
Visit6 
Survival 
Assessment7 
Cycle 1/ 
Day 1 
Cycle 1/ 
Day 84 
Cycle 1/ 
Day 
154 
Cycle 2/ 
Day 1 
Cycle 3 
onward/Day 1 
End of 
Treatment5 
Visit Window 
Day -28 to 
Day -1 
 
+/-1 
days 
+/-1 
days 
+/-3 
days 
+/-3 days 
Within 28 
days post-
dosing 
Every 6 (±1) weeks 
for 6 months then 
every 9 (±2) weeks 
thereafter 
Every 12 (±2) 
weeks until study 
closure 
Informed Consent/HIPAA 
X 
 
 
 
 
 
 
 
 
Tumor Tissue8 
X9 
 
 
 
 
 
X10 
 
 
Medical/Surgical History11 
X 
X 
 
 
 
 
 
 
 
Physical Examination12 
X 
X13 
X 
X 
X 
X 
X 
 
 
Vital Signs14 
X 
X13 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status 
X 
X13 
 
 
X 
X 
X 
 
 
Electrocardiogram (ECG) 
X 
 
 
 
 
 
X 
 
 
Pregnancy Test15 
X 
X13 
 
 
 
 
 
 
 
Hematology16 
X 
X13 
X 
X 
X 
X 
X 
 
 
Blood Chemistry16 
X 
X13 
X 
X 
X 
X 
X 
 
 
Urinalysis16 
X 
X13 
 
 
X 
X 
X 
 
 
Immunogenicity17,18 
 
X 
 
 
 
X17 
X17 
 
 
PBMC Collection18,19 
 
X 
 
 
X 
 
X 
 
 
Routine PK Sample 
Collection18,20 
 
X20 
X 
X 
X20 
X20 
X 
 
 
Disease Assessment21 
X 
 
 
 
 
 
 
X 
 
Administration of Study 
Treatment22 
 
X 
 
 
X 
X 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
X 
Concomitant Medication 
Review23 
X 
X 
X 
X 
X 
X 
X 
 
 


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11. APPENDIX: SCHEDULE OF ASSESSMENTS1
Adverse Event Monitoring24 
 
X 
X 
X 
X 
X 
X 
 
X25 


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Table  - Footnotes: 
1. 
A delay in study treatment or performance of study assessments due to holidays, weekends, inclement weather or other unforeseen circumstances will be 
permitted and not considered a protocol violation. However, such cases should be discussed with PrECOG to reach consensus on subsequent scheduling. 
2. 
Phase I: Prior to discussing protocol entry with the patient, call the assigned PrECOG Project Manager to ensure that a place on the protocol is open 
to the patient (Section 5.2.4). No study 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 glembatumumab vedotin (on a three-week cycle) until intolerance, progression of disease, or any of the other criteria for discontinuation of 
study treatment (Section 5.2.6) are met. 
4. 
The Cycle 1/Day 8 and Cycle 1/Day 15 visit is only required for patients treated in the Phase I, dose-escalation phase. 
5. 
The End of Treatment Visit should be performed within 28 days after last dose of study treatment and prior to initiation of alternate therapies. 
6. 
Disease assessments will be performed every 6 weeks (±1 week) for 6 months and every 9 weeks (±2 week) thereafter, until documented progression of disease 
or initiation of alternate anticancer therapies. If a partial or complete response is noted, a follow-up radiographic 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 will have glembatumumab vedotin temporarily withheld during treatment and for at least 21 days after completion of surgical resection or radiation 
treatment or until patient has recovered from any adverse events resulting from the surgical or radiation intervention before restarting treatment with 
glembatumumab vedotin. Patients may continue to receive study treatment until remaining lesions meet criteria for progression of disease. 
7. 
Subsequent to the End of Treatment Visit, all patients with disease progression 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. For patients who continue to be seen for disease assessments, the survival contact may occur at these visits (i.e., at a 6 or 9 week interval, as 
applicable). Otherwise, these visits may be performed by telephone. 
8. 
Assessment of gpNMB expression (by IHC) at a central laboratory (approximately 5 working day turnaround); additional analyses to be performed may also 
include 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, and localization of glembatumumab vedotin, CR011 or MMAE at the tumor site in post-treatment samples 
(Section 11.1). Sample collection, processing and shipping instructions will be provided. 
9. 
Tumor specimen(s) used to determine gpNMB status and eligibility may be obtained at any point in the course of disease; preferred tumor specimens are those 
obtained in the setting of advanced (recurrent, locally advanced or metastatic) disease and subsequent to the last anti-cancer regimen received.. Formalin-fixed 
paraffin-embedded (FFPE) diagnostic tumor tissue block(s) or 10-20 FFPE slides plus H&E slide from a tumor tissue block will be required (Section 11.1). 
NOTE: Additional samples from previous collection dates should also be submitted when feasible. Submitted cytology samples such as pleural effusions, 
bronchial washings or fine needle aspirates (FNA) will be used to evaluate feasibility of gpNMB expression analysis and to investigate correlations with other 
samples for the patient, but they will not be used for determination of study eligibility. Samples may be submitted and tested at any time prior to or during the 
28-day window for screening, provided that the patient has signed an appropriate consent (either a tumor tissue-specific consent or full study consent). Samples 
may be submitted for patients who are not yet fully eligible for the study at the investigators discretion. 
10. In the event of tumor resection, biopsy, or cytological sample collection anytime during treatment or following tumor progression, submission of these tissue 
samples for central analysis is strongly encouraged. 
11. Medical/Surgical history includes demography, race, ethnicity, cancer history, previous therapy, and pre-existing diseases. At Cycle 1, Day 1, history is updated 
with any adverse events occurring prior to administration of study drug. 
12. Complete physical exam should be performed at screening; thereafter, symptom-directed exams are acceptable. 


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13. Assessments do not need to be repeated if completed within the previous 72 hours as part of the screening assessment. NOTE: Microscopic examination of 
urinalysis is required during screening. If urinary infection is suspected, a negative urine culture is required prior to enrollment. 
14. Vital signs to include height (at screening only), weight, respiration, pulse, temperature, and resting systolic and diastolic blood pressure. On glembatumumab 
vedotin dosing days, vital signs should be assessed pre-infusion, at 45 (±15) minutes during the infusion, and within one-half hour following completion of the 
infusion. (Note: Weight is only assessed once per visit.) 
15. Serum or urine pregnancy test only for women of childbearing potential. Patients of non-childbearing potential include those who are surgically sterilized or post-
menopausal 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 follicle-stimulating hormone (FSH) and/or estradiol) are available to ensure postmenopausal status. 
16. 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 
RBC (Red Blood Count) 
Glucose (nonfasting)  
Specific gravity 
WBC (White Blood Count) 
Blood urea nitrogen (BUN) 
Blood 
Platelets 
Creatinine 
 
Differential:  
Calcium 
 
Neutrophils  
Phosphate 
 
Lymphocytes 
Alkaline phosphatase 
Microscopic 
examination 
must 
be 
performed at baseline and, if clinically 
indicated, at subsequent visits. 
Monocytes 
Alanine transaminase (ALT/SGPT) 
Eosinophils 
Aspartate transaminase (AST/SGOT) 
Basophils 
Total protein 
Differential should be reported consistently 
throughout the study as either an absolute 
count (preferred) or as a percentage. 
Albumin 
Lactate Dehydrogenase (LDH) 
Total Bilirubin 
 
 
17. 6 mL blood sample (red top tube) for serum for immunogenicity will be collected prior to dosing on Day 1 of “odd” cycles (i.e., Cycles 3, 5, 7, etc.) and End of 
Treatment. Analysis may also include circulating soluble gpNMB levels or other soluble molecules (Section 11.2). 
18. Analyses will be performed centrally. Sample collection, processing and shipping instructions will be provided. 
19. 6 mL blood sample (red top tube) for serum and 20 mL blood sample (green top tubes) for peripheral blood mononuclear cell (PBMC) will be collected on Day 
1 of Cycle 1 and 2, prior to dosing and at End of Treatment. 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 (Section 
11.2). Details on sample collection and handling will be provided. 
20. 6 mL blood sample (red top tube) for Pharmacokinetic (PK) samples will be collected (Details on sample collection and handling will be provided.): 
• 
Phase I: Day 1 of Cycles 1 and 2, prior to dosing and at end of infusion (at or within 10 minutes after completion of infusion) and 4-5 hours after the end of 
infusion. A PK sample will also be collected at Cycle 1, Days 8 and 15. Additional PK samples will be collected on Day 1 of Cycles 3 and 5 prior to dosing 
and at end of infusion (at or within 10 minutes after completion of infusion) and at End of Treatment visit. 
• 
Phase II: Day 1 of Cycle 1, 2, and 5, prior to dosing and at end of infusion (at or within 10 minutes after completion of infusion) and at End of Treatment 
visit. 
21. 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 


PrECOG, LLC 
Protocol: PrE0504 / Phase I/II  
Statistical Analysis Plan  
 
 Version: Final 1.0 / 28Oct2016 
26 
 
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. 
22. Unless otherwise specified, all study assessments should be performed prior to administration of study treatment, and may be performed up to 72 hours prior 
to treatment administration if assessments remain within the specified visit window. 
23. All concomitant medication will be reviewed 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 concomitant medications taken to treat glembatumumab vedotin-related serious 
adverse events (SAEs) should be recorded in the electronic Case Report Form (eCRF) throughout the duration of the study/follow-up. 
24. For patients who develop grade 3 treatment-related rash and who provide appropriate consent, optional punch biopsies of the rash site and optional photographs 
of the rash site, as well as uninvolved skin, are strongly encouraged. Samples may be submitted for central analyses including quantification of gpNMB 
expression; in these cases, collection, processing and shipping instructions will be provided. 
25. Events occurring >28 days after discontinuation of study treatment are only reportable if both serious (SAE) and potentially treatment-related.