Conditions: Recurrent Uveal Melanoma Stage IV Uveal Melanoma AJCC v7
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 37
Healthy volunteers: no

Brief summary:
This phase II trial studies how well glembatumumab vedotin works in treating patients with middle layer of the wall of the eye (uveal) melanoma that has spread to other parts of the body (metastatic) or has returned at or near the same place after a period of time during which the cancer could not be detected (locally recurrent). Glembatumumab vedotin may shrink the tumor by binding to tumor cells and delivering tumor-killing substances to them.

Detailed description:
PRIMARY OBJECTIVES:

I. To characterize the clinical anti-tumor activity of CDX-011 (glembatumumab vedotin) as a single-agent in the treatment of patients with metastatic uveal melanoma.

SECONDARY OBJECTIVES:

I. Description of the clinical safety and benefit of CDX-011 (glembatumumab vedotin) and pharmacodynamics changes in glycoprotein NMB (glycoprotein \[transmembrane\] NMB) (GPNMB) expression.

TERTIARY OBJECTIVES:

I. Characterization of the anti-tumor immunophenotype of patients receiving treatment.

II. Post hoc, correlation of rash with clinical benefit, or lack of rash with lack of benefit, will also be explored.

OUTLINE:

Patients receive glembatumumab vedotin intravenously (IV) over 90 minutes every 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Arms:
arm 1: Patients receive glembatumumab vedotin IV over 90 minutes every 3 weeks in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Glembatumumab Vedotin intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Correlative studies

Protocol document:
Prot_SAP_001.pdf: 
NCI Protocol #:9855 
Version Date: April 2, 2018 
i 
 
 
 
 
SUMMARY OF CHANGES – PROTOCOL 
 
For Protocol Amendment # to: A Phase 2 Study of CDX-011 (glembatumumab vedotin) for 
Metastatic Uveal Melanoma 
 
NCI Protocol #: 9855 
Local Protocol #: NCI9855 
 
NCI Version Date: April 2, 2018 
Protocol Date: April 2, 2018 
 
 
 
 
# 
Section 
Change 
1. 
TITLE 
PAGE 
Updated protocol and number date 
2. 
 3.1.4 (p. 
12) 
Updated CTCAE v4 to v5 
All prior treatment-related toxicities must be CTCAE v5 grade ≤ 1 (except 
alopecia). Certain exceptions apply, such as immunotherapy-induced 
hypothyroidism or adrenal insufficiency or panhypopituarism requiring stable 
doses of hormone replacement or rash from prior therapy. 
3. 
5.1(p.20) 
Updated CTCAE v4 to v5 
Patients with Grade 3 or 4 infusion related reactions as defined by 
CTCAE v.5.0 may be re-challenged with treatment on a case-by-case 
basis after discussion with Lead PI, CTEP drug monitor, and any others 
deemed necessary.  These cases will be tracked and monitored carefully. 
4 
6 (p.23) 
Updated CTCAE v4 to v5 
Patients with Grade 3 or 4 infusion related reactions as defined by CTCAE 
v.5.0 may be re-challenged with treatment on a case-by-case basis after 
discussion with Lead PI, CTEP drug monitor, and any others deemed necessary. 
These cases will be tracked and monitored carefully. 


NCI Protocol #:9855 
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ii 
 
 
 
# 
Section 
Change 
5 
7.2 (p.27) 
Updated CTCAE  version 4.0 to version 5.0 
CTCAE term (AE description) and grade: The descriptions and 
grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy 
of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc. 
htm. 
6 
7.3 (p.28) 
Updated the language to reflect NCI request sent on 1/25/2018 regarding the 
new term for Progressive Disease. 
Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned 
during trial registration on all reports. 
Note: A death on study requires both routine and expedited reporting, 
regardless of causality. Attribution to treatment or other cause must be 
provided. 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions.” Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted. 
Rationale: Under 7.3 Expedited Reporting Guidelines, the language needs to 
change to reflect the amendment request from NCI’s letter (attached) on 
1/25/2018 regarding new term for Progressive Disease. 


NCI Protocol #:9855 
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1 
 
 
 
 
 
TITLE PAGE 
 
NCI Protocol #: 
9855 
Local Protocol #: 
NCI9855 
ClinicalTrials.gov Identifier: NCT02363283 
 
TITLE: A Phase 2 Study of CDX-011 (glembatumumab vedotin) for Metastatic Uveal 
Melanoma 
 
 
Corresponding Organization: 
LAO-TX035 / University of Texas MD Anderson Cancer 
Center LAO 
 
*Principal Investigator: 
Sapna P. Patel, MD* 
MD Anderson Cancer Center 
Melanoma Medical Oncology 
Houston, TX 77030 
Phone: 713-792-2921 
Fax: 713-745-1046 
E-mail: sppatel@mdanderson.org 
 
Participating Organizations 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Opportunity Program 


NCI Protocol #:9855 
Version Date: April 2, 2018 
2 
 
 
 
 
 
Statistician: 
Roland Bassett 
MD Anderson Cancer Center 
1515 Holcombe Blvd  Houston, TX 77030 
Tel: 713-563-4272 
rlbasset@mdanderson.org 
Responsible Research Nurse: 
Karen Perdon 
MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit 0430 
Houston, TX 77030 
Tel: 713-794-4117 
Fax: 713-745-1046 
kbperdon@mdanderson.org 
 
Study Coordinator: 
Manolo Pasia Jr. 
Clinical Research Support Center 
MD Anderson Cancer Center 
1515 Holcombe BlvdUnit 1635 
Houston, TX 77030 
Tel: 713-563-7247 
Fax: 713-563-5468 
ClinicalResearchSupport@mdanderson.org 
Responsible Data Manager: 
Edwina Washington 
MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit 0430 
Houston, TX 77030 
Tel: 713-792-2921 
Fax: 713-745-1046 
ewwashin@mdanderson.org 
 
 
NCI Supplied Agents: 
CDX-011 (glembatumumab vedotin) (NSC 763737) 
IND #: 126619 
IND Sponsor:  DCTD, NCI 
 
Protocol Type / Version # / Version Date: Original / Version Date:   January 7, 2015 
Revision #1/Version Date: March 25, 2015 
Revision #2/Version Date: April 21, 2015 
Revision #3/Version Date: June 29, 2015 
Revision #4/Version Date: July 27, 2015 
Amendment #1/Version Date: February 29, 2016 
Amendment #2/Version Date: August 2, 2016 
Amendment #3/Version Date: September 2, 2016 
Amendment #4/Version Date: March 23, 2017 
Amendment # 5 / Version Date: April 2, 2018 


NCI Protocol #:9855 
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3 
 
 
 
 
SCHEMA 
 
This trial is a single-arm, open-label Phase II study of CDX-011 (glembatumumab vedotin) in 
patients with metastatic uveal melanoma. The primary endpoint is overall response rate (ORR) 
using RECIST 1.1. Secondary endpoints include GPNMB expression, progression-free survival 
(PFS), overall survival (OS), as well as toxicity analysis. Exploratory endpoints include 
characterizing the anti-tumor immunophenotype of patients receiving CDX-011 
(glembatumumab vedotin) as well as post-hoc correlation of rash with PFS and ORR. 
 
All treatment will be performed in the outpatient setting. Up to 34 patients will be treated with 
CDX-011 (glembatumumab vedotin). 
 
The study schema is as follows: 
 
 
 


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TABLE OF CONTENTS 
SUMMARY OF CHANGES – Protocol ......................................................................................... i 
TITLE PAGE .................................................................................................................................. 1 
SCHEMA ........................................................................................................................................ 3 
TABLE OF CONTENTS ................................................................................................................ 4 
1. 
OBJECTIVES ..................................................................................................................... 6 
1.1 
Primary Objectives .................................................................................................. 6 
1.2 
Secondary Objectives .............................................................................................. 6 
1.3 
Exploratory Objectives ........................................................................................... 6 
2. 
BACKGROUND ................................................................................................................ 6 
2.1. 
Eye Neoplasm, Uveal Melanoma ........................................................................... 6 
2.2. 
CTEP IND Agent – CDX-011 (glembatumumab vedotin) ..................................... 7 
2.3. 
Rationale for Proposed Study ............................................................................... 10 
2.4. 
Exploratory/Correlative Studies Background ....................................................... 10 
3. 
PATIENT SELECTION ................................................................................................... 11 
3.1. 
Eligibility Criteria ................................................................................................. 11 
3.2. 
Exclusion Criteria ................................................................................................. 13 
3.3. 
Inclusion of Women and Minorities ..................................................................... 14 
4. 
REGISTRATION PROCEDURES .................................................................................. 15 
4.1. 
Investigator and Research Associate Registration with CTEP ............................. 15 
4.2. 
Site Registration .................................................................................................... 16 
4.3. 
Patient Registration Procedures ............................................................................ 17 
5. 
TREATMENT PLAN ....................................................................................................... 19 
5.1. 
CDX-011 (glembatumumab vedotin) Administration .......................................... 19 
5.2. 
General Concomitant Medication and Supportive Care Guidelines ..................... 20 
5.3. 
Duration of Therapy .............................................................................................. 20 
5.4. 
Duration of Follow Up .......................................................................................... 21 
5.5. 
Criteria for Removal from Study .......................................................................... 21 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 21 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................ 23 
7.1. 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) for 
CDX-011 (glembatumumab vedotin) (CDX-011, NSC 763737) ......................... 23 
7.2. 
Adverse Event Characteristics .............................................................................. 27 
7.3. 
Expedited Adverse Event Reporting ..................................................................... 28 


NCI Protocol #:9855 
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7.4. 
Routine Adverse Event Reporting ........................................................................ 30 
7.5. 
Secondary Malignancy .......................................................................................... 31 
7.6. 
Second Malignancy ............................................................................................... 31 
8. 
PHARMACEUTICAL INFORMATION ......................................................................... 31 
8.1. 
CDX-011 (glembatumumab vedotin), NSC 763737) ........................................... 31 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 34 
9.1. 
Integral Laboratory or Imaging Studies ................................................................ 34 
9.2. 
Investigational Device Information ...................................................................... 34 
9.3. 
Integrated Correlative Studies – GPNMB expression .......................................... 34 
9.4. 
Exploratory/Ancillary Correlative Studies ............................................................ 35 
10. 
STUDY CALENDAR ....................................................................................................... 41 
11. 
MEASUREMENT OF EFFECT ....................................................................................... 42 
11.1. Antitumor Effect – Solid Tumors ......................................................................... 42 
11.2. Other Response Parameters .................................................................................. 48 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS .......................................... 48 
12.1. Data Reporting ...................................................................................................... 48 
12.2. CTEP Multicenter Guidelines ............................................................................... 50 
12.3. Collaborative Agreements Language .................................................................... 50 
13. 
STATISTICAL CONSIDERATIONS .............................................................................. 52 
13.1. Study Design/Endpoints ........................................................................................ 52 
13.2. Sample Size and Power /Accrual Rate .................................................................. 52 
13.3. Stratification Factors ............................................................................................. 54 
13.4. Analysis of Secondary Endpoints ......................................................................... 54 
13.5. Reporting and Exclusions ..................................................................................... 55 
REFERENCES .............................................................................................................................. 56 
APPENDIX A 
PERFORMANCE STATUS CRITERIA .................................................. 58 
APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS .................. 59 
APPENDIX C ADULT HYPERSENSITIVITY/ALLERGIC REACTION 
MANAGEMENT ALGORITHM 
62 
APPENDIX D INSTRUCTION MANUAL AND SPECIMEN SUBMISSION FORM .......... 65 


NCI Protocol #:9855 
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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
The primary objective of this study is to characterize the clinical anti-tumor activity of CDX-011 
(glembatumumab vedotin) as a single-agent in the treatment of patients with metastatic uveal 
melanoma.  The primary endpoint will be overall response rate (ORR) using RECIST 1.1. 
 
1.2 
Secondary Objectives 
 
Secondary objectives include a description of the clinical safety and benefit of CDX-011 
(glembatumumab vedotin) and pharmacodynamics changes in glycoprotein NMB (GPNMB) 
expression. Secondary endpoints will include progression-free survival (PFS), overall survival 
(OS), GPNMB expression via immunohistochemistry (IHC). 
 
1.3 
Exploratory Objectives 
 
Exploratory objectives for this study include characterization of the anti-tumor 
immunophenotype of patients receiving treatment. Post hoc, correlation of rash with clinical 
benefit, or lack of rash with lack of benefit, will also be explored. 
 
2. BACKGROUND 
 
2.1. Eye Neoplasm, Uveal Melanoma 
 
Uveal melanoma accounts for 5% of all melanoma diagnoses, representing approximately 2,000 
patients per year in the U.S.1 The uveal tract of the eye is not drained by lymphatics and 50% of 
uveal melanoma patients will develop metastasis via hematogenous spread, the overwhelming 
majority of which (90%) occur in the liver.2-5   Once metastatic, average survival is 6 months. 
Outside of prostate cancer metastasizing to bone, there is no other solid tumor which 
demonstrates such a predictable homing for its metastatic site. 
 
To date there is no standard of care approved treatment option for patients with metastatic uveal 
melanoma and expert consensus guidelines recommend treatment on a clinical trial. Surgical 
resection of liver metastasis plays a role in less than 10% of patients, in part due to the need for 
liver-only disease and less than 50% liver involvement, and the advanced age of metastatic uveal 
melanoma patients (50-60 years old).6 
 
A few approaches to systemic therapy have been studied or are newly underway. Chemotherapy 
alone has generated response rates of less than 1% for metastatic uveal melanoma.7-8 
Biochemotherapy consisting of bleomycin, vincristine, lomustine, dacarbazine, and interferon- 
alpha (BOLD-IFN) resulted in a response rate of 20% but its use is marred by significant 
hematologic and unpredictable pulmonary toxicity.9 
 
Targeted therapy with IMC-A12 (Cixutuxumab), an IGF-1R blocking antibody, has been studied 


NCI Protocol #:9855 
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in a Phase II trial in metastatic uveal melanoma (CTEP 8832) with zero responses seen in 18 
patients enrolled (unpublished data). AZD-6244 (Selumetinib), a selective MEK inhibitor, was 
studied in a randomized Phase II trial versus temozolomide in patients with metastatic uveal 
melanoma. Selumetinib demonstrated a final overall response rate of 10% versus 0% in the 
temozolomide arm.10 No significant difference in overall survival was noted. Imatinib and 
sunitinib trials targeting CKIT overexpression in uveal melanoma have likewise been 
unsuccessful with response rates of 0% and 5% in published clinical trials.11, 12 
 
There are several other studies in progress using various agents such as targeted therapy, 
epigenetic therapy, and immunotherapy. Trametinib, a selective MEK inhibitor, with or without 
GSK2141795 (Akt inhibitor) is being studied in a randomized Phase II trial (NCI 9445, 
NCT01979523). Currently more than 1/3 of the study population has been enrolled (N=80) with 
no interim results reported. AEB071 (PKC inhibitor, Sotrastaurin) is being studied as both 
monotherapy in a Phase I study for metastatic uveal melanoma (NCT01430416) as well as in 
combination with a MEK inhibitor, MEK162 (Binimetinib) in a separate Phase I/II study 
(NCT01801358) for this patient population.  Ipilimumab is being studied in a dedicated Phase 
I/II study solely for uveal melanoma patients at two dose levels: 3 mg/kg and 10 mg/kg 
(NCT01585194).  To date, results have not been reported.  Vorinostat as an epigenetic modifier 
is under investigation in a Phase II study to assess efficacy for metastatic uveal melanoma 
(NCT01587352).  No results have been reported for vorinostat. 
 
2.2. CTEP IND Agent – CDX-011 (glembatumumab vedotin) 
 
Glycoprotein NMB (GPNMB) is a transmembrane protein whose overexpression promotes 
invasion and metastasis of cancer cells from multiple tissue types and is expressed at high levels 
in several malignant human tissues, including uveal melanoma, relative to corresponding normal 
tissue.13,14 Preliminary data consisting of immunohistochemistry (IHC) of 21 uveal melanoma 
specimens demonstrated staining in 86% of samples tested.15   The percentage of cells positive 
per tumor ranged from 10-90% and the level of GPNMB was of variable intensity (5 tumors 1+; 
11 tumors 2+; and 2 tumors 3+). 
 
Antibody-drug conjugates offer a novel approach to treating cancer and allow for the selective 
delivery of cytotoxic agents to a tumor with the goal of reducing toxicity and enhancing efficacy 
compared with the systemic administration of cytotoxic agents or unconjugated antibodies. 
CDX-011 (glembatumumab vedotin) is a fully-human IgG2 monoclonal antibody (CR011) 
directed against GPNMB coupled via a protease-sensitive valine-citrulline peptide linker to 
monomethylauristatin E (MMAE), a potent cytotoxic microtubule inhibitor.16 This technology is 
licensed from Seattle Genetics and is identical to that used in SGN35, a promising antibody-drug 
conjugate for lymphoma.  The proposed mechanism of action is that, upon binding to GPNMB 
on tumors, the complex is internalized and MMAE is released via proteolytic cleavage of the 
valine-citrulline linker inside a lysosome. Tumor cell death occurs as a result of microtubule 
inhibition by MMAE leading to cell-cycle arrest. Bystander tumor cells may be also be killed by 
uptake of free MMAE released by dying cells. CDX-011 (glembatumumab vedotin) induced 
complete regression of GPNMB-expressing tumors derived from SK-Mel-2 and SK-Mel-5 
melanoma cell lines in xenograft mouse studies.13,14,17 


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Pharmacology 
 
CDX-011 (glembatumumab vedotin) binds to and inhibits growth of GPNMB-positive tumor  
cell lines including the melanoma lines SK-Mel-2 and SK-Mel-5 (IC50 216-300 ng/mL).13 It has 
no effect on GPNMB-negative cell lines. CDX-011 (glembatumumab vedotin) also induces cell- 
cycle arrest followed by apoptotic cell death in GPNMB-expressing melanoma cells. In SK- 
Mel-2 and SK-Mel-5 melanoma xenograft mouse models, CDX-011 (glembatumumab vedotin) 
administered intravenously (IV) once daily every 4 days x 4 led to durable tumor regression in a 
dose-dependent manner.17 
 
Pharmacokinetics 
 
The pharmacokinetics (PK) of total CR011 antibody (conjugated and free) have been assessed in 
rodents and primates. The data demonstrate dose-proportional exposure and elimination half-life 
of 11-22 hours in cynomolgus monkeys, increasing with dose. Concentration vs. time plots 
appeared non-linear with dose, suggestive of saturable elimination pathways. Overall, there was 
no significant antibody accumulation after 4 weekly doses, and levels of free MMAE were low 
compared to levels of total antibody, supporting the premise that the CR011-MMAE bond was 
stable in extracellular matrix. 
 
PK data for serum concentrations of CDX-011 (glembatumumab vedotin) were collected for 55 
melanoma patients. First-order kinetics were observed following a 90-minute IV infusion. The 
half-life (t ½) was approximately 27 hours at 1.88 mg/kg. 
 
Mechanism of Action 
 
The proposed mechanism of action of CDX-011 (glembatumumab vedotin) is via binding of the 
antibody-drug conjugate to GPNMB on tumor cells. The antibody-GPNMB complex is then 
internalized and cytotoxic MMAE is released via cleavage of the valine-citrulline peptide linker 
inside a lysosome.  MMAE leads to microtubule inhibition causing cell cycle arrest. 
 
Route of Elimination 
 
CDX-011 (glembatumumab vedotin) is cleared by the liver and excreted via the kidneys. 
Toxicology 
In cynomolgus monkeys, the no observable adverse effect level (NOAEL) for CDX-011 
(glembatumumab vedotin) administered once weekly for 4 weeks was 0.3 mg/kg in males and 1 
mg/kg in females. The major toxicity was in the hematopoietic system. All findings, including 
microscopic effect were completely reversible. Neutropenia was considered a dose-limiting 
toxicity and was reversible following a 6-week recovery period. The maximum-tolerated dose 
(MTD) in both sexes was considered to be between 1 mg/kg and 3 mg/kg. 


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In repeat-dose rat studies, dose-dependent findings were observed for CDX-011 
(glembatumumab vedotin) treated groups with similar hematopoietic findings in rats treated with 
the highest dose of CDX-011 (glembatumumab vedotin) as in rats treated with MMAE alone. 
All findings were reversible except for dose-dependent germ cell depletion in the testes of male 
animals.  No findings were attributed to CR011 antibody alone or vehicle control. 
 
Clinical activity of CDX-011 (glembatumumab vedotin) 
 
To date, CDX-011 (glembatumumab vedotin) has been administered to more than 255 cancer 
patients in three completed clinical trials.  CDX-011 (glembatumumab vedotin) has 
demonstrated clinical activity with an acceptable safety profile in a Phase I/II dose escalation and 
expansion study in advanced melanoma (n=117).18 A dose level of 1.88 mg/kg administered 
intravenously every 3 weeks was determined to be the maximum tolerated dose (MTD). At the 
MTD, the most common treatment-related toxicities included dermatologic events (rash, pruritus, 
alopecia),  fatigue,  neutropenia,  neuropathy,  and  gastrointestinal  toxicities    (diarrhea,           
nausea, dysgeusia, constipation, and vomiting). In this study, the ORR was 13% in 40 patients at 
the 1.88 mg/kg dose level, including one response that was not confirmed. The disease control 
rate (DCR = PR + SD ≥ 12 months) was 81%.  PFS at the MTD was 3.3 months. 
 
In the melanoma study, treatment-related adverse events that occurred in >20% of patients at the 
MTD, also known as the Phase II dose, were fatigue, rash, nausea, neuropathy, alopecia, pruritus, 
constipation, diarrhea, anorexia, and dysgeusia. Grade 3 or greater treatment-related events 
consisted primarily of neutropenia, neuropathy, fatigue, and rash. Three fatal events considered 
potentially related to CDX-011 (glembatumumab vedotin) treatment occurred in the melanoma 
study: pneumococcal sepsis, acute renal failure and toxic epidermal necrolysis. 
 
Results from the CDX-011 (glembatumumab vedotin) studies completed to date have revealed 
the following: 
• CDX-011 (glembatumumab vedotin) is active in both breast cancer and melanoma. 
Activity data (objective response rates and progression-free survival) for patients treated 
at the Phase II dose across all studies have been favorable for the heavily-pretreated 
populations studied. 
• Alternate dosing schedules (every 1 week, every 2 weeks, and every 3 weeks) were 
evaluated in the melanoma study. Although indications of increased activity were noted 
in the more frequent dosing cohorts, this was associated with increased toxicity. 
• Although sample sizes are small, patients with tumors expressing higher levels of 
GPNMB consistently appear to derive greater clinical benefit from CDX-011 
(glembatumumab vedotin) as compared the entire population of treated patients. 
• In both breast cancer studies, the subset of patients with triple-negative breast cancer, 
where treatment options are limited, also appeared to derive greater clinical benefit from 
CDX-011 (glembatumumab vedotin). 
• In the melanoma study, development of rash of any grade, which may be related to the 
presence of GPNMB in the skin, within the first 21 days of treatment was associated with 
greater progression-free survival (PFS) and objective response rate.18 Rash also 


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correlated with prolonged PFS in the Phase II breast cancer study (EMERGE), although 
this correlation was not observed in the earlier Phase I/II breast cancer study (CR011- 
CLN-20).19 
 
 
2.3. Rationale for Proposed Study 
 
GPNMB is a transmembrane protein whose overexpression promotes invasion and metastasis of 
cancer cells from multiple tissue types and is expressed at high levels in several malignant 
human tissues, including uveal melanoma, relative to corresponding normal tissue.13,14 GPNMB 
is associated with induction of matrix metalloproteinase-3, which may provide a mechanism by 
which this protein promotes tumor invasion. In previous work from MD Anderson Cancer 
Center, IHC analysis of 21 uveal melanoma specimens demonstrated staining in 86% of samples 
tested.15 The percentage of cells positive per tumor ranged from 10-90% and the level of 
GPNMB was of variable intensity (5 tumors 1+; 11 tumors 2+; and 2 tumors 3+). 
 
Because of this high-frequency expression on uveal melanoma cells, targeting GPNMB with 
CDX-011 (glembatumumab vedotin) represents a possible therapeutic avenue. In previous 
clinical experience using CDX-011 (glembatumumab vedotin) in cutaneous melanoma patients, 
overall response rate of 13% was seen in patients treated at the MTD, also known as the Phase II 
dose. Clinical experience with CDX-011 (glembatumumab vedotin) in uveal melanoma patients 
is not yet known and an effective therapy for metastatic uveal melanoma patients is a current 
unmet need. 
 
Patients with metastatic uveal melanoma will be eligible regardless of upfront GPNMB status. 
This is due to the high frequency of GPNMB expression in uveal melanoma samples (86%) 
noted previously.15 To clarify pharmacodynamics of CDX-011 (glembatumumab vedotin), 
baseline samples as well as Day 21 on-treatment tumor tissue samples will be analyzed 
retrospectively for GPNMB expression. 
 
2.4. Exploratory/Correlative Studies Background 
Immunophenotype of patients 
Because GPNMB inhibition with CDX-011 (glembatumumab vedotin) may alter the tumor 
microenvironment, we plan as an exploratory endpoint to analyze immune and inflammatory cell 
infiltrates in tumor samples. These findings will help coordinate future efforts of combining 
CDX-011 (glembatumumab) with either immunotherapy such as checkpoint blockade or with 
anti-inflammatory agents such as iNOS inhibitors or triterpenoid anti-inflammatory agents. The 
timing of combination therapy may be elucidated if infiltrates change in response to treatment. 
 
The immune effects of targeted therapy in cutaneous melanoma has been described in vitro as 
well as in patients receiving BRAF-targeted therapy.20 Treatment with either BRAF inhibitor 
alone or in combination with MEK inhibitor is associated with an increased expression of 
melanoma antigens MART-1 and gp100 and an increase in CD8+ T-cell infiltrate. Similarly, 


NCI Protocol #:9855 
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immunosuppressive cytokines interleukin-6 and interleuin-8 are decreased with treatment while 
tumor programmed death ligand-1 (PDL1) increased with treatment. 
These same markers of immune effects can be measured in uveal melanoma patients receiving 
targeted therapy with CDX-011 (glembatumumab vedotin). IHC for melanoma antigens and 
enumeration of T-cell infiltrate is planned at baseline and after 21 days on treatment. 
Additionally, evaluation for NK cells, Foxp3+ regulatory T lymphocytes, macrophages 
(CD68+), as well as markers of mature activated dendritic cells (CD40+/CD83+) is planned. It is 
hypothesized that treatment with CDX-011 (glembatumumab vedotin) will increase cytotoxic 
CD8+ T-cell infiltrate while decreasing immunosuppressive cytokines. If true, this can form the 
rational basis for timed combination therapy with checkpoint blockade, as was similarly 
elucidated in cutaneous melanoma patients receiving BRAF-targeted therapy.21 
 
Correlate rash with response 
 
In the melanoma study CR011-CLN-11, development of rash, which may be related to the 
presence of GPNMB in the skin, was associated with greater PFS and ORR.18 Rash also 
correlated with prolonged PFS in the Phase II breast cancer study (EMERGE), although this 
correlation was not observed in the earlier Phase I/II breast cancer study (CR011-CLN-20).19 
 
For this study, patients with uveal melanoma will be assessed for development of rash and this 
will be correlated with ORR and PFS. 
 
3. PATIENT SELECTION 
 
3.1. Eligibility Criteria 
 
 
3.1.1. Patients must have histologically or cytologically confirmed metastatic or locally 
recurrent uveal melanoma. Because histologic or cytologic confirmation of primary 
uveal melanoma is not always possible the confirmation of the clinical diagnosis of 
uveal melanoma by the treating investigator is allowed. Clinical diagnosis of uveal 
melanoma is often made by an ophthalmologist, not by tissue diagnosis. If an 
ophthalmologist diagnosed and treated a patient for uveal melanoma in the past, it is 
sufficient for a clinical diagnosis. 


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3.1.2. Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for 
non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) with 
conventional techniques or as ≥10 mm (≥1 cm) with spiral CT scan, MRI, or 
calipers by clinical exam. See Section 11 for the evaluation of measurable disease. 
 
3.1.3. The study will be limited to patients who are chemotherapy-naïve. Patients may 
have received prior systemic or liver-directed local therapies for advanced uveal 
melanoma as long as those treatments do not involve chemotherapy. This includes, 
but is not limited to:, immunotherapy, targeted therapy, , transarterial embolization, 
radiofrequency ablation, or cryoablation. Treatment must be completed at least 28 
days prior to initiation of study therapy. Radiation therapy is also allowed and must 
be completed at least 28 days prior to initiation of study therapy. Lesions treated via 
radiation or liver-directed therapy may not be used as target lesions unless they 
demonstrate growth over a minimum of 3 months on subsequent imaging. 
 
3.1.4. All prior treatment-related toxicities must be CTCAE V5 grade ≤ 1 (except 
alopecia). Certain exceptions apply, such as immunotherapy-induced 
hypothyroidism or adrenal insufficiency or panhypopituarism requiring stable doses 
of hormone replacement or rash from prior therapy. 
 
3.1.5. Age ≥18 years. Because no dosing or adverse event data are currently available 
on the use of CDX-011 (glembatumumab vedotin) in patients <18 years of age, 
children are excluded from this study but will be eligible for future pediatric trials. 
 
3.1.6. ECOG performance status ≤2 
 
3.1.7. Life expectancy of greater than 3 months. 
 
3.1.8. Patients must have normal organ and marrow function as defined below: 
 
− 
leukocytes 
≥3,000/µL 
− 
absolute neutrophil count 
≥1,500/ µL 
− 
platelets 
≥100,000/ µL 
− 
total bilirubin ≤ 1.5 x institutional upper limit of normal 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal; 
≤5 x institutional upper limit of normal if liver metastasis present 
− 
Creatinine ≤ institutional upper limit of normal 
OR 
− 
creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal 
 
3.1.9. The effects of CDX-011 (glembatumumab vedotin) on the developing human 
fetus are unknown. For this reason, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; 


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abstinence) prior to study entry, for the duration of study participation, and for 4 
months after last CDX-011 (glembatumumab vedotin) dose. Women of child- 
bearing potential must have a negative serum pregnancy test within 14 days prior to 
start of protocol treatment. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men and women treated or enrolled on this 
protocol must also agree to use adequate contraception prior to the study, for the 
duration of study participation, and 4 months after completion of CDX-011 
(glembatumumab vedotin) administration. 
 
3.1.10. Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2. Exclusion Criteria 


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3.2.1. Patients with a history of another malignancy except for those who have been 
disease-free for 2 years. Patients with a history of definitively treated non-melanoma 
skin cancer or squamous cell carcinoma of the cervix are eligible. Patients with 
definitively treated in-situ cancers are eligible, regardless of timeframe. 
 
3.2.2. Patients with neuropathy > grade 1. 
 
3.2.3. Patients who are receiving any other investigational agents. If the patient 
received a previous investigational or other agent or treatment, a washout period of 
4 weeks is required. 
 
3.2.4. Patients receiving any medications or substances that are substrates of 
CYP3A4will be closely monitored for toxicity. Because the lists of these agents are 
constantly changing, it is important to regularly consult a frequently-updated list; 
medical reference texts such as the Physicians’ Desk Reference may also provide 
this information. As part of the enrollment/informed consent procedures, the patient 
will be counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-the- 
counter medicine or herbal product. 
 
3.2.5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.2.6. HIV-positive patients on antiretroviral medications that are CYP3A4 substrates 
will be closely monitored. HIV-positive patients will be excluded if they have a 
CD4 count <200 as these patients have an increased risk of lethal infections when 
treated with marrow-suppressive therapy. 
 
3.2.7. Pregnant or nursing women. 
 
3.2.8. Patients who have previously received CDX-011 (glembatumumab vedotin) or 
other MMAE-containing agents. 
 
3.2.9. Patients with a history of allergic reactions attributed to compounds of similar 
composition to dolastatin or auristatin (e.g. Auristatin PHE, Auristatin PE, and 
symplostatin). 
 
 
3.3. Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH- 
defined clinical research unless a clear and compelling rationale and justification establishes to 


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the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research. Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification. Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources. Women of 
childbearing potential should not be routinely excluded from participation in clinical research. 
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1.Investigator and Research Associate Registration with CTEP 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all investigators participating in any NCI-sponsored clinical trial to register and to renew 
their registration annually. 
 
Registration requires the submission of: 
 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. 
 
For questions about Investigator Registration, please contact the CTEP Investigator Registration 
Help Desk by email at pmbregpend@ctep.nci.nih.gov. 
 
CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all physicians 
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in 
the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and annual re- 
registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only.  (See CTEP 


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Investigator Registration Procedures above for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account is required to access all CTEP applications and, if applicable 
(e.g., all Network trials), all Cancer Trials Support Unit (CTSU) applications and websites. 
 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm. 
 
For questions about Associate Registration or CTEP-IAM Account Creation, please contact the 
CTEP Associate Registration Help Desk by email at ctepreghelp@ctep.nci.nih.gov. 
 
4.2. Site Registration 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain Institutional Review 
Board (IRB) approval for this protocol and submit all required regulatory documents (including 
any protocol specific documents) to the CTSU Regulatory Office before they can be approved to 
enroll patients. 
 
The CTSU Regulatory Office tracks receipt of these documents in the CTSU Regulatory Support 
System (RSS), reviews for compliance, and transmits site approval data to CTEP. 
 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study are not 
required to submit separate IRB approval documentation to the CTSU Regulatory Office for 
initial, continuing, or amendment review  However, sites must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB (via IRBManager) to indicate their intention to 
open the study locally. The CIRB’s approval of the SSW is then communicated to the CTSU 
Regulatory Office for compliance in the RSS. The Signatory site may be contacted by the CTSU 
Regulatory Office or asked to complete information verifying the participating institutions on the 
study. Other site registration requirements (i.e., laboratory certifications, protocol-specific 
training certifications, or modality credentialing) must be submitted to the CTSU Regulatory 
Office or compliance communicated per protocol instructions. 
 
4.2.1 Downloading Regulatory Documents 
 
 
Site registration forms may be downloaded from the 9855 protocol page located on the CTSU 
Web site. Permission to view and download this protocol is restricted and is based on person and 
site roster data housed in the CTSU RSS. To participate, Investigators and Associates must be 
associated with the Corresponding or Participating protocol organization in the RSS. 
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and password 
• Click on the Protocols tab in the upper left of your screen 
• Click on the Lead Organization folder to expand, then select LAO-TX035, and protocol 


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#9855. 
• Click on LPO Documents, select the Site Registration documents link, and download and 
complete the forms provided. (Note: For sites under the CIRB initiative, IRB data will 
automatically load to RSS.) 
 
 
4.2.2 Submitting Regulatory Documents 
 
Submit completed forms along with a copy of your IRB Approval (and if applicable, Model 
Informed Consent) to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS. 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
 
4.2.3 Checking Site Registration Status 
 
Sites can check the status of their registration packets by querying the Site Registration subtab of 
the members’ section of the CTSU Web site. (Note: Sites will not receive formal notification of 
regulatory approval from the CTSU Regulatory Office.) 
 
Go to https://www.ctsu.org and log in using your CTEP IAM username and password. 
Click on the Regulatory tab at the top of your screen. 
Click on the Site Registration subtab. 
Enter your 5-character CTEP Institution Code and click on Go. 
 
Note: If possible, please allow three working days for site registration approval before attempting 
to enroll your first patient. 
 
4.3. Patient Registration Procedures 
 
 
OPEN/ IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). 
OPEN is a web-based registration system available to users on a 24/7 basis. It is integrated with 
the CTSU Enterprise System for regulatory and roster data interchange and with the Theradex 
Interactive Web Response System (IWRS) for retrieval of patient registration/randomization 
assignment. Patient enrollment data entered by Registrars in OPEN will automatically transfer to 
the NCI’s clinical data management system, Medidata Rave. 
 
NCI 9855 will use the IWRS slot reservation system. For trials with slot reservation 


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requirements, OPEN will connect to IWRS at enrollment initiation to check slot availability. 
Registration staff should ensure that a slot is available and secured for the patient before 
completing an enrollment. Please refer to the section below for additional instructions on how to 
use the IWRS slot reservation system. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records. 
 
OPEN/IWRS User Requirements 
 
OPEN users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations: Be on an ETCTN Corresponding or 
Participating Organization roster with the role of Registrar. 
• To approve slot reservations or access cohort management: Be identified to Theradex as 
the “Client Admin” for the study. 
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the CTSU web site as a tool to verify 
eligibility. 
• All patients have signed an appropriate consent form and HIPAA authorization form. 
 
 
Patient Enrollment Instructions 
 
• Sites must reserve a slot in IWRS. Each site is allowed 2 slot reservations at a 
time with a 2 day guaranteed hold for each slot. 
 
• Next, fax the following documents for review: 
1. Latest clinic note 
2. Pathology report 
3. Radiology report 
 
• Fax to: K. Perdon/S. Patel, MD at (713) 794-1493. Include your contact 
information in the fax cover sheet. 
 
• Each reservation will need to be authorized and approved by an MD Anderson 
designee prior to registering the patient in OPEN. Once the slot is approved in 
IWRS, you may proceed with registering your patient in OPEN. 
 
Following registration, patients should begin protocol treatment within 7 days. Issues 


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that would cause treatment delays should be discussed with the Principal Investigator. If 
a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled. The Study Coordinator should be notified of 
cancellations as soon as possible. 
 
 
 
OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org. For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website: 
 
http://www.theradex.com/downloads/IWRS%20User%20Guide.pdf) 
 
This link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk at 609-619-7802 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com 
 
 
CORe registration at MD Anderson sites only 
 
In addition to OPEN registration, patients will also be registered in Clinical Oncology Research 
System (CORe, www.oncologyresearch.org) 
 
To register a patient, the research nurse will: 
• Confirm patient eligibility 
• Obtain informed consent, electronic or paper version 
• Confirm insurance approval of clinical trial treatment 
To complete the registration process, the research nurse will: 
• Register the patient in CORe 
• Assign a patient study number 
• Assign the patient a treatment start date 
 
 
5. TREATMENT PLAN 
 
5.1. CDX-011 (glembatumumab vedotin) Administration 
 
Treatment will be administered on an outpatient basis at a starting dose of CDX-011 
(glembatumumab vedotin) of 1.9 mg/kg IV every 3 weeks.  Reported adverse events and 


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potential risks are described in Section 7. Appropriate dose modifications are described in 
Section 6. No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy. 
 
• CDX-011 (glembatumumab vedotin) solution is diluted with 5% dextrose injection 
before infusion. CDX-011 (glembatumumab vedotin) is administered as a 90-minute(+/- 
10 minutes) IV infusion using a 0.22 µm in-line filter at a dose of 1.9 mg/kg IV every 3 
weeks (+/- 3 days) 
 
• There are no premedications recommended for CDX-011 (glembatumumab vedotin) on 
the first dose. Subjects should be carefully monitored for infusion reactions during CDX- 
011 (glembatumumab vedotin) administration. If an acute infusion reaction is noted, 
subjects should be managed according to Appendix C.  After symptoms have resolved, 
the infusion may be resumed at half the initial rate, or as otherwise directed by the 
attending physician/PI. 
 
• If an infusion reaction occurs, vital signs should be monitored every 5 minutes during 
infusion until stable. After infusion is complete, vital signs should be monitored per 
institutional infusion standard. 
 
• Patients with Grade 3 or 4 infusion related reactions as defined by CTCAE v.5.0 may be 
re-challenged with treatment on a case-by-case basis after discussion with Lead PI, CTEP 
drug monitor, and any others deemed necessary. These cases will be tracked and 
monitored carefully. 
 
• Actual body weight will be recorded and used to calculate dose prior to each infusion. 
 
 
5.2. General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of CDX-011 (glembatumumab vedotin) with other 
concomitantly administered drugs through the cytochrome P450 system, the case report form 
must capture the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies. The Principal Investigator should be alerted if the patient is taking any agent known to 
affect or with the potential to affect selected CYP450 isoenzymes, specifically CYP3A4. 
Appendix B presents guidelines for identifying medications/substances that could potentially 
interact with the study agent(s). 
 
5.3. Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Disease progression, 


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• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s), 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
5.4. Duration of Follow Up 
 
Patients will be followed for 30 days after removal from study or until death, whichever occurs 
first. Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. Patients removed prior to progression of disease 
will be followed for PFS and OS per intent-to-treat analysis. 
 
5.5. Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies. The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
CDX-011 (glembatumumab vedotin) should be administered at a dose of 1.9 mg/kg IV every 3 
weeks. Dosing delays are allowed up to 3 weeks. A delay longer than 3 weeks warrants removal 
from study. 
 
 
Dose Level 
CDX-011 (glembatumumab vedotin) Dose 
0 
1.9 mg/kg every 3 weeks 
-1 
1.3 mg/kg every 3 weeks 
-2 
1 mg/kg every 3 weeks 
 
 
Dose reduction levels are outlined in the table above. Criteria for dose modifications include 
nausea, diarrhea, and neutropenia and are outlined in the tables below. If a patient experiences 
several adverse events and there are conflicting recommendations, the investigator should use the 
recommended dose adjustment that reduces the dose to the lowest level. 


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Diarrhea 
Management/Next Dose for CDX-011 (glembatumumab vedotin) 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule: 4 mg at first onset, followed by 2 mg with each loose motion until diarrhea- 
free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
 
Neutropenia 
Management/Next Dose for CDX-011 (glembatumumab vedotin) 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management: Growth factor support 
 
Rash 
Management/Next Dose for CDX-011 (glembatumumab vedotin) 
Grade 1-2 
No change in dose 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management: topical or systemic corticosteroids 
 
Neuropathy 
Management/Next Dose for CDX-011 (glembatumumab vedotin) 
Grade 1 
No change in dose 
Grade 2 
Hold* until ≤ Grade 1.  Resume at one dose level lower, if indicated.** 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management: anaglesia 
 
Fatigue 
Management/Next Dose for CDX-011 (glembatumumab vedotin) 
Grade 1-2 
No change in dose 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 


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Fatigue 
Management/Next Dose for CDX-011 (glembatumumab vedotin) 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
Thrombocytopenia 
Management/Next Dose for CDX-011 (glembatumumab vedotin) 
Grade 4 
Hold* until ≤ Grade 1.  Resume at one dose level lower, if indicated.** 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management: Growth factor support 
 
Non-Hematologic 
Toxicity 
Management/Next Dose for CDX-011 (glembatumumab vedotin) 
Grade 3-4 
Hold* until ≤ Grade 2. 
Resume at one dose level lower, if not resolved to ≤ Grade 2 after 72 
hours.** 
Supportive measures as clinically indicated. 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
• If an infusion reaction occurs, vital signs should be monitored every 5 minutes during 
infusion until stable. After infusion is complete, vital signs should be monitored per 
institutional infusion standard. 
 
• Patients with Grade 3 or 4 infusion related reactions as defined by CTCAE v.5.0 may be 
re-challenged with treatment on a case-by-case basis after discussion with Lead PI, CTEP 
drug monitor, and any others deemed necessary. These cases will be tracked and 
monitored carefully. 
 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
7.1. Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) for CDX-011 
(glembatumumab vedotin) (CDX-011, NSC 763737) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 


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Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 
Frequency is provided based on 255 patients. Below is the CAEPR for CDX-011 
(glembatumumab vedotin) (CDX-011). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
 
 
 
 
Version 2.1 August 3, 20161 
Adverse Events with Possible 
Relationship to CDX-011 (glembatumumab vedotin) 
(CTCAE 4.0 Term) 
[n= 255] 
Specific Protocol Exceptions 
to Expedited 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
Anemia (Gr 2) 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
Constipation 
Constipation (Gr 2) 
Diarrhea 
Diarrhea (Gr 2) 
Dyspepsia 
Mucositis oral 
Nausea 
Nausea (Gr 2) 
Vomiting 
Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Chills 
Edema limbs 
Fatigue 
Fatigue (Gr 2) 
Fever 
Fever (Gr 2) 
Infusion site extravasation 
Pain 
INFECTIONS AND INFESTATIONS 
Infection2 
INVESTIGATIONS 
Neutrophil count decreased 
Neutrophil count decreased (Gr 2) 
Platelet count decreased 
White blood cell decreased 


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Adverse Events with Possible 
Relationship to CDX-011 (glembatumumab vedotin) 
(CTCAE 4.0 Term) 
[n= 255] 
Specific Protocol Exceptions 
to Expedited 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
Anorexia (Gr 2) 
Dehydration 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Arthralgia 
Myalgia 
Pain in extremity 
NERVOUS SYSTEM DISORDERS 
Dizziness 
Dysgeusia 
Dysgeusia (Gr 2) 
Headache 
Nervous system disorders - Other 
(peripheral neuropathy)3 
Nervous system disorders- Other 
(peripheral neuropathy)3 (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Dyspnea 
Pharyngolaryngeal pain 
Respiratory, thoracic and 
mediastinal disorders - Other 
(pulmonary embolism) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Alopecia 
Alopecia (Gr 2) 
Dry skin 
Hyperhidrosis 
Palmar-plantar 
erythrodysesthesia syndrome 
Pruritus 
Pruritus (Gr 2) 
Skin and subcutaneous tissue 
disorders - Other (nail disorder)4 
Skin and subcutaneous tissue 
disorders - Other (rash)5 
Skin and subcutaneous tissue 
disorders - Other (rash)5 (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be 
distributed to all Principal Investigators at the time of revision. The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Infection may include any of the 75 infection sites under the INFECTIONS AND 
INFESTATIONS SOC. 
 
3Peripheral neuropathy includes Peripheral motor neuropathy and Peripheral sensory neuropathy 
under the NERVOUS SYSTEM DISORDERS SOC. 
 
4Rash includes exfloliative rash, Erythema, Rash erythematous, Rash generalized, Rash macular, 


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Rash papular, Rash maculo- papular, Catheter site rash and Infusion site erythema under SKIN 
AND SUBCUTANEOUS TISSUE DISORDERS SOC. 
 
5Nail disorder includes nail loss, onychoclasis and dermatomyositis under SKIN AND 
SUBCUTANEOUS TISSUE DISORDERS SOC. 
 
Adverse events also reported on CDX-011 (glembatumumab vedotin) (CDX-011) trials but with 
the relationship to CDX-011 (glembatumumab vedotin) (CDX-011) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (pancytopenia, bone marrow failure); Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Palpitations; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (hypoacusis); Ear 
pain 
Endocrine disorders - Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Conjunctivitis; Dry eye; Eye disorders - Other 
(ocular hyperemia); Photophobia; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Dry mouth; 
Dysphagia; Fecal incontinence; Flatulence; Gastroesophageal reflux disease; Gastrointestinal 
disorders - Other (eructation); Gastrointestinal disorders - Other (hyperchlorhydria); 
Gastrointestinal disorders - Other (tongue ulceration); Gastrointestinal pain; Gingival pain; 
Hemorrhoids; Ileus; Oral dysesthesia; Oral pain; Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; 
Flu like symptoms; Gait disturbance; General disorders and administration site conditions - 
Other (axillary pain); Injection site reaction; Irritability; Localized edema; Malaise; Non-cardiac 
chest pain 
Hepatobiliary disorders - Hepatic pain 
Immune system disorders - Allergic reaction 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and 
procedural complications - Other (excoriation); Wound complication 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase 
increased; Creatinine increased; GGT increased; Lymphocyte count decreased; Urine output 
decreased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; 
Bone pain; Flank pain; Generalized muscle weakness; Musculoskeletal and connective tissue 
disorder - Other (groin pain); Musculoskeletal and connective tissue disorder - Other (muscle 
spasms); Musculoskeletal and connective tissue disorder - Other (restless legs syndrome); 
Musculoskeletal and connective tissue disorder - Other (shoulder pain); Musculoskeletal and 
connective tissue disorder - Other (trigger finger); Neck pain 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Tumor pain 
NERVOUS SYSTEM DISORDERS – Ataxia; Dysesthesia; Lethargy; Memory impairment; 
Nervous system disorders - Other (burning sensation); Neuralgia; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido 


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decreased; Psychiatric disorders - Other (mental status changes); Psychiatric disorders - Other 
(mood altered) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; Renal and urinary 
disorders - Other (bladder disorder); Renal and urinary disorders - Other (dysuria); Urinary 
retention 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Reproductive 
system and breast disorders - Other (genital rash) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Bronchospasm; Cough; Epistaxis; Hiccups; Nasal congestion; Postnasal drip; 
Pulmonary fibrosis; Respiratory, thoracic and mediastinal disorders - Other (dry throat); 
Respiratory, thoracic and mediastinal disorders - Other (pharyngeal edema); Respiratory, 
thoracic and mediastinal disorders - Other (throat tightness); Voice alteration; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Erythema 
multiforme; Pain of skin; Periorbital edema; Photosensitivity; Purpura; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (ephelides); Skin and subcutaneous tissue disorders - Other 
(madarosis); Skin and subcutaneous tissue disorders - Other (skin swelling); Skin 
hyperpigmentation; Skin hypopigmentation; Skin ulceration; Toxic epidermal necrolysis; 
Urticaria 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; 
Thromboembolic event 
 
 
Note: CDX-011 (glembatumumab vedotin) (CDX-011) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be caused by the other agent, or 
the combination may result in events never previously associated with either agent. 
 
 
7.2. Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only: 
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed 
in the SPEER column, Section 7.1) should be reported through CTEP-AERS 
only if the grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined 
in section 7.3.4. 
 
• Attribution of the AE: 


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- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3. Expedited Adverse Event Reporting 
 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP Web site (https://eapps-ctep.nci.nih.gov/ctepaers). The 
reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” 
which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
 
Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals: Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients. 
 
Expedited Reporting Guidelines 
 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note: A death on study requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” 
in the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 


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Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening adverse event 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timefra 
mes 
Grade 2 
Timeframe 
s 
Grade 3 
Timeframe
s 
Grade 
4 & 5 
Timef 
rames 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found 
in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically 
within 24 hours of learning of the AE, followed by a complete expedited report 
within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted 
electronically within 10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite 
require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 
radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was 
last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 


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30 
 
 
 
 
 
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via CTEP- 
AERS. However, they still must be reported through the routine reporting mechanism (Section 
7.4): 
 
CTCAE SOC Adverse Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
Investigations Alanine 
aminotransfera
s e 
≤2 
N/A 
Possibly or 
Unrelated 
90% of uveal 
melanoma patients 
on this study will 
have liver mets, 
elevated LFTs will 
be commonplace 
and are not listed on 
CAEPR for this 
drug 
Investigations Aspartate 
aminotransfera
s e 
≤2 
N/A 
Possibly or 
Unrelated 
90% of uveal 
melanoma patients 
on this study will 
have liver mets, 
elevated LFTs will 
be commonplace 
and are not listed on 
CAEPR for this 
drug 
Investigations Blood bilirubin ≤2 
N/A 
Possibly or 
Unrelated 
90% of uveal 
melanoma patients 
on this study will 
have liver mets, 
elevated LFTs will 
be commonplace 
and are not listed on 
CAEPR for this 
drug 
 
7.4. Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data submissions. 


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The following paragraph only applies to trials using Medidata Rave; other trials may delete: 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5. Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to 
describe the event: 
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML]) 
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
 
Indicate form for reporting in Rave, timeframes, and if loading of the pathology report is 
required. 
 
7.6. Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
 
8.1. CDX-011 (glembatumumab vedotin), NSC 763737) 


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8.1.1 Classification: 
monoclonal IgG2 antibody (CR0111) conjugate to monomethyl- 
Auristatin E (MMAE) 
 
8.1.2 CAS registry number: 1182215-65-1 
 
8.1.3 Mode of Action: 
 
CDX-011 combines a tumor-targeting antibody with a potent cytotoxic microtubule inhibitor, 
monomethylauristatin E (MMAE). The fully-human IgG2 monoclonal antibody, CR011, is 
directed against glycoprotein NMB (gpNMB), a transmembrane protein which is highly 
expressed in breast cancer and other tumors. 
 
8.1.4 Availability / How supplied: 
 
CDX-011 is supplied by Celldex Therapeutics and distributed by the CTEP, DCTD, NCI. CDX- 
011 drug product solution (injection concentrate) contains CDX-011, Sucrose NF, Histidine 
USP, Histidine-Hydrochloride Monohydrate EP, and Polysorbate 20 NF, at pH of 6.0 ± 0.5. It is 
supplied in 10 mL Clear Type-I glass vials with stoppers and aluminum crimp seals containing 
50 mg per vial (5 mg/mL, 10 mL). 
 
8.1.5 Storage: 
 
Store intact vials at 2°-8°C (36°-46°F). The prepared dilution may be stored in the infusion bag 
at ambient room temperature (15 - 25°C [59 - 77°F]) for not more than 8 hours before infusion. 
 
8.1.6 Stability: Stability of the intact vials is ongoing. 
 
8.1.7 Route of Adinistration: 
IV infusion only 
 
8.1.8 Preparation / Administration: 
 
CDX-011 solution must be further diluted in 250 mL of 5% Dextrose. The prepared 
dilution is administered as an IV infusion through an in-line 0.22 micron filter over 90- 
minutes. 
 
8.1.9 Dose: The starting dose of CDX-011 is 1.9 mg/kg every 3 weeks.The appropriate dose 
of CDX-011 should be re-calculated for each dose based on the current weight of the patient. 
Doses may be rounded to the nearest 0.1 mL (0.5 mg). 
 
8.1.10 Side Effects: See CAEPR (section 7) 
 
8.1.11 Potential Interactions: 
 
The effect of CDX-011 on the absorption, metabolism, or excretion of other drugs has not 
been studied. To date, there have been no unexpected interactions observed between CDX-011 


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and other drugs. 
 
In a study of a different antibody drug-conjugate containing MMAE, brentuximab 
vedotin, free MMAE was primarily excreted in the feces, although this represents a minor 
component of elimination. MMAE was also found to be metabolized by cytochrome P450 3A4 
(CYP3A4) and co-administration of ketoconazole, a potent CYP3A4 inhibitor, increased MMAE 
exposure by approximately one-third (Adcetris [brentuximab vedotin] package insert, September 
2013 and FDA Approval Package). Therefore, drugs known to strongly inhibit CYP3A4 should 
be used with caution while patients are exposed to CDX-011, and patients should be closely 
monitored for adverse reactions. 
 
Co-administration of brentuximab vedotin with rifampin, a potent CYP3A4 inducer, 
reduced exposure to MMAE by almost 50%. Concomitant administration of drugs known to be 
potent CYP3A4 inducers should be avoided, if at all possible. 
 
Because the concentration of free MMAE is very low, if potent CYP3A4-modifying 
drugs are administered concomitantly with CDX-011, dose modifications of CDX-011 are not 
recommended unless necessitated by toxicity. 
 
In addition, MMAE is also a substrate of the efflux transporter P-glycoprotein (P-gp). 
Co- administration of brentuximab vedotin with P-gp inhibitors may increase exposure to 
MMAE; thus, per the brentuximab package insert (September 2013), patients who are receiving 
P-gp inhibitors concomitantly with brentuximab vedotin should also be closely monitored for 
adverse reactions. 
 
8.1.12 Agent ordering 
 
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), 
Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure Form 
(FDF). If there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead investigator at 
that institution 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status and a 
“current” password. 
 
Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly 
to the institution where the patient is to be treated. PMB does not permit the transfer of agents 
between institutions. 


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Questions about drug orders, transfers, returns, or accountability should be addressed to 
the PMB by calling 240-276-6575 Monday through Friday between 8:30 AM and 4:30 PM 
Eastern Time 
 
Agent Returns: All unused drug supplies must be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient permanently 
discontinues protocol treatment, expired vials recalled by the PMB), investigators must return the 
study drug to the PMB using the NCI Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov) or by calling the PMB at (240) 276-6575. 
Agent Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of all drugs 
received from the PMB using the NCI Investigational Agent Accountability Record available on 
the NCI home page (http://ctep.cancer.gov) or by calling the PMB at (240) 276-6575. 
 
 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1. Integral Laboratory or Imaging Studies 
N/A 
 
9.2. Investigational Device Information 
N/A 
 
9.3. Integrated Correlative Studies – GPNMB expression 
For full details, refer to Appendices 
Background 
 
CDX-011 (glembatumumab vedotin) is an antibody-drug conjugate directed against GPNMB. 
Therefore, tumor expression of GPNMB is expected to correlate with response to treatment. As 
preliminary evidence suggests uveal melanomas highly express GPNMB (86% of samples 
positive)18, patients will not be screened prior to treatment. However, to clarify 
pharmacodynamics of CDX-011 (glembatumumab vedotin), pre-study tumor samples as well as 
on-treatment tumor samples will be analyzed retrospectively for GPNMB expression. The effect 
of CDX-011 (glembatumumab vedotin) on GPNMB expression will be studied from the second 
tumor sample, and is a mandatory component for all patients on study. Patients also have the 
option for tissue acquisition and analysis for GPNMB at the time of progression of disease. The 
purpose of this biopsy is to evaluate mechanisms of resistance to treatment.  There is no 
minimum number of patients required to undergo a biopsy at progression as information on even 
a modicum of patients is an opportunity to learn about resistance. ORR and PFS are expected to 
correlate with presence of GPNMB. 
 
34 


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Sample Collection 
• Appendix D is the lab instruction manual and submission form for acquisition, handling, 
and shipping of tissue specimens for GPNMB testing. 
• Fax or email the completed Specimen Submittal Form located in Appendix D to Mosaic 
Laboratories at (949) 340-7330 (fax) or <clinicaltrials@mosaiclabs.com>. 
• At some institutions, research-only biopsies may not generate formal Pathology Reports. 
In those cases, the reason for lack of a Pathology Report should be noted on the 
Specimen Submittal Form. 
 
 
 
 
 
 
GPNMB Reporting 
 
Study GPNMB result reports will not be provided to the clinical sites. All testing is performed as 
a per-protocol retrospective analysis. Please contact the Clinical Trial Manager with ad hoc 
requests for a specific patient’s GPNMB test results. 
 
Tissue Block Repatriation 
 
All tissue blocks will be repatriated to the originating investigative site at the end of the study. 
 
Expedited repatriation may be requested ad hoc by sites with an urgent clinical need to access the 
tissue block provided. 
 
• Expedited repatriation does not extend to slides provided by investigator sites or 
prepared during the processing of the samples. 
• When completing Specimen Submission Form, note that expedited processing is 
requested. 
• Fax or email the completed Request Form to Mosaic Laboratories. (fax number: 
949-340-7330; email: clinicaltrials@mosaiclabs.com 
• Specimens for urgent/ad hoc repatriation will be shipped by Mosaic Laboratories 
within 10 business days from the receipt date of the samples. 
 
9.4. Exploratory/Ancillary Correlative Studies 
 
Immunophenotype of Patients Treated with CDX-011 (glembatumumab vedotin) 
 
As an optional correlative endeavor, we plan to utilize metastatic tumor tissue samples at 
baseline and after 1 cycle of treatment (+/- 3 days) and at progression of disease to characterize 
the immune cell and inflammatory infiltrates in uveal melanoma tumors. We will capitalize on 
outstanding efforts with the MD Anderson Melanoma MoonShot Biospecimen team for tissue 
 
35 


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acquisition and will collaborate with experienced immunology and melanoma laboratories to 
analyze via immunohistochemistry tumor cells for CD4, CD8, Foxp3, CD68, CD40, CD83, 
TGF-beta, MIF, IDO, IFN-gamma, PD-L1, iNOS, NT, Cox-2, SNO, Arginase, NFkB, pSTAT3, 
Bcl-2. To minimize interpersonal variations and maximize consistency, computerized barcode- 
driven automatic immunostainers will be used to increase precision of results. 
 
 
Background and Hypothesis 
 
The etiology behind the poor response to therapy in patients with metastatic uveal melanoma is 
not clear, however several factors may contribute to this. The innate immune system includes 
natural killer (NK) cells, granulocytes, and macrophages and is capable of inducing ocular 
damage. This is balanced by a variety of anti-inflammatory cytokines and scavengers of free 
radical species that neutralize pro-inflammatory markers. The eye has evolved to become an 
immune privileged organ to protect itself from damage associated with inflammation because its 
capacity for tissue regeneration is restricted. 
 
The adaptive immune system, represented mainly by activated cytotoxic T-lymphocytes, is 
capable of recognizing viral and tumor antigens that are appropriately presented in the context of 
major histocompatibility complex class I (MHC I) molecules. MHC class I is expressed on 
normal human tissues and prevents NK-cell mediated destruction. Interestingly, MHC class I is 
expressed at very low levels in the eye (8, 10, 11) NK-cell mediated cytotoxic activity that is 
normally prompted by lack of MHC class I expression is neutralized in the eye by macrophage 
migration inhibitor factor (MIF) and by transforming growth factor-beta (TGF-beta). PD-L1, a 
member of the B7 family of membrane proteins, is expressed in the human eye and serves to 
down-regulate T-cell proliferation.  Together, these mechanisms lead to down regulation of T 
cell activation and apoptosis of inflammatory cells in the microenvironment of the eye, and 
preserving the antigen privileged state of the eye. 
 
Notably, 40% of tumor infiltrating lymphocytes (TIL) isolated from primary uveal melanomas 
express NK-cell markers. But NK-cell mediated cytolysis of uveal melanoma tumor tissue 
lacking MHC class I expression is inhibited by TGF-beta and MIF in the aqueous humor of the 
eye. Once metastatic, uveal melanomas preferentially metastasize to the liver in 90% of cases. 
Although the liver houses the highest concentration of NK cells in the body, which would 
otherwise rapidly eliminate cells lacking MHC class I expression (such as uveal melanomas), 
uveal melanomas have instead adopted strategies employed in the ocular environment to block 
NK-cell mediated cytolysis.  This includes increasing MIF secretion to twice the levels of 
primary uveal melanoma as well as up-regulating MHC Class I expression 10-fold in comparison 
to primary uveal melanomas. Finally, TGF-beta2, an isoform of TGF-beta that suppresses NK 
cells, is expressed by metastatic uveal melanomas. 
 
There is also evidence that uveal melanomas have an altered response to adaptive T cell- 
mediated immunity, though this has not been thoroughly studied. One mechanism of this is 
through increased indoleamine 2,3-dioxygenase (IDO) expression in the eye. T-lymphocytes are 
dependent upon tryptophan for their metabolism and are unable to survive in the absence of this 


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37 
 
 
 
key building block amino acid. IDO catalyzes tryptophan degradation leading to termination of 
T-cell activation. IDO is expressed in many ocular tissues and is thought to be a strategy for 
further evasion of immune surveillance by uveal melanomas. Although IDO expression is 
dynamic, it is induced by interferon (IFN)-gamma exposure.  Therefore, uveal melanoma cells 
can generate IDO in the presence of innate or adaptive immune elements such as IFN-gamma. 
Likewise, IFN-gamma induces expression of programmed death ligand-1 (PD-L1) on primary 
and metastatic uveal melanoma cell lines. PD-L1 contributes to immune privilege by interacting 
with its receptor PD-1 on T cells leading to down-regulation of T lymphocytes. Taken together, 
uveal melanoma cells are genetically programmed to respond to a pro-inflammatory environment 
(via IFN-gamma) and upregulate T-lymphocyte suppressive pathways such as IDO and PD-L1 to 
counteract immune-mediated surveillance and elimination. While this has been seen in tumors 
such as cutaneous melanoma and renal cell carcinoma, the mechanism of PD-L1 upregulation in 
uveal melanoma remains unknown. 
 
The inflammatory microenvironment has been implicated in tumor growth in adult cancers, 
including melanoma.  Inflammation is often induced hand-in-hand by immune cells and 
cytokines and chemokines which promote reactive oxygen and nitrogen species to potentiate 
tumor progression. Cytokine-drive inducible nitric oxide synthase (iNOS) iNOS has been shown 
to promote a pro-oxidant and pro-inflammatory state in melanoma.  Expression of iNOS in vivo 
is prognostic of poor survival as patients whose melanomas express higher levels of iNOS have 
decreased survival. Reactive oxygen and nitrogen species react with proteins intra-tumorally via 
S-nitrosylation (SNO) and nitration of tyrosines (NT). This post-translational modification of 
proteins is irreversible and can alter antigenicity. For example, nitrosylation of the MHC Class I 
receptor inhibits presentation of tumor antigen to cytotoxic T lymphocytes. NF-kB represents 
another pro-inflammatory cancer target gene where tumor cell cytotoxicity is related to NF-kB 
expression.  NF-kB inhibits anti-oxidation and activates anti-apoptotic genes (Bcl-2) in addition 
to upregulating other factors involved in metastasis such as angiogenesis and expression of of 
immunosuppressive mediators (Arginase, Cox-2, STAT3 activation). 
 
Based on the immune privilege of the eye and the low level of cytotoxic T cell infiltrate in 
primary uveal melanomas associated with elevated inhibitory cytokines TGF-beta and MIF, we 
expect a similar infiltrate in metastatic uveal melanomas where we mechanisms for immune 
evasion likely persist. Immunphenotype in metastatic tumor tissue is expected to be of low 
cytotoxic T cell quantity with high inhibitory, regulatory, and inflammatory markers.   Markers 
to be evaluated include, but are not limited to: CD4, CD8, Foxp3, CD68, CD40, CD83, TGF- 
beta, MIF, IDO, IFN-gamma, PD-L1, iNOS, NT, Cox-2, SNO, Arginase, NFkB, pSTAT3, Bcl-2. 
 
Tissue quality will be variable in metastatic tumors as they will consist mainly of core needle 
biopsies from various metastatic sites. To address this, all slides will undergo path quality 
control by a dermatopathologist, and areas of viable tumor will be circled on each slide. 
 
This work is currently funded by a peer-reviewed institutional research grant to investigate 
differential immunophenotypes in uveal melanoma. Preliminary data is from the grant is not 
currently available. 


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Methods 
 
For this optional exploratory correlative analysis, MD Anderson Cancer Center (MDACC) 
patients will be co-consented to protocol 2012-0846, a laboratory collection and use protocol 
entitled “Longitudinal biopsy tissue acquisition protocol” or awarded institutional funds will be 
used to cover biopsy costs. Non-MDACC sites will obtain tissue for optional correlative studies 
per local institutional guidelines. Archival tissue at baseline in the form of formalin-fixed, 
paraffin-embedded tumor tissue can be utilized. On-treatment optional tumor tissue will be 
obtained after the first cycle of treatment (+/- 3 days) and can be piggybacked onto the 
mandatory clinical trial biopsy that occurs at this timepoint for GPNMB expression. At 
progression of disease, patients have the option to undergo another tumor biopsy for correlative 
studies. Tissue may be obtained via incisional biopsy, excisional biopsy, core needle biopsy, or 
fine needle aspiration. 
 
These tumor samples will be analyzed via immunohistochemistry for the following markers: 
CD4, CD8, Foxp3, CD68, CD40, CD83, TGF-beta, MIF, IDO, IFN-gamma, PD-L1, iNOS, NT, 
Cox-2, SNO, Arginase, NFkB, pSTAT3, Bcl-2. The relative percentages and changes in of these 
immune infiltrates will be descriptively summarized. 
IntelliPATH FLX™ Automated Slide 
Staining System will be used to perform immunohistochemistry. This system increases the 
reproducibility of results using barcode-drive immunostainers to dispense reagents, control 
washing, mixing, heating, and to optimize reaction kinetics. This system is compatible with 
reagents from any source, thereby increasing ease of use, and is currently utilized in MDACC 
laboratories. RT-PCR will be used to monitor cytokine expression in the tumor 
microenvironment. Flow cytometry-based analysis will used to monitor the population of 
cytokine producing T cells. 
 
 
Collection of Specimens(s) 
 
Metastatic tumor tissue will be collected at baseline (archival tissue is allowed) as well as after 
the first cycle of treatment (+/- 3 days). Core biopsies will be performed using a 21-gauge 
needle or institutional protocol for safe tissue acquisition. 
 
Handling of Specimens(s) 
 
a. Tissue will be fixed in 10% neutral buffered formalin and embedded in 
paraffin per local procedures. 
b. Samples will be adhered as 4-µm sections to glass slides (no minimum or 
maximum number of slides are required). 
c. Slides will be evaluated by a dedicated dermatopathologist who will identify 
areas of viable tumor tissue. 
 
Shipping of Specimen(s) 
• Where available, include a Pathology Report with the sample. 
• Black out subject identifiers such as name, address, telephone number, and social security 


NCI Protocol #:9855 
Version Date:  April 2, 2018 
39 
 
 
 
number on the Pathology Report. Do not black out Accession number, date of birth, age, 
date of specimen collection, site of specimen collection. 
• Label slides with pathology Accession number, date slides were cut, subject initials, 
CTSU subject number. 
• Email ClinicalResearchSupport@mdanderson.org to report shipping of slides. 
• Package and ship slides in accordance with local institutional policies and procedures. 
Please use frozen gel packs for instances of extreme heat. The shipping address for 
optional correlative study specimens is: 
Sapna Patel, M.D. 
MD Anderson Melanoma Oncology 
Attention: NCI9855 / CDX011 study 
1515 Holcombe Blvd, Unit 0430 
Houston, TX 77030 
 
 
Site(s) Performing Correlative Study 
 
MD Anderson Cancer Center will perform the correlative studies described in this section. 
Statistical Analysis 
The relative percentages of immune and inflammatory infiltrates will be descriptively 
summarized by a dedicated dermatopathologist for each time point. Paired t-tests or Wilcoxon 
signed-rank tests will be used to compare infiltrate percentages by time point. In addition, the 
levels of infiltrates from each time point and the change in infiltrate between time points will be 
compared with clinical outcomes such as time to progression using Kaplan-Meier survival 
curves, Cox proportional hazards regression, and t-tests or Wilcoxon rank sum tests. 
 
If possible, two group t-tests or Wilcoxon rank sum tests will be used to compare infiltrates by 
tissue type (hepatic, extra-hepatic) or by gene expression profile, if that data is available about 
the primary uveal melanoma 
 
Correlation of Rash with Clinical Benefit 
Background and Hypothesis 
In the melanoma Phase I/II study CR011-CLN-11, development of rash of any grade, which may 
be related to the presence of GPNMB in the skin, within the first 21 days of treatment was 
associated with greater PFS and ORR.18 Patients who developed rash in cycle 1 had a median 
PFS of 4.4 months compared with PFS of 1.3 months in patients who did not develop a rash (HR 
0.37, P=0.001). Rash also correlated with prolonged PFS in the Phase II breast cancer study 
(EMERGE), although this correlation was not observed in the earlier Phase I/II breast cancer 
study (CR011-CLN-20).19   For this study, we expect development of rash in cycle 1 will 
similarly correlate with improvement in PFS and ORR. 


NCI Protocol #:9855 
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40 
 
 
 
 
Methods 
 
All patients who receive 1 dose of study drug will be followed for development of rash. Rash of 
any type and any grade that develops at any time during treatment will be captured. 
 
Collection of Specimen(s) 
N/A 
 
Handling of Specimens(s) 
N/A 
 
Shipping of Specimen(s) 
N/A 
 
Site(s) Performing Correlative Study 
 
MD Anderson Cancer Center will perform the correlative studies described in this section. 
Statistical Analysis 
Descriptive statistics will be used to report the development and grade of rash in patients on 
treatment, with particular attention to development of rash during cycle 1. Wilcoxon rank sum, 
Cox proportional hazards regression, and Kaplan-Meier survival curves will be used to correlate 
rash and/or severity with PFS and ORR. 


NCI Protocol #:9855 
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41 
 
 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy. Scans 
and x-rays must be done <4 weeks prior to the start of therapy. In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
 
Pre 
- 
Stu 
dy 
C 
1 
W 
k 
1 
C 
1 
W 
k 
2 
C 
1 
W 
k 
3 
C2 
W 
k 
4d 
C 
2 
W 
k 
5 
C 
2 
W 
k 
6 
C 
3 
W 
k 
7 
C 
3 
W 
k 
8 
C 
3 
W 
k 
9 
C 
4g 
W 
k 
10 
C4 
g 
W 
k 
11 
C4 
g 
W 
k 
12 
Off 
Study 
Treat 
mentc 
Survival 
follow- 
up 
CDX-011 
(glembatumuma 
b vedotin) 
X 
X 
X 
X 
Informed 
consent 
X 
Demographics 
X 
Medical history X 
Concurrent 
meds 
X 
Assessed at the beginning of each cycle 
Physical exam 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
Performance 
status 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts X 
X X X X 
X X X X X X 
X 
X 
X 
Serum 
chemistry
X 
X X X X 
X X X X X X 
X 
X 
X 
Adverse event 
evaluation 
Assessed at the beginning of each cycle and as 
they emerge or are reported 
X 
Tumor 
measurements 
X 
Tumor measurements are repeated every 6 
weeks. Documentation (radiologic) must be 
provided for patients removed from study for 
progressive disease. 
X 
Radiologic 
evaluation 
X 
Radiologic measurements should be performed 
every 6 weeks. 
X 
B-HCG 
Xb 
Tumor tissue 
(archival for 
Pre-Study is 
acceptable) for 
X 
X 
e 
X 
(optio 
nal) 


NCI Protocol #:9855 
Version Date:  April 2, 2018 
42 
 
 
 
GPNMB 
expression by 
IHC 
Optional 
correlative 
studies 
X 
X 
e 
X 
(optio 
nal) 
Documentation 
of vital status 
Xf 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, 
SGOT [AST], SGPT [ALT], sodium. 
b: 
Serum pregnancy test (women of childbearing potential). 
c: 
To be performed within 30 days of last treatment dose. 
d: 
Cycle 2 and beyond infusions and assessments have a window of +/- 3 
days. If treatment is delayed, labs and other assessments are valid if performed 
within 3 days of treatment. 
e: 
On-treatment tumor biopsy can occur at the end of Week 3 just prior to 
beginning Cycle 2, +/- 3 days. 
f: 
Patients will be followed for at least 30 days after discontinuation of study 
treatment or until death, whichever comes first. Subsequently, vital status will be 
extracted from the medical chart or public records, where available. 
g. 
Subsequent cycles will have the same schedule as Cycle 4 
 
 
11. MEASUREMENT OF EFFECT 
 
 
11.1. 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with CDX-011 (glembatumumab vedotin). 


NCI Protocol #:9855 
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43 
 
 
 
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
 
Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in follow-up, 
only the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] 
short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic 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 non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 


NCI Protocol #:9855 
Version Date:  April 2, 2018 
44 
 
 
 
with the longest diameter), be representative of all involved organs, but in addition 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. 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. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 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 is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable. 
 
Conventional CT and MRI This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans have slice 
thickness greater than 5 mm (0.5 cm), 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). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 


NCI Protocol #:9855 
Version Date:  April 2, 2018 
45 
 
 
 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT 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 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. 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. 
 
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. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
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 (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. 
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 


NCI Protocol #:9855 
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46 
 
 
 
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. 
c. 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.  The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note: 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. 
 
Response Criteria 
Evaluation of Target Lesions 
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 (<1 cm). 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the 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 (0.5 cm). (Note: the appearance of one or more new lesions is 
also considered progressions). 
 
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. 
 
Evaluation of Non-Target Lesions 
 
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 [<1 cm] short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 


NCI Protocol #:9855 
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47 
 
 
 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesion
Non-
Target 
New 
Lesion
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non- 
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Confirmation not required for Protocol 9855. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 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 the objective 
progression even after discontinuation of treatment. 


NCI Protocol #:9855 
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48 
 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
 
 
11.2. 
Other Response Parameters 
N/A 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1. 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave. Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS). To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam) and the 


NCI Protocol #:9855 
Version Date:  April 2, 2018 
 
 
appropriate Rave role (Rave CRA, Read-Only, or Site Investigator) on either the Corresponding 
Organization or Participating Organization roster at the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e- 
mail at ctsucontact@westat.com. 
 
Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP). Information on CTMS reporting is available at: 
http://www.theradex.com/CTMS. On-site audits will be conducted on an 18-36 month basis as 
part of routine cancer center site visits. More frequent audits may be conducted if warranted by 
accrual or due to concerns regarding data quality or timely submission. For CTMS monitored 
studies, after users have activated their accounts, please contact the Theradex Help Desk at (609) 
799-7580 or by email at ctms@theradex.com for additional support with Rave and completion of 
CRFs. 
 
 
Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave. 
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks. The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS. Metrics for timeliness will be followed and assessed on a quarterly basis. 
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
49 


NCI Protocol #:9855 
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Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received. Queries will be issued by CTMS directly within Rave. The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve. Monthly web- 
based reports are posted for review by the Drug Monitors in the IDB, CTEP. Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics- 
resources/interoperability-and-semantics/metadata-and-models). Customized eCRFs will be 
included when appropriate to meet unique study requirements. The PI is encouraged to review 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation. CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex. CDUS submissions are performed by Theradex on a monthly 
basis. The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
12.2. 
CTEP Multicenter Guidelines 
N/A 
12.3. 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
50 


NCI Protocol #:9855 
Version Date:  April 2, 2018 
 
 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be 
maintained as such by the investigators. The protocol documents for studies utilizing Agents 
contain confidential information and should not be shared or distributed without the permission 
of the NCI. If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and use 
of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as "Multi-Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and 
unless additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non- 
51 


NCI Protocol #:9855 
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Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication. Collaborator(s) will have 30 days from the date of 
receipt for review. Collaborator shall have the right to request that publication be delayed for up 
to an additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, 
in addition to Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts 
must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as 
possible and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and other media 
presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, 
abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1. 
Study Design/Endpoints 
 
This trial is a single-arm, open-label Phase II study of CDX-011 (glembatumumab vedotin) in 
patients with metastatic uveal melanoma. The primary endpoint is overall response rate (ORR) 
using RECIST 1.1. Secondary endpoints include GPNMB expression, progression-free survival 
(PFS), overall survival (OS), safety and toxicity. Exploratory endpoints include characterizing 
the anti-tumor immunophenotype of patients receiving CDX-011 (glembatumumab vedotin) as 
well as post-hoc correlation of rash with PFS and ORR. Simon’s two-stage design will be used 
to monitor the primary endpoint. 
 
All patients who receive study drug will be eligible for evaluation of the primary endpoint of 
ORR. All patients who receive study drug will also be evaluated for secondary endpoints of 
PFS, OS, safety, toxicity, and GPNMB expression. 
 
Toxicity will be reported by type, frequency, and severity according to the NCI Common 
Toxicity Criteria v5.0. All patients who receive any amount of study drug will be evaluable for 
toxicity. 
 
13.2. 
Sample Size and Power /Accrual Rate 
 
The historical response rate to metastatic treatments in this population is 5%. We will target a 
24% ORR in GPNMB-positive patients. We expect the ORR in GPNMB-negative patients to be 
close to zero, and we assume 15% of uveal melanoma patients will be GPNMB-negative based 
on prior evidence.15 Thus, overall we will target a (0.24 * 85%) + (0 * 15%) = 20% ORR. We 
will use a Simon’s two-stage design.22   In the first stage, 18 evaluable patients will be enrolled 
52 


NCI Protocol #:9855 
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53 
 
 
 
and assessed for response. If no responses are seen, the study will stop and reject CDX-011 
(glembatumumab vedotin) for further study in this population. If at least 1 response is seen, the 
study will proceed with stage 2 where 14 additional patients will be enrolled and evaluated for 
response. For logistical purposes, after 18 patients have been enrolled, Stage 2 will not begin 
until at least one patient has experienced a response. At the end of the trial, if at least 4 patients 
have an objective response, the trial will be declared a success, and CDX-011 (glembatumumab 
vedotin) will be considered for future study. If 3 or fewer patients have an objective response, 
the drug will be rejected. 
 
If the true ORR is 5%, the probability that the study terminates after the first stage is 39.7%, and 
the probability that the drug is incorrectly considered for future study (Type I error) is 7.2%. If 
the true ORR is 20%, the probability that the drug is incorrectly rejected (Type II error) is 9.8% 
 
Patients will be enrolled at MD Anderson Cancer Center at an expected rate of 2-3 patients per 
month. 32 evaluable patients are needed for statistical analysis in Stage 1 and Stage 2. Allowing 
for attrition of patients who do not remain on study long enough to be evaluable for the primary 
endpoint, the maximum enrollment for this study will be 35 patients. 
 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
0 
0 
1 
0 
1 
White 
15 
17 
0 
1 
32 
More Than One Race 
0 
0 
0 
0 
0 
Total 
15 
18 
1 
1 
35 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
OMB No. 0925- 
0001/0002 


NCI Protocol #:9855 
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54 
 
 
 
 
 
13.3. 
Stratification Factors 
N/A 
13.4. 
Analysis of Secondary Endpoints 
 
Analysis of secondary endpoints will be exploratory and hypothesis-generating. For secondary 
endpoints, all eligible patients will be included in the analyses. 
 
GPNMB expression 
 
GPNMB IHC will be performed retrospectively on baseline tumor tissue in all patients included 
on study. GPNMB IHC will also be performed on tumor tissue on all patients at Day 21 on 
study. Changes in percentage of GPNMB-positive tumor cells will be reported and descriptive 
statistics will be used to further report staining intensity and frequency in baseline and on- 
treatment tumor samples. 
 
In testing the analytical performance and precision of GPNMB IHC, sections from 3 human 
melanoma tissues and 2 cell lines were stained in 6 replicates on a single batch and scored by one 
pathologist.  The differences in percentage of the stained cells ranged from 0-6%. 
 
Because samples from this study are going to be analyzed retrospectively in one batch and 
scored by the same pathologist, a change in GPNMB expression greater than 10% will be 
considered a positive signal. 
 
Progression-free survival (PFS) overall survival (OS). 
 
PFS and OS survival curves will be calculated using the method of Kaplan-Meier. Median PFS 
and OS will be reported with 95% confidence intervals. All patients who receive study drug will 
be followed for PFS and OS. 
 
Safety Analysis 
 
Toxicity will be reported by type, frequency, and severity according to the NCI Common 
Toxicity Criteria. 
 
Toxicity will be continuously monitored in all patients who receive study drug and reported in 
real time to the local PI as the study team is made aware. Toxicity will also be reviewed at 
monthly protocol meetings at each enrolling site. If multiple sites register patients, a monthly 
teleconference will be scheduled to review safety and toxicity in aggregate as well as patient 
outcomes. 


NCI Protocol #:9855 
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55 
 
 
 
 
13.5. 
Reporting and Exclusions 
Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with CDX-011 
(glembatumumab vedotin). 
 
Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of 
the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data). [Note: By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate. If a 
patient does not receive study drug, then he or she will not be evaluated for ORR, PFS, OS, 
GPNMB expression, safety, or toxicity and the position in statistical analysis will be replaced by 
an evaluable patient.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression). Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate. Precise 
definitions for categories 4-9 will be protocol specific. 
 
All conclusions should be based on all eligible patients. Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be provided. 


NCI Protocol #:9855 
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56 
 
 
 
REFERENCES 
 
1. Singh AD, Topham A. Survival rates with uveal melanoma in the United States: 1973-
1997. Ophthalmol. 2003; 110(5):962-65. 
2. Lorigan JG, Wallace S, Mavligit GM. The prevalence and location of metastases from 
ocular melanoma: imaging study in 110 patients. Am J Roentgenol. 1991; 157(6):1279-81. 
3. Collaborative Ocular Melanoma Study Group. Assessment of metastatic disease status at 
death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma 
Study (COMS): COMS report no. 15. Arch Ophthalmol 2001; 119(5):670-6. 
4. Collaborative Ocular Melanoma Study Group. Development of metastatic disease after 
enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular 
Melanoma Study (COMS) Group Report No. 26. Arch Ophthalmol. 2005; 123(12):1639-43. 
5. Sato T, Han F, Yamamoto A. The biology and management of uveal melanoma. Curr Oncol 
Rep. 2008; 10(5):431-8. 
6. Mariani P, Piperno-Neumann S, Servois V, Berry MG, Dorval T, Plancher C et al. Surgical 
management of liver metastases from uveal melanoma: 16 years' experience at the Institut 
Curie. European journal of surgical oncology : the journal of the European Society of 
Surgical Oncology and the British Association of Surgical Oncology. 2009; 35(11):1192-7. 
7. Bedikian AY, Legha SS, Mavligit G, Carrasco CH, Khorana S, Plager C et al. Treatment of 
uveal melanoma metastatic to the liver: a review of the M. D. Anderson Cancer Center 
experience and prognostic factors. Cancer. 1995; 76(9):1665-70. 
8. Bedikian AY, Papadopoulos N, Plager C, Eton O, Ring S. Phase II evaluation of 
temozolomide in metastatic choroidal melanoma. Melanoma research. 2003; 13(3):303-6. 
9. Vuoristo MS, Hahka-Kemppinen M, Parvinen LM, Pyrhonen S, Seppa H, Korpela M et al. 
Randomized trial of dacarbazine versus bleomycin, vincristine, lomustine and dacarbazine 
(BOLD) chemotherapy combined with natural or recombinant interferon-alpha in patients 
with advanced melanoma. Melanoma research. 2005; 15(4):291-6. 
10. Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR et al. 
Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a 
randomized clinical trial. JAMA 2014; 311(23): 2397-2405. 
11. Hofmann UB, Kauczok-Vetter CS, Houben R, Becker JC. Overexpression of the KIT/SCF in 
uveal melanoma does not translate into clinical efficacy of imatinib mesylate. Clinical cancer 
research : an official journal of the American Association for Cancer Research. 2009; 
15(1):324-9. 
12. Mahipal A, Tijani L, Chan K, Laudadio M, Mastrangelo MJ, Sato T. A pilot study of 
sunitinib malate in patients with metastatic uveal melanoma. Melanoma research. 2012; 
22(6):440-6. 
13. Tse KF, Jeffers M, Pollack VA, McCabe DA, Shadish ML, Khramtsov NV, et al. CR011, a 
fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma. 
Clin Cancer Res. 2006; 12(4):1373-82. 
14. Qian X, Mills E, Torgov M, LaRochelle WJ, Jeffers M. Pharmacologically enhanced 
expression of GPNMB increases the sensitivity of melanoma cells to the CR011-vcMMAE 
antibody-drug conjugate. Mol Oncol. 2008; 2(1):81-93. 
15. Williams MD, Esmaeli B, Soheili A, Simantov R, Gombos DS, Bedikian AY, Hwu P. 
GPNMB expression in uveal melanoma: a potential for targeted therapy. Melanoma 


NCI Protocol #:9855 
Version Date:  April 2, 2018 
57 
 
 
 
Research 2010; 20:184–190. 
16. Naumovski L, Junutula JR. Glembatumumab vedotin, a conjugate of an anti-glycoprotein 
non- metastatic melanoma protein B mAb and monomethyl auristatin  E  for the 
treatment of melanoma and breast cancer. Curr Opin Mol Ther. 2010; 12(2):248-57. 
17. Pollack VA, Alvarez E, Tse KF, Torgov MY, Xie S, Shenoy SG, et al. Treatment parameters 
modulating regression of human melanoma xenografts by an antibody-drug conjugate 
(CR011- vcMMAE) targeting GPNMB. Cancer Chemother Pharmacol. 2007; 60(3):423-35. 
18. Ott PA, Hamid O, Pavlick AC, Kluger H, Kim KB, Boasberg PD et al. Phase I/II Study of 
the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients With Advanced 
Melanoma. J Clin Oncol. 2014; 32(32):3659-66. 
19. Bendell J, Saleh M, Rose AA, Siegel PM, Hart L, Sirpal S et al. Phase I/II study of the 
antibody-drug conjugate glembatumumab vedotin in patients with locally advanced or 
metastatic breast cancer. J Clin Oncol. 2014; 32(32):3619-25. 
20. Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR et al. BRAF 
inhibition is associated with enhanced melanoma antigen expression and a more favorable 
tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013; 
19(5):1225-31. 
21. Cooper ZA, Juneja VR, Sage PT, Frederick DT, Piris A, Mitra D et al. Response to BRAF 
inhibition in melanoma is enhanced when comined with immune checkpoint blockade. 
Cancer Immunol Res. 2014; 2(7):643-54. 
22. Thall PF, Simon R, Ellenberg SS, Shrager R. Optimal two-stage designs for clinical trials 
with binary response. Stat Med. 1988; 7(5):571-9. 


NCI Protocol #:9855 
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58 
 
 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
5 
Dead. 


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APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers and 
Non-Study Healthcare Team 
 
The patient 
is enrolled on a clinical trial using the 
experimental agent CDX-011 (glembatumumab vedotin). This clinical trial is sponsored by 
the National Cancer Institute. This form is addressed to the patient, but includes important 
information for others who care for this patient. 
 
CDX-011 (glembatumumab vedotin) interacts with many drugs that are processed by your liver. 
Because of this, it is very important to tell your study doctors about all of your medicine before 
you start this study. It is also very important to tell them if you stop taking any regular medicine, 
or if you start taking a new medicine while you take part in this study. When you talk about your 
medicine with your study doctor, include medicine you buy without a prescription at the drug 
store (over-the-counter remedy), or herbal supplements such as St. John’s wort. 
 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet. These are 
the things that you and they need to know: 
 
CDX-011 (glembatumumab vedotin) interacts with (a) certain specific enzyme(s) in your liver. 
• The enzyme(s) in question is/are CYP3A4, and CDX-011 (glembatumumab vedotin) is 
broken down by this enzyme in order to be cleared from your system. 
• CDX-011 (glembatumumab vedotin) must be used very carefully with other medicines 
that need these liver enzymes to be effective or to be cleared from your system. 
• Other medicines may also affect the activity of the enzyme. 
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
• You and healthcare providers who prescribe drugs for you must be careful about adding 
or removing any drug in this category. 
• Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
CYP3A4. 
• Your prescribers should consult a medical reference to see if any medicine they want to 
prescribe is on a list of drugs to avoid. 
• Please be very careful! Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye. They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list. Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction. 


60 
NCI Protocol #:9855 
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• Be careful: 
o If you take acetaminophen regularly: You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age. 
Read labels carefully! Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit: Avoid these until the study is over. 
o If you take herbal medicine regularly: You should not take St. John’s wort while 
you are taking CDX-011 (glembatumumab vedotin). 
o If you take the blood thinner warfarin. INR levels may be affected by 
concomitant administration of warfarin with CDX-011 (glembatumumab 
vedotin). Additionally, the effectiveness of CDX-011 (glembatumumab vedotin) 
may be affected by warfarin metabolism. 
o If you take antifungals such as ketoconazole as these medicines lead to decreased 
levels of CDX-011 (glembatumumab vedotin) and may result in decreased anti- 
tumor activity. 
 
Other medicines can be a problem with your study drugs. 
 
• You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement. 
 
• Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you. Your study 
doctor’s name is 
 
 
 
 
 
 
and he or she can be contacted at 
 
  
. 


61 
NCI Protocol #:9855 
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INFORMATION ON POSSIBLE DRUG 
INTERACTIONS 
You are enrolled on a clinical trial using the 
experimental agent CDX-011 
(glembatumumab vedotin).  This clinical 
trial is sponsored by the NCI.  CDX-011 
(glembatumumab vedotin) interacts with 
drugs that are processed by your liver. 
Because of this, it is very important to: 
 Tell your doctors if you stop taking 
CDX-011  (glembatumumab vedotin) 
interacts with a specific liver enzyme called 
CYP3A4 and must be used very carefully with 
other medicines that interact with this enzyme. 
 Before you start the study, your study 
doctor will record any medicines you take 
that are considered “strong 
inducers/inhibitors or substrates of 
CYP3A4.” 
 Before prescribing new medicines, your 


NCI Protocol #:9855 
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APPENDIX C ADULT HYPERSENSITIVITY/ALLERGIC REACTION 
MANAGEMENT ALGORITHM 
 
 


NCI Protocol #:9855 
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63 
 
 
 
 


NCI Protocol #:9855 
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64 
 
 
 
 


NCI Protocol #:9855 
Version Date: April 2, 2018 
 
 
 
 
 
 
 
 
1.0 
PURPOSE 
 
This instructional guide is supplied to facilitate the proper acquisition and handling of human tissue 
specimens for shipment to Mosaic Laboratories for NCI clinical trial P9855/CDX011-51. These 
instructions define the types of specimens, how to process the specimen samples, and how to ship 
the samples to Mosaic Laboratories. 
 
2.0 
SCOPE 
 
This instructional guide pertains to institutions enrolling subjects who have given consent to obtain 
specimens for the study P9855/ CDX011-51. The specimens are to be sent to Mosaic Laboratories. 
These procedures and guidelines should be followed to ensure that only high quality human 
specimens are obtained. Any personnel involved with the processing of these specimens should 
read, understand and follow these instructions. 
 
3.1 
MATERIALS PROVIDED BY MOSAIC LABORATORIES 
 
• 
Specimen Submittal Form (Appendix A) 
 
4.1 
MATERIALS PROVIDED BY SITE 
 
• 
At least 10 positive-charged glass slides 
• 
Shipping Materials 
• 
Microtome 
• 
Blade 
• 
Waterbath 
 
5.0 
SPECIMEN PREPARATION 
 
5.1 
Only specimens obtained from a patient being screened for inclusion into and/or 
participating in CDX011-51 / P9855 and consented to specimen collection may be 
submitted to Mosaic Laboratories. 
 
5.2 
Obtain and handle human paraffin material using standard of care technique and universal 
precautions. Appropriate care should be taken to preserve the integrity of the samples. 
 
6.0 
PROCEDURE FOR ARCHIVAL TUMOR SECTIONING 
 
6.1 
Ten (10) sections should be cut at 4 to 5 microns using a clean waterbath. Do not add any 
adhesives to the waterbath. Please use positively-charged slides. 
 
 
65 
INSTRUCTION MANUAL 
CDX011-51 / P9855 
Archival Tumor Sample Collection 
Mosaic Laboratories 
Attention: Clinical Trials 
12 Spectrum Pointe Drive 
Lake Forest, CA 92630 
Phone:     (949) 340-7598 
Fax: 
(949) 340-7330 
clinicaltrials@mosaiclabs.com 
CLIA ID# 05D1059086 
Eric Olsen, M.D. Medical Director 
APPENDIX D INSTRUCTION MANUAL AND SPECIMEN SUBMISSION FORM 


NCI Protocol #:9855 
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66 
 
 
 
6.1.1 
Clean waterbath: A kimwipe should be placed on top of the water to collect any 
remaining fragments of tissue and paraffin in between each sample. This will help 
to prevent any carryover of other tissue that might stick to the slide. 
 
6.1.2 
Please ensure that each specimen submitted contains predominantly tumor tissue. 
 
6.1.3 
Position the section in the center of the slide, one section per slide. 
 
6.1.4 
Drain excess water from slide by standing slide vertically on a paper towel until 
water runs down to the bottom. 
 
6.1.5 
Gently tap slide on paper towel to remove any excess water. 
 
6.1.6 
Slides should air dried only. 
 
6.1.7 
Provide 10 slides for analysis. 3-4 slides will be used for prospective IHC staining 
and 6-7 slides will be retained for retrospective PCR analysis to assess correlation 
between IHC and PCR methods of gpNMB detection. In cases where 10 slides 
are not available, at least 4 slides must be submitted for analysis. 
 
6.2 
The corresponding Pathology Report must be submitted along with every specimen, 
labeled with the Subject number and the Block ID. 
 
6.2.1 
Pathology specimens without an accompanying Pathology Report are considered 
incomplete. Ensure the local pathology accession number (block ID) is visible and 
legible on the tumor block or specimen submission and that slides are labeled with 
the block ID of the originating block. 
 
6.2.2 
Circle or underline the pathology accession number and block ID on the pathology 
report for the pathology specimens submitted. Submit a copy of the corresponding 
Pathology Report. 
 
6.2.3 
Black out the subject identifiers on the pathology report such as name, address 
and social security number. DO NOT: black out/remove information such as 
pathology accession number, date of birth, age, date of specimen collection, etc. 
Verify that the pathology accession number and block ID has been circled or 
underlined on the report. 
 
6.3 
Patient Identification for slides 
 
6.3.1 
All slides made from the block should be labeled with the local pathology accession 
number (Block ID), date slides were cut (if space permits), subject number, patient 
DOB, and patient initials (not the patient name). Unlabeled slides will be rejected. 
 
7.0 
DOCUMENTATION 
 
7.1 
Specimen Submittal Form 
 
7.1.1 
Ensure each specimen is appropriately labeled. 
 
7.1.2 
Complete one Specimen Submittal Form per specimen. 
 
7.1.3 
FAX or email as directed on the form. 


NCI Protocol #:9855 
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67 
 
 
 
7.1.4 
Include a copy of the pathology report for each block (if available). 
 
7.1.5 
Complete a shipping Airbill (not provided). The tracking number will need to be 
manually written on the Specimen Submittal Form. 
 
8.0 
PACKAGING AND SHIPPING ARCHIVAL TUMOR SLIDES 
 
8.1 
NOTE: Tumor samples should be shipped on Monday through Friday using overnight 
shipping. Tumor Tissue may be shipped for Saturday Delivery. Mosaic Laboratories does 
not accept deliveries on the following US holidays: New Year’s Day, Memorial Day, 
Independence Day, Labor Day, Thanksgiving Day, and Christmas Day. 
 
8.2 
Complete the Specimen Submittal Form (Appendix A) to accompany the slides. 
 
8.3 
Fax or email the completed Specimen Submittal Form (Appendix A) to Mosaic 
Laboratories. (fax number: 949-340-7330; email: clinicaltrials@mosaiclabs.com). 
 
8.3.1 
IMPORTANT: For tracking purposes, email or fax the Specimen Submittal Form 
(Appendix A) the day the samples are sent. 
 
8.4 
Package and ship samples in accordance with institutional procedures. The shipping 
address is: 
 
Mosaic Laboratories 
Attention: Clinical Trials (CDX011-51 / P9855) 
12 Spectrum Pointe Drive 
Lake Forest, CA 92630 
 
8.5 
Please use frozen gel packs in cases of extreme heat. 
 
8.5.1 
Ensure the gel packs have been frozen for at least 24 hours. 
 
8.5.2 
All slide samples and paraffin blocks should be shipped ambient. However during 
extreme heat (e.g. ambient temperature exceeding 90˚F or during warm summer 
months), samples should be shipped with a cold pack placed inside the box, 
between the instruction panel and the box lid. 
 
8.6 
While waiting for pick-up, packages should be protected from temperature fluctuations 
(direct sunlight or outside loading docks), as fluctuations in temperature may affect 
immunostaining results. 
 
9.0 
QUESTIONS 
 
9.1 For questions  relating to sample collection, please call  Mosaic  Laboratories  (949-340- 
7598) or email clinicaltrials@mosaiclabs.com and reference your clinical trial (CDX011-51 
/ P9855).  The project manager for this study is Lisa Dauffenbach (primary). 
 
10.0 
REPORTING RESULTS 
 
10.1 Samples will be analyzed in batches at Mosaic Laboratories. Mosaic Laboratories will 
provide gpNMB staining results to MD Anderson (lead investigator) upon request. 


NCI Protocol #:9855 
Version Date: April 2, 2018 
68 
 
 
 
10.1.1 If the tissue does not contain tumor, the site will be notified immediately so that 
additional tissue may be procured. 


NCI Protocol #:9855 
Version Date: April 2, 2018 
 
 
 
INSTRUCTION MANUAL 
CDX011-51 / P9855 
Archival Tumor Sample Collection 
Mosaic Laboratories 
Attention: Clinical Trials 
12 Spectrum Pointe Drive 
Lake Forest, CA 92630 
Phone:    (949) 340-7598 
Fax: 
(949) 340-7330 
clinicaltrials@mosaiclabs.com 
CLIA ID# 05D1059086 
Eric Olsen, M.D. Medical Director 
 
Appendix A: Specimen Submittal Form 
Please complete form and FAX or Email to: 
FAX: (949) 340-7330; Email: clinicaltrials@mosaiclabs.com 
Please include the following in the subject line: CDX011-51 / P9855 
 
 
SITE TO COMPLETE THIS SECTION; COMPLETE ONE FORM PER SPECIMEN 
 
 
 
HUMAN SUBJECT INFORMATION 
Site / Subject Number 
Date of Birth 
  
  
 - 
 
 
-    
  
 
Subject 
Initials 
  
- 
- 
Gender 
Male 
Female 
Day 
Month (3 letters) 
Year 
First – Middle - Last 
CLINICAL SITE INFORMATION 
Primary Contact (Name / Phone / Email): 
Address: 
TUMOR SAMPLE AND SHIPPING INFORMATION 
Tissue Slides; Qty: 
 
(Minimum of 10, positive 
charged required) 
Pathology 
Report 
included? 
Ye
s 
Block ID or Slide ID 
Timeframe of Tissue 
Collection: 
Archival 
Tumor 
Type 
Uveal 
Melanoma 
Tumor 
Site 
Primary 
Metastatic 
Body Site 
Collection 
Date 
Collection 
Method 
Core biopsy 
Excision biopsy 
Resection 
Other specify: 
 
_ 
Date of Sectioning 
Comments 
Shipping Condition: 
Date of Shipment 
Tracking Number 
Person Responsible 
 
 
MOSAIC LABORATORIES TO COMPLETE THIS SECTION 
 
 
 
69 


NCI Protocol #:9855 
Version Date:  April 2, 2018 
 
 
SPECIMEN RECEIPT & PROCESSING 
Specimen Condition: 
 Good  Other:   
  
Mosaic ID:   
  
Shipper Kit Contents: 
Date/Time/Initials Processed: 
Comments: 
QC 
Initials/Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
70