Conditions: Recurrent Osteosarcoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: no

Brief summary:
This phase II trial studies how well glembatumumab vedotin works in treating patients with osteosarcoma that has come back (recurrent) or does not respond to treatment (refractory). Monoclonal antibodies, such as glembatumumab vedotin, may find tumor cells and help kill them.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate whether CDX-011 (glembatumumab vedotin) therapy either increases the disease control rate at 4 months in patients with recurrent measurable osteosarcoma as compared to an historical Children's Oncology Group (COG) experience or produces an objective response rate in patients without previous eribulin (eribulin mesylate) treatment.

SECONDARY OBJECTIVES:

I. To assess the feasibility and toxicity profile of CDX-011 in patients with recurrent osteosarcoma.

II. To describe the pharmacokinetics of CDX-011 in adolescents and young adults with recurrent osteosarcoma enrolled at COG sites and COG phase I consortium sites only.

III. To determine if there is a relationship between tumor GPNMB expression by immunohistochemistry (IHC) and response to CDX-011 therapy.

IV. To estimate, in the cohort of patients previously treated with eribulin, the proportion who will experience disease progression during the first 4 months of CDX-011 therapy and the proportion of patients who experience a Response Evaluation Criteria in Solid Tumors (RECIST)-defined complete or partial response.

OUTLINE:

Patients receive glembatumumab vedotin intravenously (IV) over 90 minutes on day 1. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Arms:
arm 1: Patients receive glembatumumab vedotin IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 18 courses 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_000.pdf: 
  
 
i 
 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Kristin Coffan 
coffank@email.chop.edu 
 
Group Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
September 6, 2016 
 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
The Study Committee for AOST1521, A Phase 2 Study of GPNMB-targeted Antibody-Drug 
Conjugate, CDX-011 (Glembatumumab Vedotin, CR011-vcMMAE; IND# 128248, NSC# 
763737), in Recurrent or Refractory Osteosarcoma, has provided Amendment #1 for CTEP 
review.  
 
This amendment is being submitted in response to Request for Rapid Response (RRA) from 
Dr. Jeff Moscow (Jeffery.moscow@nih.gov). Revisions to the protocol are detailed in the 
pages below.  
 
The AOST1521 study committee looks forward to approval of this amendment. Please 
contact me with any questions or concerns. 
 
 
Sincerely,  
 
 
Meg Stahlman, Protocol Coordinator (for)  
Lisa Kopp, DO, AOST1521 Study Chair 
Peter Adamson, MD, Children’s Oncology Group Chair 


 
 
 
 
 
 
 
AOST1521 
ii 
 
SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the protocol. 
Additions are in boldfaced font and deletions in strikethrough font. 
# 
Section 
Page(s) 
Change 
1. 
Title Page 
1 
Version date updated and Amendment number updated. . 
2. 
6.1 
 
Drug monograph revised to use CDX-011 in the title to match the new 
CAEPR. The date has been updated. 
 
Insertion of revised CAEPR (Version 2.1, August 3, 2016) which includes 
an added new risk: 
• 
  
 
 
 
 
SUMMARY OF CHANGES: CONSENT DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the protocol. 
Additions are in boldfaced font and deletions in strikethrough font. 
# 
Section 
Page(s) 
Change 
1. 
Throughout 
1 
Version date updated. . 
2. 
Risks of 
Study 
6 
Added New Risks: 
• 
Rare: Blood clot which may cause swelling, pain, 
shortness of breath;  
• 
Rare: Swelling and redness at the site of the medication 
injection 
 
 


 
 
 
 
 
 
 
AOST1521 
1 
Version date: 09/06/16 
 
Activated: 
02/16/16 
Version Date: 
09/06/16 
Closed: 
      
Amendment: 
#1 
 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
AOST1521 
 
 
A Phase 2 Study of GPNMB-targeted Antibody-Drug Conjugate, CDX-011 (Glembatumumab 
Vedotin, CR011-vcMMAE; IND# 128248, NSC# 763737), in Recurrent or Refractory 
Osteosarcoma 
 
 
 
An Intergroup NCTN Phase 2 Study 
 
NCI Supplied Agent: CDX-011 (IND# 128248, NSC# 763737) 
 
IND Sponsor for CDX-011: DCTD, NCI 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY 
OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO 
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY.  RESEARCH MEANS A 
SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO 
DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY 
THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY QUESTIONS 
AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED 
MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT.  THE PROCEDURES IN THIS PROTOCOL 
ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT 
PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED 
TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR 
HEALTHCARE INSTITUTION. 
 
 
 
STUDY CHAIR 
 
Lisa M. Kopp, DO 
The University of Arizona Medical Center 
1501 North Campbell Avenue, Room 534 
Tucson, AZ 85724 
Phone: (520) 626-2021 
E-mail: lkopp@peds.arizona.edu 
 
 
 
 


 
 
 
 
 
 
 
AOST1521 
2 
Version date: 09/06/16 
 
 
Participating Organizations 
 
COG / Children's Oncology Group 
 
ALLIANCE / Alliance for Clinical Trials in Oncology 
 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
 
NRG / NRG Oncology  
 
SWOG / SWOG 
 
 
CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory 
documents only) 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which 
can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Please see the 
Data Submission Schedule in the 
CRF packet for further 
instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Access to the 
CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and Access 
Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username and 
password. Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead Protocol 
Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence 
will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 


 
 
 
AOST1521 
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Version date: 09/06/16 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
1.1 
Primary Aims 
9 
1.2 
Secondary Aims 
9 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development 
9 
2.2 
Preclinical Studies 
10 
2.3 
Adult Studies 
11 
2.4 
Pediatric Studies 
13 
2.5 
Dosing Rationale 
13 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
13 
3.1 
Study Enrollment 
13 
3.2 
Patient Eligibility Criteria 
16 
4.0 
TREATMENT PROGRAM 
20 
4.1 
Overview of Treatment Plan 
20 
4.2 
Therapy Delivery Map – CDX-011 
23 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
26 
5.1 
Definition of Toxicities 
26 
5.2 
Dose Modifications for Adverse Events 
27 
6.0 
DRUG INFORMATION 
32 
6.1 
GLEMBATUMUMAB VEDOTIN 
32 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
39 
7.1 
End of Therapy & Follow-up 
39 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
39 
8.1 
Criteria for Removal from Protocol Therapy 
39 
8.2 
Off Study Criteria 
40 
9.0 
STATISTICAL CONSIDERATIONS 
40 
9.1 
Sample Size and Study Duration 
40 
9.2 
Study Design 
40 
9.3 
Methods of Analysis for Pharmacokinetics (Aim 1.2.2) 
42 
9.4 
Evaluability for Disease Control and Response 
42 
9.5 
Evaluability for Toxicity 
43 
9.6 
Estimation of Disease Control and RECIST Response Rates 
43 
9.7 
Statistical Considerations for Secondary Aim 1.2.3 
44 
9.8 
Gender and Minority Accrual Estimates 
44 


 
 
 
AOST1521 
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Version date: 09/06/16 
10.0 
EVALUATION CRITERIA 
44 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
44 
10.2 
Response Criteria for Patients with Solid Tumors 
45 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
50 
11.1 
Purpose 
50 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
50 
11.3 
Specific Examples for Expedited Reporting 
50 
11.4 
Reporting Requirements for Specialized AEs 
52 
11.5 
Exceptions to Expedited Reporting 
53 
11.6 
Reporting Requirements - Investigator Responsibility 
53 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
54 
11.8 
Reporting Table for Late Phase 2 and Phase 3 Studies 
56 
11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
57 
11.10 Routine Reporting of Adverse Events 
57 
12.0 
STUDY REPORTING AND MONITORING 
57 
12.1 
CDUS 
57 
12.2 
Data and Safety Monitoring Committee 
57 
12.3 
CRADA/CTA 
57 
13.0 
SURGICAL GUIDELINES 
59 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
59 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
60 
15.1 
Tumor GPNMB Expression (mandatory participation) 
60 
 
 
61 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
64 
APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
69 
APPENDIX II:  YOUTH INFORMATION SHEETS 
71 
APPENDIX III:  POSSIBLE DRUG INTERACTIONS 
73 
APPENDIX IV:  PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
74 
REFERENCES 
76 
 
 
 


  
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STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Lisa M. Kopp, DO 
Brenda J. Weigel, MD 
Hematology/Oncology 
Hematology/Oncology 
The University of Arizona Medical Center 
University of Minnesota/Masonic Cancer Center 
1501N. Campbell Ave., Room 534 
420 Delaware Street, SE, MMC 366 
Tucson, AZ 85724 
Minneapolis, MN 55455 
Phone: (520) 626-2021 
Phone: (612) 626-5501 
Email: lkopp@peds.arizona.edu 
Fax: 
(612) 624-3913 
 
Email: weig007@umn.edu 
STUDY VICE CO-CHAIR 
 
Katherine Janeway, MD 
Lisa A. Teot, MD 
Hematology/Oncology 
Pathology 
Dana Farber Cancer Institute 
Dana-Farber Cancer Institute 
450 Brookline Ave Street, Dana 3 
300 Longwood Avenue Bader 110 
Boston, MA 02215 
Boston, MA 02115 
Phone: (617) 632-4994  
Phone: (857) 218-4962 
Fax: 
(617) 632-5710 
Fax: 
(617) 730-0207 
E-mail: katherine_janeway@dfci.harvard.edu 
Email: lisa.teot@childrens.harvard.edu 
 
 
STUDY VICE CO-CHAIR 
Justin Cates, MD PhD 
Suman Malempati, MD 
Pathology 
Hematology/Oncology 
Vanderbilt University/Ingram Cancer Center 
Oregon Health and Science University 
1161 21st Avenue South, MCN C-3322 
3181 SW Sam Jackson Park Road 
Nashville, TN 37232 
Portland, OR 97239 
Phone: (615) 936-6694  
Phone: (503) 494-1543  
Fax: 
(615) 322-0511 
Fax: 
(503) 494-0714 
E-mail: justin.m.cates@vanderbilt.edu 
E-mail: malempat@ohsu.edu 
 
 
Amy R. Newman, RN 
STUDY STATISTICIAN 
Nursing 
Mark Krailo, PhD 
Midwest Children’s Cancer Center 
Biostatistics 
9000 W. Wisconsin Ave. 
Children’s Oncology Group 
Milwaukee, WI 53201 
222 E. Huntington Dr., Suite 100 
Phone: (414) 266-6931 
Monrovia, CA. 91016 
Fax: 
(414) 266-3058 
Phone: (626) 241-1529      
E-mail: anewman@chw.org 
Fax: 
(626) 445-4334     
 
E-mail: mkrailo@childrensoncologygroup.org 
Victor M. Villalobos, MD, PhD 
 
University of Colorado Denver 
STUDY COMMITTEE MEMBERS 
1665 Aurora Ct., ACP Rm. 5329 MS F704 
Richard G. Gorlick, MD 
Aurora, CO 80045 
Hematology/Oncology 
Phone: (720) 848-0467 
Montefiore Medical Center – Moses Campus 
Fax: 
(720) 848-1413 
Section of Pediatric Hematology/Oncology 
Email: victor.m.villalobos@ucdenver.edu 
3415 Bainbridge Ave, Rosenthal 3rd floor 
 
Bronx, NY. 10467 
 
Phone: (718) 741-2342      
 
Fax: 
(718) 920-6506     
 
E-mail: rgorlick@montefiore.org      
 
 
 
 
 


  
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STUDY COMMITTEE MEMBERS 
RESEARCH COORDINATOR 
Joel M. Reid, PhD 
Justin Davis 
Mayo Clinic 
Children’s Oncology Group 
200 First Street SW, 19-365 Gonda Building 
Statistics & Data Center 
Rochester, MN 55905 
222 E. Huntington Drive, Suite 100 
Phone: (507) 284-0822  
Monrovia, CA 91016 
Fax: 
(507) 284-3906 
Phone: (626) 241-1509 
E-mail: reid.joel@mayo.edu 
Fax: 
(626) 447-2204 
 
Email: jdavis@childrensoncologygroup.org 
Robert Lor Randall, MD FACS 
 
Surgery 
PROTOCOL COORDINATOR 
Primary Children’s Hospital 
Meg Stahlman 
200 Circle of Hope Drive, Room 4262 
Children’s Oncology Group 
Salt Lake City, UT 84112 
Study Development Office 
Phone: (801) 585-0300 
222 E. Huntington Dr., Suite 100 
Fax: 
(801) 585-7084 
Monrovia, CA. 91016 
Email: r.lor.randall@hci.utah.edu 
Phone: (626) 241-1626 
 
Fax: 
(626) 445-4334 
Grace Lin, PharmD 
E-mail: mstahlman@childrensoncologygroup.org 
Pharmacy 
 
Lucile Packard Children’s Hospital Stanford University 
 
725 Welch Road 
 
Palo Alto, CA 94304 
 
Phone: (650) 497-8776 
 
Email: glin@lpch.org 
 
 
 
Alisa Eicher, BS CCRP 
 
Clinical Research Associate 
 
Oregon Health and Science University 
 
3181 SW Sam Jackson Park Rd. 
 
Portland, OR 97239-3098 
 
Phone: (503) 418-5336 
 
Fax: 
(503)418-5337 
 
Email: eichera@ohsu.edu 
 
 
AGENT 
 
NSC# 
 
IND# 
 
CDX-011 
 
763737  
128248 
 
IND sponsor for CDX-011: DCTD, NCI 
 
SEE SECTION 15.0 FOR SPECIMEN SHIPPING ADDRESSES 
 
 


  
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AOST1521 
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Version date: 09/06/16 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies.  
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings.  However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances.  For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others 
 
 
ABSTRACT 
The prognosis of patients with recurrent or refractory osteosarcoma remains poor, with 10-year overall 
survival rates around 20%. Given the continued poor prognosis in this group of patients, novel treatment 
strategies are needed. There are no standard chemotherapeutic agents or targeted therapies proven to 
prolong survival in recurrent osteosarcoma. Glycoprotein non-metastatic B (GPNMB) is a type I 
transmembrane glycoprotein that is normally expressed in a variety of cell types including osteoblasts and 
osteoclasts, dendritic cells, macrophages, hematopoietic cells, melanocytes and keratinocytes. Aberrant and 
over expression of GPNMB has been demonstrated in a variety of cancers including osteosarcoma. GPNMB 
is predominantly expressed on the cell surface of malignant cells, whereas in normal tissues it is generally 
restricted to intracellular compartments. This unique expression pattern makes GPNMB an attractive target 
for antibody drug conjugate (ADC) targeted therapy. CDX-011 is an ADC directed against GPNMB. It is 
comprised of a fully-human IgG2 monoclonal antibody (CR011) conjugated to the potent microtubule 
inhibitor, monomethyl auristatin E (MMAE), via a protease-sensitive valine-citrulline peptide linker and p-
aminobenzoic acid (PABA) spacer. CDX-011 is theorized to exert its antitumor activity by selectively 
delivering the potent cytotoxin MMAE to GPNMB-expressing tumor cells. Pre-clinical data suggest that 
CDX-011 may have anti-tumor activity in osteosarcoma. In this Phase 2 study, eligible patients between 
the ages of 12 months and 50 years with unresected, recurrent or refractory osteosarcoma will receive CDX-
011, administered once every 21 days for up to 14 months. Progression free survival and response to therapy 
will be assessed. In addition, the tolerability and pharmacokinetic (PK) disposition of CDX-011 will be 
evaluated. 
 
 
 


  
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
Off Protocol 
Therapy 
Glembatumumab vedotin* 
Continue for up to 14 months in total 
or 18 cycles, whichever occurs first 
End Protocol 
Therapy 
Cycle 5-6 
Glembatumumab 
vedotin* 
Evaluation 
Evaluation 
Study Entry 
Evaluation 
Progressive Disease or 
Unacceptable Toxicity 
Unresected Recurrent or 
Refractory Osteosarcoma 
Cycle 3-4 
Glembatumumab 
vedotin* 
Evaluation following 
every 3rd cycle 
Cycle 1-2 
Glembatumumab 
vedotin* 
Off Protocol 
Therapy 
*Glembatumumab vedotin will be given on Day 1 of each 21-day cycle 
 
Note: Patients who undergo surgical resection of or radiation to any site of measurable disease prior 
to completion of the 6th cycle of therapy will be taken off protocol therapy. 
 
Progressive Disease or 
Unacceptable Toxicity 


  
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Aims 
 
1.1.1 
To estimate whether CDX-011 therapy either improves the disease control rate at 
4 months in patients with recurrent measurable osteosarcoma as compared to an 
historical COG experience or produces an objective response rate in patients 
without previous eribulin treatment. 
 
1.2 
Secondary Aims 
 
1.2.1 
To assess the feasibility and toxicity profile of CDX-011 in patients with recurrent 
osteosarcoma. 
 
1.2.2 
To describe the pharmacokinetics of CDX-011 in adolescents and young adults 
with recurrent osteosarcoma enrolled at COG sites and COG Phase 1 Consortium 
sites only. 
 
1.2.3 
To determine if there is a relationship between tumor GPNMB expression by IHC 
and response to CDX-011 therapy. 
 
1.2.4 
To estimate, in the cohort of patients previously treated with eribulin, the 
proportion who will experience disease progression during the first 4 months of 
CDX-011 therapy and the proportion of patients who experience a RECIST-
defined complete or partial response. 
 
 
2.0 
BACKGROUND 
2.1 
Introduction/Rationale for Development 
The outcome of patients with newly diagnosed, localized osteosarcoma improved 
following the addition of multi-agent chemotherapy to complete surgical resection.1,2 
Current results in contemporary cooperative group studies reveal 3-year event-free survival 
(EFS) ranging between 50-75%.3-6 Cisplatin7,8 and doxorubicin9,10 are the most active 
agents, and standard chemotherapy includes the use of these two agents alone5,11 or in 
combination with high-dose methotrexate6,12 and/or ifosfamide.4,12-14 The prognosis is poor 
for the 30-40% of patients who develop recurrent disease,15 as well as for those with 
clinically detectable metastases at the time of initial diagnosis6,13,16 with 2-year survival 
rates of 20-30%.4,6,13,16-21  
 
The aggregate EFS for patients with recurrent osteosarcoma enrolled on seven closed Phase 
2 studies from the COG or its predecessor groups is poor, with an overall 12% EFS at 
4 months [95% CI: 6.0%-19%]. 
 
Due to the lack of progress seen in treatment of osteosarcoma over the past 25 years and 
overall poor prognosis for children, adolescents and young adults with recurrent or 
refractory osteosarcoma, novel treatment strategies are needed.  
 


  
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CDX-011 is an antibody drug conjugate (ADC) directed against Glycoprotein non-
metastatic B. The preclinical data that establishes the rationale for proceeding with a Phase 
2 evaluation in patients with relapsed or refractory osteosarcoma is described below.  
 
Glycoprotein non-metastatic B (GPNMB) as a therapeutic target: GPNMB (also known 
as osteoactivin, dendritic cell-heparin integrin ligand, or hematopoietic growth factor 
inducible neurokinin-1 type) is a type I transmembrane glycoprotein22-32 that is normally 
expressed in a variety of cell types including osteoblasts and osteoclasts, dendritic cells, 
macrophages, hematopoietic cells, melanocytes and keratinocytes.22-25,28,32-36 While its 
exact function in normal cells is not fully understood, it is thought to play a role in tissue 
repair, cellular adhesion, and regulation of cell growth and differentiation.23,33-38 Aberrant 
or overexpression of GPNMB has also been demonstrated in a variety of cancers including 
melanoma, breast cancer, glioma, hepatocellular carcinoma, and osteosarcoma.23,24,26-
29,31,32,39 In vitro and in vivo studies have demonstrated a role for GPNMB in T cell 
activation, osteoblast development, osteoclast differentiation and fibroblast differentiation. 
GPNMB over expression was demonstrated to increase tumor invasiveness and metastasis 
by promoting angiogenesis and decreasing apoptosis in breast cancer, glioma and 
hepatocellular carcinoma cell lines.23,25-30,32,33,40 GPNMB is predominantly expressed on 
the surface of malignant cells, whereas in normal tissues it is generally restricted to 
intracellular compartments. This unique expression pattern makes GPNMB an attractive 
target for ADC targeted therapy.25,27,32,39-42  
 
CDX-011: CDX-011 consists of a fully-human IgG2 monoclonal antibody (CR011) 
conjugated to the potent microtubule inhibitor, monomethyl auristatin E (MMAE) via a 
protease-sensitive valine-citrulline peptide linker and p-aminobenzoic acid (PABA) 
spacer. CDX-011 is theorized to exert its antitumor activity by selectively delivering the 
potent cytotoxin MMAE to GPNMB-expressing tumor cells. After intravenous (IV) 
administration, CDX-011 binds to GPNMB on the surface of tumor cells. Lysosome 
internalization of the CDX-011-GPNMB complex leads to the proteolytic cleavage of the 
valine-citrulline linker and the release of free MMAE into the cytoplasm. Microtubule 
inhibition by MMAE leads to cell cycle arrest and subsequently tumor cell death.  
 
Antitumor activity of CDX-011 has been demonstrated in xenograft models of melanoma, 
breast cancer, and osteosarcoma.23,27,31,34,38,43,44 Additionally, clinical efficacy was observed 
in adult breast cancer and melanoma trials, making CDX-011 an attractive agent for Phase 
2 testing in patients with osteosarcoma. A positive result in this study in addition to the 
results of other planned studies of CDX-011 will help inform the design of future clinical 
trials for patients with osteosarcoma. 
 
2.2 
Preclinical Studies  
The activity of CDX-011 in pediatric tumors was recently investigated through the 
Pediatric Preclinical Testing Program. GPNMB gene expression was evaluated in a variety 
of solid tumor and leukemia xenograft models. Given the consistent expression of GPNMB 
in the osteosarcoma xenografts, the in vivo anti-tumor activity was investigated in 6 female 
CB-17SC mice bearing osteosarcoma. The mice received 2.5 mg/kg of CDX-011 IV 
weekly for 3 doses, followed by 3 weeks of observation. Complete tumor responses were 
seen in 3/6 osteosarcoma xenografts. Of the 3 responding xenografts, 2 had the highest 
levels of GPNMB expression. The lowest GPNMB-expressing osteosarcoma xenograft had 
minimal response to CDX-011 treatment (Figure 1).23,45 GPNMB protein expression 
through immunohistochemistry and by enzyme-linked immunosorbent assay (ELISA) has 


  
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also been assessed in human osteosarcoma cell lines. Sixty-seven human osteosarcoma 
samples were tested and 92.5% of osteosarcoma samples expressed GPNMB. CDX-011 
induced cytotoxic effects in 74% of osteosarcoma cell lines and GPNMB protein levels 
correlated with CDX-011 in vitro cytotoxicity.46 
 
 
 
Figure 1. CDX-011 in vivo objective response activity for osteosarcoma models. Kaplan–Meier curves for EFS 
(left), median relative tumor volume graphs (center), and individual tumor volume graphs (right) are shown for 
selected lines. Treated (black lines), statistical significance (P values) of the difference between treated and 
control groups are included. 
 
2.3 
 
 
  
 
 
  
 
 
  
 
 


  
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In this trial a tumor sample to test for GPNMB expression by immunohistochemistry 
(IHC), similar to the previous breast cancer and melanoma clinical trials, will be required. 
This will allow us to determine if higher levels of GPNMB expression by IHC correlates 
with tumor response to CDX-011 in osteosarcoma patients. 
 


  
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2.4 
Pediatric Studies 
There are no data regarding the use of CDX-011 in children. Therefore, this trial will 
evaluate CDX-011 using a dosage and a schedule of administration that has been shown to 
be safe in patients with breast cancer and patients with melanoma. In order to assess the 
tolerability of this dose, 1.88 mg/kg rounded to 1.9 mg/kg, the first six children aged less 
than 18 years (‘younger patients’) who enroll on the trial will receive protocol therapy with 
close toxicity monitoring. Accrual of younger patients will temporarily be suspended after 
the sixth such patient is enrolled and these patients will be followed to ensure that there are 
not unanticipated toxicities. Accrual will resume at this dose if fewer than one-third of 
toxicity evaluable patients experience a DLT. We will continue to monitor closely for 
toxicities, as we do with all active COG Phase 2 trials. Enrollment of patients 18 years of 
age or older will continue during the evaluation of toxicity for younger patients. 
Pharmacokinetic studies are mandatory for the first 6 evaluable patients 14 years of age or 
less enrolled at any COG member institution. Consent for pharmacokinetic studies for any 
patient greater than 14 years of age and less than or equal to 21 years of age enrolled at any 
COG member institution is optional. PK sampling will not be sought for patients who are 
older than 21 years of age at the time of enrollment.  
 
2.5 
Dosing Rationale 
CDX-011 will be administered intravenously at a dose of 1.9 mg/kg over 90 minutes on 
Day 1 of each 3 week cycle. The half-life is 40 hours. This dosing is based on the dosing 
guidelines used in the Phase 1/2 trial in patients with localized and advanced metastatic 
breast cancer and stage III or IV melanoma. 
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
3.1 
Study Enrollment 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number.  
 
COG sites: This number is obtained via the COG Registry system once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help.   
 
Non-COG sites: Fax the patient registration information (demography) to the 
Cancer Trials Support Unit (CTSU) registrar at 1-888-691-8039. Sites may notify 
the registration office of an incoming fax by calling 1888-462-3009; the office 
hours are 9:00 – 5:30 pm Eastern Time, Monday – Friday. The CTSU registrar will 
then register the patient within the COG system on behalf of the institution and 
obtain a COG patient ID number. The CTSU registrar will provide the COG patient 
ID number to the site which can then enroll the patient in the OPEN system.  
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol.  
 


  
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Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and CTSU Registration Procedures including: how to download site 
registration documents; requirements for site registration, submission of regulatory 
documents and how to check your site’s registration status. 
 
3.1.2 
IRB Approval 
Sites must obtain IRB/REB approval for this protocol and submit IRB/REB 
approval and supporting documentation to the CTSU Regulatory Office before 
they can be approved to enroll patients. Allow 3 business days for processing. The 
submission must include a fax coversheet (or optional CTSU IRB Transmittal 
Sheet) and the IRB approval document(s). The CTSU IRB Certification Form may 
be submitted in lieu of the signed IRB approval letter. All CTSU forms can be 
located on the CTSU web page (https://www.ctsu.org). Any other regulatory 
documents needed for access to the study enrollment screens will be listed for the 
study on the CTSU Member’s Website under the RSS Tab.  
 
IRB/REB approval documents may be faxed (1-215-569-0206), 
E-mailed (CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory 
office.  
 
When a site has a pending patient enrollment within the next 24 hours, this is 
considered a “Time of Need” registration. For Time of Need registrations, in 
addition to marking your submissions as ‘URGENT’ and faxing the regulatory 
documents, call the CTSU Regulatory Helpdesk at: 1-866-651-CTSU. For general 
(non-regulatory) questions call the CTSU General Helpdesk at: 1-888-823-5923. 
 
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU 
members’ web site by entering credentials at https://www.ctsu.org. For sites under 
the CIRB initiative, IRB data will automatically load to RSS. 
 
Note: 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. This information will be provided to the CTSU Regulatory 
Office from the CIRB at the time the site’s Signatory Institution accepts the CIRB 
approval. 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 (ie, laboratory certifications, protocol-specific 
training certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
3.1.3 
Reservation Requirements 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps below. Reservations may be obtained 24 hours a day 
through the Oncology Patient Enrollment Network (OPEN) system.  
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system in OPEN. Prior to discussing 
protocol entry with the patient, site staff must use the CTSU OPEN Slot 


  
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Reservation System to ensure that a slot on the protocol is available for the patient. 
Once a slot-reservation confirmation is obtained, site staff may then proceed to 
enroll the patient to this study.  
 
If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and 
password.  
2) In order to make a reservation, the patient must have an OPEN patient number. 
Click on the ‘Slot Reservation’ tab to create an OPEN patient number, under 
‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient.  
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the 
COG Patient ID, and choose the required stratum (if applicable) in order to 
obtain a reservation. 
 
Refer to the ‘SITE – Slot Reservation Quick Reference’ guide posted under 
the ‘Help’ tab in OPEN for detailed instructions:  
https://www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_Q
uickReference_SiteUserGuide_102612.pdf&ftype=PDF 
 
3.1.4 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 
24/7 basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on 
either the lead protocol organization (LPO) or participating organization roster. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org.  
 
Prior to accessing OPEN, site staff should verify the following: 
 
•
All eligibility criteria have been met within the protocol stated timeframes. 
•
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 


  
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3.1.5 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than seven (7) business days after the date of 
study enrollment. Patients who are started on protocol therapy on a Phase 2 
study prior to study enrollment will be considered ineligible.  
 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 
 
Institutions are advised to plan ahead to ensure adequate and timely delivery of the 
investigational agent (see Section 6.1 for details).  
 
3.1.6 
Participation in Biology Studies  
In order to minimize the potential for non-compliance once enrolled, 
patients/guardians must be made aware that some of the biology research studies 
are mandatory and understand that a number of non-standard blood samples will 
be required. 
 
3.1.7 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this study. 
 
3.2 
Patient Eligibility Criteria 
 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived. All clinical and laboratory data required for determining eligibility 
of a patient enrolled on this trial must be available in the patient's medical/research 
record which will serve as the source document for verification at the time of audit.  
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside 
the limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy. Imaging studies, if applicable, must be obtained 
within 2 weeks prior to start of protocol therapy (repeat the tumor imaging if 
necessary). 
 
See Section 4.2.1 for required studies to be obtained prior to starting protocol therapy. 
 
3.2.1 
Age 
Patients must be equal to or greater than 12 years of age but less than 50 years of age 
at the time of enrollment.  
 


  
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3.2.2 
Diagnosis  
3.2.2.1 
Patients must have had histologic verification of osteosarcoma at original 
diagnosis or relapse. 
 
3.2.2.2 
Patients must have measurable disease according to RECIST 1.1 (see 
Section 10.2), and have relapsed or become refractory to conventional 
therapy. 
 
3.2.3 
Specimen Submission  
Patient must have archival tumor specimen available for submission (see 
Section 15.1). 
 
3.2.4 
Performance Level  
Patients must have a performance status corresponding to ECOG scores of 0, 1 or 
2. Use Karnofsky for patients > 16 years of age and Lansky for patients  16 years 
of age. See  
https://members.childrensoncologygroup.org/prot/reference_materials.asp under 
Standard Sections for Protocols. 
 
3.2.5 
Prior Therapy 
Patients must have fully recovered from the acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to entering this study. 
 
a. 
Myelosuppressive chemotherapy: Must not have received within 2 weeks 
of entry onto this study (4 weeks if prior nitrosourea). 
 
b. 
Biologic (anti-neoplastic agent): At least 7 days since the completion of 
therapy with a biologic agent.  
 
c. 
Radiation therapy (RT):  2 weeks for local palliative RT (small port); 
 6 months must have elapsed if prior craniospinal RT or if  50% 
radiation of pelvis;  6 weeks must have elapsed if other substantial BM 
radiation. 
 
d. 
Monoclonal antibodies: Must not have received any monoclonal based 
therapies within 4 weeks, and all other immunotherapy (tumor vaccine, 
cytokine, or growth factor given to control the cancer) within 2 weeks, 
prior to study enrollment. 
 
Please see Section 4.1.1 for the concomitant therapy restrictions for patients during 
treatment. 
 
3.2.6 
Organ Function Requirements 
3.2.6.1 
Adequate Bone Marrow Function Defined As: 
- Peripheral absolute neutrophil count (ANC)  1000/L 
- Platelet count  75,000/L (transfusion independent) 
- Hemoglobin  8.0 g/dL (may receive RBC transfusions) 
 
3.2.6.2 
Adequate Renal Function Defined As: 
- 
Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or 


  
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- 
A serum creatinine based on age/gender as follows: 
 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR50 utilizing child length and stature data published 
by the CDC. 
 
3.2.6.3 
Adequate Liver Function Defined As: 
- 
Total bilirubin  1.5 x upper limit of normal (ULN) for age, and 
- 
SGOT (AST) or SGPT (ALT) < 110 U/L. For the purposes of this 
study the ULN for SGPT is defined as 45 U/L.  
- 
Serum albumin > 2 g/dL 
 
3.2.6.4 
Adequate Cardiac Function Defined As: 
- 
Shortening fraction of  27% by echocardiogram, or 
- 
Ejection fraction of ≥ 50% by radionuclide angiogram. 
 
3.2.7 
Exclusion Criteria 
3.2.7.1 
Patients with > Grade 2 neuropathy according to the Modified (“Balis”) 
Pediatric Scale (see Section 5.2.4) of Peripheral Neuropathies will be 
excluded except in cases in which neuropathy is secondary to prior 
surgery. 
 
3.2.7.2 
Patients who have previously received CDX-011 (CR011-vcMMAE; 
CDX-011) or other MMAE-containing agents. 
 
3.2.7.3 
Patients who have received other investigational drugs within 2 weeks 
or 5 half-lives (whichever is longer) prior to study enrollment. 
 
3.2.7.4 
Patients with a history of allergic reactions attributed to compounds of 
similar composition to dolastatin or auristatin. Compounds of similar 
composition include Auristatin PHE as an anti-fungal agent, Auristatin 
PE (TZT-1027, Soblidotin, NSC-654663) as an anti-tumor agent and 
symplostatin 1 as an anti-tumor agent. 
 
3.2.7.5 
Patients with known central nervous system metastasis are not eligible. 
 
3.2.7.6 
Patients who have had major surgery within 2 weeks prior to enrollment 
are not eligible. Procedures such as placement of a central vascular 
catheter, or limited tumor biopsy, are not considered major surgery. 
 


  
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3.2.7.7 
Pregnancy and Breast Feeding  
3.2.7.7.1 
Female patients who are pregnant are ineligible since 
there is yet no available information regarding human 
fetal or teratogenic toxicities. 
 
3.2.7.7.2 
Lactating females are not eligible unless they have agreed 
not to breastfeed their infants. 
 
3.2.7.7.3 
Female patients of childbearing potential are not eligible 
unless a negative pregnancy test result has been obtained. 
 
3.2.7.7.4 
Sexually active patients of reproductive potential are not 
eligible unless they have agreed to use an effective 
contraceptive method for the duration of their study 
participation and for 2 months after the end of study 
treatment. 
 
3.2.8 
Regulatory Requirements 
3.2.8.1 
All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.8.2 
All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
 
 


  
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4.0 
TREATMENT PROGRAM 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
This is a single arm Phase 2 study to evaluate the use of CDX-011, an ADC directed against 
GPNMB. All subjects will receive CDX-011 at 1.9 mg/kg intravenously over 90 minutes 
every 21 days. Treatment will be discontinued if there is evidence of progressive disease 
or drug related toxicity that requires removal from therapy, as defined in Section 5.0. 
Therapy may otherwise continue for a maximum duration of 14 months or ~18 cycles, 
whichever occurs first. Radiographic imaging assessments of disease status obtained after 
Cycles 2, 4 and 6 will be compared to imaging done just prior to initiating therapy. For 
those patients remaining on protocol therapy, subsequent imaging studies for assessment 
of disease status will occur after every 3rd cycle. 
 
Other therapy: Although not encouraged, subjects who achieve a partial response after 
Cycle 2 that is confirmed after Cycle 6 will be allowed to undergo resection of sites of 
disease or radiation and remain on protocol therapy. Therapy will be held during surgery 
and resumed when recovered from surgery but at least 2 weeks after surgery. CDX-011 
therapy will be held during radiation and may be resumed upon completion of the radiation 
treatment course. If the patient has not recovered from surgery within 6 weeks the patient 
will go off protocol therapy. Surgery or radiation performed on any site of measurable 
disease before the end of the sixth cycle will render the patient inevaluable for disease 
control assessment and they will be removed from protocol therapy.  
 
4.1.1 
Concomitant Therapy 
4.1.1.1 CYP3A4 inducers and inhibitors 
The use of the following medications should be discontinued prior to 
initiation of protocol therapy and should be avoided during protocol 
therapy if reasonable alternatives exist. This is not an inclusive list; please 
refer 
to 
other 
resources 
such 
as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or other frequently 
updated medical reference for additional information. 
 
CYP3A4 substrates  
Strong 
Inhibitors* 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Inducers 
alfentanil  
amiodarone 
aprepitant 
benzodiazepines 
bortezomib 
brentuximab 
budesonide 
calcium channel blockers 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
conivaptan 
delavirdine 
fosamprenavir 
indinavir 
aprepitant 
atazanavir 
cimetidine 
crizotinib 
cyclosporine  
desipramine 
diltiazem 
erythromycin 
amiodarone 
ciprofloxacin 
doxycycline 
mifepristone 
metronidazole 
nicardipine 
propofol 
quinidine 
armodafinil 
barbiturates 
bosentan 
carbamazepine 
deferasirox 
efavirenz 
etravirine 
fosphenytoin 


  
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cisapride 
citalopram/escitalopram 
glucocorticoids 
crizotinib 
cyclosporine 
cyclophosphamide  
dapsone 
dasatinib 
dihydroergotamine 
docetaxel 
doxorubicin 
ergotamine 
erlotinib 
esomeprazole 
estrogens 
etoposide 
fentanyl 
fosaprepitant 
gefitinib 
haloperidol 
HIV antiretrovirals 
HMG Co-A inhibitors 
ifosfamide 
imatinib 
irinotecan  
itraconazole 
ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin 
macrolide antibiotics 
medroxyprogesterone 
methadone 
midazolam 
modafinil 
monteleukast 
nefazodone 
nilotinib 
omeprazole 
ondansetron 
paclitaxel 
pazopanib 
quinidine  
sildenafil 
sirolimus  
sunitinib 
tacrolimus terfenadine 
telaprevir 
tamoxifen 
itraconazole 
ketoconazole 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
fluconazole 
fluvoxamine 
fosaprepitant 
grapefruit 
grapefruit 
juice 
imatinib 
norfloxacin 
tetracycline 
verapamil 
sertraline 
tacrolimus 
 
 
 
glucocorticoids 
modafinil 
nafcillin 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
primidone 
rifabutin 
rifampin 
rifapentin 
ritonavir 
St. John’s wort 
topiramate 
 


  
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temsirolimus 
teniposide 
trimethoprim 
vinca alkaloids 
zolpidem 
* Certain fruits and fruit juices (star fruit, Seville oranges, pomegranate) may inhibit CYP 3A4 isozyme, 
however, the degree of that inhibition is unknown.  
 
4.1.1.2 The administration of P-gp inhibitors should be avoided while the patient 
is receiving protocol therapy due to risk of increased exposure to MMAE. 
 
4.1.1.3 No other antineoplastic agents may be given while the patient is receiving 
protocol therapy. 
 
4.1.1.4 Growth factors that support white cell number or function should only be 
administered for culture proven bacteremia, invasive fungal infection, or 
if there was a Grade 4 ANC of > 7 days duration in a previous cycle or a 
delay of > 14 days between cycles for neutropenia.  
 
For COG Supportive Care Guidelines see: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard 
Sections for Protocols. 
 
 
 


  
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All Cycles 
 
 
4.2 
Therapy Delivery Map – CDX-011 
 
4.2.1 
Therapy Delivery Map – All Cycles of CDX-011 
Each cycle lasts 3 weeks (21 days). Treatment may continue for up to 14 months or 18 cycles, 
whichever occurs first. One cycle of treatment is described in this TDM. This TDM is on 2 pages. 
Use a copy of this page once for each cycle (please note cycle number below). 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
 
Begin CDX-011 therapy only when ANC ≥ 1000/µL; Platelets ≥ 75,000/µL (transfusion independent); Hemoglobin  8.0 g/dL (RBC transfusions 
allowed); Cr clearance or radioisotope GFR  70 mL/min/1.73 m2 or a serum creatinine based on age/gender as per Section 4.2.3; Total bilirubin 
 1.5 x ULN for age; SGOT (AST) or SGPT (ALT) ≤ 110 U/L, and Serum albumin > 2 g/dL. 
 
DRUG 
ROUTE 
DOSAGE 
DAY 
IMPORTANT NOTES 
CDX-011 (glembatumumab 
vedotin) 
IND# 128248 
IV over 90 minutes 
1.9 mg/kg/dose 
Day 1 
Recalculate the dose prior to each infusion. Round dose to the 
nearest 1 mg. See Section 4.2.3 for complete details. 
 
Enter Cycle #: _____  
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
CDX-011 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
____mg 
a-l 
 
 
 
8* 
(a-f)* 
 
 
21 
g, h, i 
Start the next cycle on Day 22 or as soon as starting criteria are met, whichever occurs later. Treatment should continue up to 14 months (or 18 cycles, whichever occurs 
first) in the absence of disease progression or unacceptable toxicity. If disease progression or unacceptable toxicity occurs, the patient will be taken off protocol therapy. 
Note: Patients who receive surgery or radiation on any site of measurable disease prior to completion of the 6th cycle of therapy will be taken off protocol therapy. 
* Cycle 1 only 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
Page 1 of 2 


  
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All Cycles 
 
4.2.2 
Required Observations Prior to Cycle 1 and During All Cycles  
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below. For Cycle 1 only, observations a-f can be 
performed up to 7 days before the start of therapy and imaging studies may 
be obtained within 2 weeks prior to the start of therapy. 
 
a. 
Hx/PE/Wt /Ht. Prior to each cycle and on Day 8 of Cycle 1. 
b. CBC/diff/platelets. Prior to each cycle and on Day 8 of Cycle 1. 
c. 
Bilirubin & Creatinine. Prior to each cycle and on Day 8 of Cycle 1. 
d. Electrolytes, BUN, Ca++, PO4, Mg++. Prior to each cycle and on Day 8 of Cycle 1. 
e. 
AST, ALT, albumin. Prior to each cycle and on Day 8 of Cycle 1. 
f. 
Neurologic evaluation. Prior to each cycle and on Day 8 of Cycle 1. Assess for NCI CTCAE 
> Grade 2 neuropathy. 
g. CT chest. Prior to Cycle 1 and following Cycles 2, 4, 6 and every 3rd cycle thereafter. 
h. Tumor disease evaluation. Prior to Cycle 1 and following Cycles 2, 4, 6, and every 3rd cycle 
thereafter. Evaluations should include CT or MRI of all lesions meeting eligibility criteria. Use 
the same imaging modality for all disease evaluations. Patients who had a RECIST response (CR 
or PR) at Cycle 6 imaging evaluation are required to have a confirmatory scan following Cycle 8. 
For patients who undergo a surgical resection following Cycle 6, either a CT scan or MRI post-
surgery to establish a new baseline is strongly recommended prior to re-initiating CDX-011 
therapy. See Section 16.0 for details. 
i. 
18FDG PET or Bone Scan. Prior to Cycle 1 and following Cycles 2, 4, 6, and every 3rd cycle 
thereafter. 18FDG PET or bone scan is required at baseline. 18FDG PET scan is an optional study, 
but if completed then a bone scan is not necessary. It is recommended to obtain MRI or CT scan 
of any lesion positive on bone or 18FDG PET scan. Bone or 18FDG PET scan is required to assess 
for new disease after Cycles 2, 4 and 6. Further bone scan or 18FDG PET should be completed as 
clinically indicated at investigator discretion. For consistency, investigators are encouraged to 
utilize the same modality used at baseline to follow positive lesions that are identified with 18FDG 
PET or bone scan. See Section 16.0 for details. 
j. 
Pharmacokinetics. Cycle 1 only, Day 1 pre-dose, end of infusion, 1, 2, 4, 8 and 24 (+/- 4 hours) 
hours post infusion, 4 days (+/- 1 day) post infusion, 7 and 21 days post infusion. Required for the 
first 6 evaluable patients ≤ 14 years of age enrolled at COG sites. Optional for patients > 14 years 
of age and ≤ 21 years of age enrolled at COG sites. See Section 15.2 for details. 
k. Tumor GPNMB expression (required). Submission of a formalin-fixed, paraffin-embedded 
(FFPE) sample of tumor tissue (block or 10 slides) from the most recent surgery (preferred) or 
from any previous biopsy or resection is mandatory within 4 weeks of enrollment. See Section 
15.1 for details. 
l. 
Pregnancy test. Prior to Cycle 1. Female patients of childbearing potential require a negative 
pregnancy test prior to starting treatment; sexually active patients must use an acceptable method of 
birth control.  
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments (Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
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All Cycles 
4.2.3 
Therapy During Cycle 1 and Subsequent Cycles 
One cycle of CDX-011 treatment is described below. A cycle may be repeated 
every 21 days (3 weeks) if the patient has at least stable disease and has again met 
laboratory parameters as defined in the eligibility section, and detailed below. 
 
CDX-011 (glembatumumab vedotin): Intravenously over 90 minutes 
Day: 1 
Dose: 1.9 mg/kg/dose. Round doses to the nearest 1 mg. 
Actual body weight will be recorded and used to calculate dose prior to each 
infusion. CDX-011 is to be diluted with D5W and administered using a 0.22 µm 
low protein binding in-line filter. Patient should receive post-infusion flush with 
appropriate volume of D5W administered at the same rate as CDX-011 infusion.  
 
Note: Premedication is not required, but may be used as clinically indicated. 
 
Monitoring during CDX-011 infusion:  
• 
Vital signs should be assessed every 15 minutes for the first hour of the 
infusion, followed by every 30 minute assessment for the remainder of the 
infusion and post-infusion flush. More frequent assessment may be 
required based on the patient’s clinical condition.  
 
Criteria to start each cycle 
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  


  
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
5.1 
Definition of Toxicities 
NOTE: Any suspected or confirmed dose-limiting toxicity should be reported to the Study 
Chair within 24 hours of site knowledge of its occurrence. 
 
5.1.1 
Definition of Dose-Limiting Toxicity (DLT)  
DLT will be defined as any of the following events that are possibly, probably or 
definitely attributable to protocol therapy.  
 
Note: Dose limiting hematological and non-hematological toxicities are defined 
differently. 
 
5.1.1.1 
Hematological Dose Limiting Toxicity  
• 
Grade 4 neutropenia for > 7 days 
• 
Grade 4 febrile neutropenia 
• 
Platelet count < 25,000/L on 2 separate days, or requiring a platelet 
transfusion on 2 separate days, within a 7 day period  
• 
Myelosuppression that causes a delay of > 14 days between 
treatment cycles.  
 
5.1.1.2 
Non-Hematological Dose-Limiting Toxicity 
•
Any Grade 3 or greater non-hematological toxicity, except for the 
following: 
o Grade 3 nausea and/or vomiting of < 3 days duration 
o Grade 3 or 4 fever < 5 days duration 
o Grade 3 infection < 5 days duration 
o Grade 3 rash < 5 days duration 
o Grade 3 pruritis < 5 days duration 
o Grade 3 fatigue < 5 days duration 
o Grade 3 non-hematologic laboratory abnormalities that resolve 
within 14 days to Grade 1, or to initial eligibility criteria, or to 
baseline (if the patient entered the study with existing toxicity). 
Note: for the purposes of this study the ULN for SGPT (ALT) is 
defined as 45 U/L. 
o Grade 3 infusion-related reactions < 24 hours duration (see 
Section 5.2.3) 
o Grade 3 hypophosphatemia, hypokalemia, hypocalcemia, or 
hypomagnesemia responsive to oral supplementation. 
 
•
Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and 
is considered sufficiently medically significant or sufficiently 
intolerable by patients that it requires treatment interruption will also be 
considered a DLT.  
 
 


  
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5.2 
Dose Modifications for Adverse Events 
The Study Chair must be notified of any use of myeloid growth factor for hematologic 
toxicity and of any other dosage modification described below. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
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Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies 
 
Peripheral Motor Neuropathy: 
• Grade 1: Subjective weakness, but no deficits detected on neurological exam, other than abnormal deep tendon 
reflexes. 
 
• Grade 2: Weakness that alters fine motor skills (buttoning shirt, coloring, writing or drawing, using eating utensils) 
or gait without abrogating ability to perform these tasks. 
 
• Grade 3: Unable to perform fine motor tasks (buttoning shirt, coloring, writing or drawing, using eating utensils) or 
unable to ambulate without assistance. 
 
• Grade 4: Paralysis. 
 
Peripheral Sensory Neuropathy: 
• Grade 1: Paresthesias, pain, or numbness that do not require treatment or interfere with extremity function. 
 
• Grade 2: Paresthesias, pain, or numbness that are controlled by non-narcotic medications (without causing loss of 
function), or alteration of fine motor skills (buttoning shirt, writing or drawing, using eating utensils) or gait, without 
abrogating ability to perform these tasks. 
 
• Grade 3: Paresthesias or pain that are controlled by narcotics, or interfere with extremity function (gait, fine motor 
skills as outlined above), or quality of life (loss of sleep, ability to perform normal activities severely impaired). 
 
• Grade 4: Complete loss of sensation, or pain that is not controlled by narcotics. 


  
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6.0 
DRUG INFORMATION  
6.1 
CDX-011 
(GLEMBATUMUMAB VEDOTIN, CR011-vcMMAE) NSC# 763737, IND# 128248  
 
 
 
 
 
 
 
 
 
           (09/01/16) 
 
Source and Pharmacology: 
CDX-011 is an antibody-drug conjugate (ADC) comprised of a fully-human IgG2 
monoclonal antibody (CR011) directed against glycoprotein NMB (GPNMB) and 
conjugated to the tubulin-binding cytotoxic agent monomethylauristatin E (MMAE) via a 
protease-sensitive valine-citrulline linker and p-aminobenzoic acid (PABA) spacer. The 
average MMAE: antibody molar ratio is approximately 4.5:1. The antibody is 
manufactured by Chinese Hamster Ovary (CHO) cell culture, and the drug-linker 
combination vcMMAE is manufactured by chemical synthesis.  
 
The proposed mechanism of action of CDX-011 is as follows: After the ADC binds to 
GPNMB on tumor cells, the complex is internalized and MMAE is released via proteolytic 
cleavage of the valine-citrulline linker in a lysosomal compartment. Tumor cell death 
occurs as a result of microtubule inhibition by MMAE with resultant cell cycle arrest.  
 
Pharmacokinetics  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
.    
 
 


  
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Toxicity: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
CDX-011 (glembatumumab vedotin, 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 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). 
 
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. 


  
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Guidelines for Administration:  
See Treatment and Dose Modification sections of the protocol for complete details. CDX-011 
is diluted with D5W and administered as a 90-minute IV infusion using a 0.22 μm low 
protein binding in-line filter. Patient should receive post-infusion flush with appropriate 
volume of D5W administered at the same rate as CDX-011 infusion. 
 
Supplier:   
CDX-011 is supplied by Celldex Therapeutics and distributed by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 


  
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Obtaining the Agent 
Agent Ordering 
To comply with the timing requirement for study enrollment (Section 3.1.5), 
participating institutions are advised to plan ahead to ensure adequate and timely 
delivery of the investigational agent. Participating institutions may have to use their 
express courier account for overnight shipping when ordering the agent. 
 
NCI supplied agent may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the patient is to be treated. PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB 
is obtained). The CTEP assigned protocol number must be used for ordering all CTEP 
supplied investigational agents. 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 must 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. For questions about drug orders, transfers, returns, or 
accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm 
(ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
Agent Accountability 
Agent Inventory Records: 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of all agents received from DCTD using the 
NCI Drug Accountability Record Form (DARF). See the CTEP home page at 
http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage and to obtain 
a copy of the DARF and Clinical Drug Request form. 
 
Agent Returns: 
Investigators/Designees must return unused DCTD supplied investigational agent to the 
NCI clinical repository as soon as possible when: the agent is no longer required because 
the study is completed or discontinued and the agent cannot be transferred to another DCTD 
sponsored protocol; the agent is outdated or the agent is damaged or unfit for use. 
Regulations require that all agents received from the DCTD, NCI be returned to the DCTD, 
NCI for accountability and disposition. Return only unused vials/bottles. Do NOT return 
opened or partially used vials/bottles unless specifically requested otherwise in the protocol. 
See the CTEP web site for Policy and Guidelines for Investigational agent Returns at: 
http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs. The appropriate 
forms may be obtained at: http://ctep.cancer.gov/forms/docs/return_form.pdf.  
 
 


  
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
 
7.1 
End of Therapy & Follow-up 
 
 
STUDIES TO BE OBTAINED 
End of Therapy 
History 
X 
Physical exam with VS 
X 
Performance status 
X 
CBC, differential, platelets 
X 
Electrolytes including Ca++, PO4, Mg++ 
X 
Creatinine, SGPT, bilirubin 
X 
Total protein/albumin 
X 
Tumor disease evaluation (see Section 16.0) 
X 
 
See COG Late Effects Guidelines for recommended post treatment follow-up:  
 
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data must be submitted in accordance with the Case Report Forms (CRFs) 
schedule. 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) Progressive disease. 
b) Unacceptable toxicity due to protocol therapy (see Section 5.0). 
c) Refusal of further protocol therapy by patient/parent/guardian. 
d) Completion of planned therapy. 
e) Physician determines it is in patient’s best interest. 
f) Development of a second malignancy. 
g) Repeat eligibility studies (if required) are outside the parameters required for eligibility 
(see Section 3.2). 
h) Surgery or radiation performed on any site of measurable disease before the end of the 6th 
cycle. 
i) 
Failure to recover from surgery within 6 weeks. 
j) 
Pregnancy. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see 
below). Follow-up data will be required unless patient is taken off study. 
 


  
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8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (eg, at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) The fifth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Sample Size and Study Duration 
A review of enrollment on COG single-agent Phase 2 studies demonstrates that 
approximately 1.8 patients per month will potentially be eligible for AOST1521. A 
maximum of 29 outcome evaluable patients will be required for the evaluation of CDX-
011 amongst patients without prior treatment with eribulin. Eribulin has not been used as 
a component of therapy for newly diagnosed patients in pediatric protocols and there has 
been only one COG study of that agent for patients with recurrent disease. As such, we 
expected no more than 15% of patients who are eligible for this study to have received 
eribulin as part of therapy prior to potential enrollment on this study. Providing for possible 
ineligible and inevaluable patients, the maximum enrollment will be 38 patients. 
 
With these entry rates, the probability we will accrue at least 38 patients in 24 months is 
80% and the corresponding probability for 30 months is in excess of 99%. The study will 
likely require 2 to 2.5 years to enroll sufficient patients. A maximum of 38 patients is 
anticipated. 
 
9.2 
Study Design 
Feasibility Cohort: The first six (6) younger patients (< 18 years of age) who are evaluable 
for toxicity will be considered as the feasibility cohort. All such patients will be assigned 
to receive 1.9 mg/kg/dose. Enrollment to this cohort will not be segregated by prior 
treatment with eribulin. Study accrual will be suspended after the sixth patient is enrolled; 
enrollment of patients 18 years of age or older will continue regardless of the result in the 
feasibility cohort. If dose limiting toxicity (DLT) during the first cycle of therapy occurs 
in one or fewer evaluable patients then the trial accrual will proceed as outlined below. 
Patients who are enrolled in the toxicity cohort who receive the “feasible” dose of CDX-
011 will be considered in the outcome evaluation rules presented below for the relevant 
patient stratum as it relates to prior eribulin exposure. 
 
Patients will be enrolled in two stages. In the first stage, 19 disease control and RECIST 
response evaluable patients will be enrolled. Each patient will be evaluated for both 
outcome measures: (1) disease control success; and (2) RECIST response (CR or PR v. not 
CR or PR). The decision rule for the two stage study design is summarized as: 
 
 
Stage 
Number of 
Patients Enrolled 
in Stage 
Cumulative 
Response Results 
Decision 
I 
19 
4 or fewer disease 
control successes 
Terminate the trial 
with the conclusion 
that Glembatumumab 


  
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and 1 or fewer 
RECIST responders 
Vedotin is not 
associated with 
sufficient activity for 
further single agent 
investigation 
5 or more disease 
control success or 2 
or more RECIST 
responders 
Continue to stage II 
II 
10 
8 or fewer disease 
control successes 
and 4 or fewer 
RECIST responders 
Terminate the trial 
with the conclusion 
that Glembatumumab 
Vedotin is not 
associated with 
sufficient activity for 
further single agent 
investigation 
9 or more disease 
control successes or 
5 or more RECIST 
responders 
Terminate the trial 
with the conclusion 
that Glembatumumab 
Vedotin is associated 
with sufficient 
activity for further 
single agent 
investigation 
 
Design Characteristics: Each patient enrolled will be evaluated for: (1) complete or partial 
response as defined by the RECIST criteria where the first evaluation of CR or PR is made 
at or before the end of the sixth cycle of study therapy (denoted as R below); or (2) stable 
disease after four months of therapy or at the end of the sixth cycle, whichever occurs first 
(denoted as S below). We will not be interested in promoting the agent for further 
investigation if the probability of response in any particular individual is less than or equal 
to 0.05 (P(R)≤0.05) and the probability of remaining analytic event free in any particular 
individual is less than or equal to 0.20 (P(S)≤0.20). We will be interested in promoting the 
agent for further investigation if the probability of response in any particular individual is 
at least 0.22 (P(R)≥0.22) or the probability of remaining analytic event free in any 
particular individual is at least 0.42 (P(S)≥0.42). 
 
For the calculations below, it is assumed 


Pr
|
0.90.
S R 
 
 
The statistical characteristics of this design are: 
Probability of four 
month disease 
control 
Probability of 
RECIST 
response 
Probability of 
Stopping After Stage 
1 (and concluding the 
drug is ineffective) 
Probability of 
Concluding the 
Drug is Ineffective 
at the Conclusion 
of the Trial 
Probability of 
Concluding the 
Drug is Effective 
at the Conclusion 
of the Trial 
0.20 
0.05 
0.56 
0.89 
0.11 
0.42 
0.22 
0.014 
0.05 
0.95 
0.42 
0.05 
0.044 
0.096 
0.904 
0.20 
0.22 
0.056 
0.21 
0.79 
 


  
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Prior Treatment with Eribulin: As noted in Section 9.1, we expect no more than 15% of 
patients will have been treated with eribulin prior to enrollment on AOST1521. Patients 
will be evaluated for S and R as described above. Enrollment to this stratum will be 
terminated when we can determine there are sufficient patients to fully evaluate the efficacy 
of CDX-011 in the stratum of patients without prior eribulin therapy. If 19 patients with 
prior eribulin therapy are enrolled, the staged design described above for patients without 
prior eribulin therapy will be applied to this stratum. 
 
9.3 
Methods of Analysis for Pharmacokinetics (Aim 1.2.2) 
Data from all patients who provide samples for pharmacokinetic analysis will be aggregated. 
The sample mean and variance of the AUC, clearance and half-life will be calculated. No 
formal statistical testing will be done. 
 
Pharmacokinetic studies are mandatory for the first 6 evaluable patients 14 years of age or less 
who are enrolled at an institution which is a member of COG. Consent for pharmacokinetic 
studies for any patient greater than 14 years of age and less than or equal to 21 years of age 
who is enrolled at a COG member institution is optional. PK sampling will not be sought for 
patients who are older than 21 years of age at the time of enrollment.  
 
9.4 
Evaluability for Disease Control and Response 
Which Patients will be Considered Evaluable for RECIST Response: 
Any eligible patient who receives at least one dose of CDX-011 will be considered 
evaluable for response with the following exception: if a patient receives non-protocol anti-
cancer therapy during the response evaluation period after the patient is considered as 
having a partial or complete response but prior to confirmation of this status by tumor 
imaging and before progressive disease is noted, the individual will be considered 
inevaluable for the response endpoint. Further, patients who stop CDX-011 after the 1st 
evaluation because of toxicities or death will be considered evaluable for the response 
evaluation and will be counted as non-responders for the response endpoint. 
 
Which Patients Will Be Considered Evaluable for Disease Control Success: 
Any eligible patient who receives at least one dose of CDX-011 will be considered 
evaluable for response with the following exception: if a patient receives non-protocol anti-
cancer therapy during the first four months of therapy or first six cycles of therapy, 
whichever occurs first, is considered as having a partial or complete response but prior to 
confirmation of this status by tumor imaging and before progressive disease is noted, the 
individual will be considered inevaluable for the disease control success endpoint. 
 
Which Patients Will be Considered a Disease Control Success: 
Any patient who is evaluated free of all detectable disease (complete response) or is 
considered as having a partial response or is considered as having stable disease (‘at least 
stable disease’) after four months of therapy or at the end of the sixth cycle, whichever 
occurs first. 
 
Which Patients Will be Considered Not a Disease Control Success: 
Any evaluable patient who does not meet the criteria for disease control success (complete 
response, partial response or stable disease) will be considered to not have experienced 
disease control success. 
In particular, any patient who dies because of treatment-related toxicity during the first six 
cycles of therapy and within the first four months since starting treatment will be 


  
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considered not to have experienced disease control success. Also, any patient who is 
eligible, receives one dose of CDX-011 and is lost to follow-up at (for example) the end of 
cycle 2 will be considered not a disease control success (complete response, partial 
response or stable disease).  
 
Patients who are not evaluable for both disease control and response evaluation may be 
replaced for the purposes of the statistical rule. 
 
9.5 
Evaluability for Toxicity  
Tolerability of CDX-011 - An eligible patient will be considered for toxicity monitoring if 
one of the following occurs: (1) complete one cycle of CDX-011 prior to receiving non-
protocol anticancer therapy; (2) die on protocol therapy for a reason considered possibly, 
probably or likely related to CDX-011; or (3) are removed from protocol therapy because 
of an adverse experience possibly, probably or likely related to CDX-011. A toxicity-
evaluable patient will be considered in the analysis during the interval from study 
enrollment until the termination of protocol therapy. A toxicity-evaluable patient will be 
considered to have experienced an excessive toxicity event if: (1) the patient dies on 
protocol therapy for a reason considered possibly, probably or likely related to; or 
(2) experiences a dose-limiting toxicity (DLT). DLTs will be as defined in Section 5.1.1 of 
the protocol:  
 
The analytic unit for monitoring for excessive toxicity will be the patient-cycle: Each cycle 
where the patient receives CDX-011 and does not receive non-protocol anticancer therapy 
will be considered in the analysis. If there is overwhelming evidence that the dose selected 
for this trial has a per-cycle-DLT probability of more than 30%, we will identify the 
regimen to the COG DSMC, Bone Tumor Committee leadership and CTEP as associated 
with a toxicity profile that may require modification of the regimen. We will use a Bayesian 
rule to monitor for excessive toxicity. We will assume a beta prior to distribution with 
α=0.6 and β=1.4. If this posterior probability of the chance of DLT is at least 30% exceeds 
80%, we will identify the regimen to the COG DSMC, Bone Tumor leadership and CTEP 
as associated with a toxicity profile that may require modification of the regimen.  
 
9.6 
Estimation of Disease Control and RECIST Response Rates 
P(R) and P(S) for each cohort defined by prior eribulin exposure will be estimated using 
the maximum likelihood estimates, viz., 
 
 


ˆ
;
ˆ
4
ˆ
ˆ
R
S
Number of Patients Considered as PR or CR
P R
p
Number of Evaluable Patients in Cohort
Number of Patients With DiseaseControl at
Months
P S
p
Number of Evaluable Patients in Cohort




  
 
Confidence intervals will be constructed using the approximate normal distribution of each 
of the estimates and their asymptotic variances: 
 


  
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







ˆ
ˆ
1
ˆ
;
ˆ
ˆ
ˆ
1
ˆ
ˆ
R
R
R
S
S
S
p
p
V p
Number of Evaluable Patients in Cohort
p
p
V p
Number of Evaluable Patients in Cohort




  
 
9.7 
Statistical Considerations for Secondary Aim 1.2.3 
 
9.7.1 
To determine the relationship of GPNMB expression by IHC to response in tumor 
specimens from patients: Submission of archival tissue will be required for this 
study. The primary cohort to address this aim will be the patients who were not 
previously treated with eribulin. The GPNMB expression IHC result will be coded 
as an integer between 0 and 3 with 0 being no GPNMB expression and 3 indicating 
strong GPNMB expression. The outcome measure will be DC success (Yes v. No). 
Logistic regression using the categorical IHC result will be fitted to the data. The 
fitted coefficients from the logistic regression, and the p-value for the test of the 
hypothesis of no relationship between IHC result and probability of DC success 
will be used to characterize this secondary analysis. Trend will also be assessed 
using the actual IHC numerical value.  
 
9.8 
Gender and Minority Accrual Estimates 
 
The gender and minority distribution of the study population is expected to be: 
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 
0 
0 
0 
0 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
2 
6 
0 
0 
8 
White 
9 
17 
1 
3 
30 
More Than One Race 
0 
0 
0 
0 
0 
Total 
11 
23 
1 
3 
38 
 
This distribution was derived from ADVL0821, ADVL0921, ADVL1221. 
 
 
10.0 
EVALUATION CRITERIA 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website  


  
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(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE 
v4.0 as referenced on the CTEP website (ie, v4.02 and all subsequent iterations prior to 
version 5.0). 
 
10.2 
Response Criteria for Patients with Solid Tumors 
For the purposes of this study, patients should be evaluated for response following Cycles 
2, 4 and 6 and following every 3rd cycle thereafter. Patients who have a RECIST response 
(CR or PR) at Cycle 6 will have confirmatory imaging after Cycle 8. 
 
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).51 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. 
 
10.2.1 Disease Parameters 
10.2.1.1 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 by chest x-ray, as ≥ 10 mm with CT scan, or 
≥ 10 mm with calipers by clinical exam. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
10.2.1.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
10.2.1.3 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥ 10 to < 15 mm 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. 
 
10.2.1.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 


  
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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 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. 
 
10.2.1.5 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.  
 
10.2.2 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. 
 
10.2.2.1 Clinical lesions: Clinical lesions will only be considered measurable 
when they are superficial (eg, skin nodules and palpable lymph nodes) 
and  10 mm diameter as assessed using calipers (eg, skin nodules). In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
10.2.2.2 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.  
 
10.2.2.3 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 or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (eg, for body 
scans). 
 


  
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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 
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. 
 
10.2.2.4 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. 
 
10.2.2.5 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. 
 
10.2.2.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (eg, residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
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. 
 
10.2.3 Response Criteria 
 
10.2.3.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have 


  
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reduction in short axis to <10 mm. 
 
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. (Note: the appearance of 
one or more new lesions is also considered 
progression). 
 
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. 
 
10.2.3.2 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 
short axis). 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits 
 
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). 
 
10.2.3.3 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. 


  
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For Patients with Measurable Disease (ie, Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
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. 
**Only for non-randomized trials with response as primary endpoint. 
***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. 
 
For Patients with Non-Measurable Disease (ie, 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 
 
10.2.4 Duration of Response 
 
10.2.4.1 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. 


  
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10.2.4.2 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.  
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
11.1 
Purpose 
Adverse event (AE) 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. Certain adverse events must be 
reported in an expedited manner to allow for timelier monitoring of patient safety and care. 
The following sections provide information about expedited reporting. 
 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI 
requires that AEs be submitted according to the timeframes in the AE reporting table 
assigned to the protocol, using the CTEP Adverse Event Reporting System (CTEP-AERS). 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
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 a serious adverse drug experience 
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. 
 
11.3 
Specific Examples for Expedited Reporting  
11.3.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of a 
possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting table in this protocol.  
 
11.3.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it 


  
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occurs at any time following treatment with an agent under a NCI IND/IDE since 
these are considered serious AEs. 
 
11.3.3 Death 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: A disorder characterized by cessation of life during the first 
28 days of life.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
o Death due to progressive disease should be reported as Grade 5 “Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other 
(Progressive Disease)” under the system organ class (SOC) of the same 
name. 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.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours.  
 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.3.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (eg, treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
The NCI requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
•
Leukemia secondary to oncology chemotherapy  
•
Myelodysplastic syndrome  
•
Treatment related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
 
11.3.5 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 reporting via CDUS unless otherwise specified. 
 
11.3.6 Pregnancy, Fetal Death, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form, available at: 


  
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http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to 301-230-0159. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.3.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents that may be teratogenic. For this reason, pregnancy needs 
to be reported in an expedited manner via CTEP-AERS as  
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
 
Pregnancy needs to be followed until the outcome is known. If the baby 
is born with a birth defect or anomaly, then a second CTEP-AERS report 
is required. 
 
11.3.6.2 Fetal Death 
Fetal death, defined in CTCAE as “A disorder characterized by death in 
utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation”, needs to 
be reported expeditiously, as Grade 4 “Pregnancy, puerperium and 
perinatal conditions - Other (pregnancy loss)”. Do NOT report a fetal 
death as a Grade 5 event since CTEP-AERS recognizes any Grade 5 
event as a patient death. 
 
11.3.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” needs to be 
reported expeditiously, as Grade 4 “General disorders and 
administration - Other (neonatal loss)” when the death is the result of 
a patient pregnancy or pregnancy in partners of men on study. Do 
NOT report a neonatal death resulting from a patient pregnancy or 
pregnancy in partners of men on study as a Grade 5 event since CTEP-
AERS recognizes any Grade 5 event as a patient death.  
 
11.4 
Reporting Requirements for Specialized AEs  
11.4.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (eg, elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
a. If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event 
to determine if an expedited report is required. 


  
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c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.4.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 
 
11.4.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.5 
Exceptions to Expedited Reporting 
11.5.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and 
Potential Risks (CAEPR) that contains a list of events that are considered expected 
for CTEP-AERS reporting purposes. (Formerly referred to as the Agent Specific 
Adverse Event List (ASAEL).)  
 
AEs listed on the SPEER should be reported expeditiously by investigators to the 
NCI via CTEP-AERS ONLY if they exceed the grade of the event listed in 
parentheses after the event. If the CAEPR is part of a combination IND using 
multiple investigational agents and has an SAE listed on different SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
 
11.5.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed under the 
CTEP-AERS reporting table for this protocol. 
 
11.6 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports 
in a timely manner.  
 


  
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Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database.   
 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
The descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting and are located on 
the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
appropriate treatment areas should have access to a copy of the CTCAE. 
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted 
electronically 
to 
NCI 
via 
CTEP-AERS 
at: 
https://eapps-
ctep.nci.nih.gov/ctepaers 
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to 
be made to the NCI for agents supplied under a CTEP IND by telephone call to 301-897-
7497.  
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of the 
report at the site.   
 
•
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event.  
 
•
Any event that results in a persistent or significant incapacity/substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect, or is 
an IME, which based upon the medical judgment of the investigator may jeopardize 
the patient and require intervention to prevent a serious AE, must be reported via 
CTEP-AERS if the event occurs following investigational agent administration.  
 
•
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 
hours.  
•
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE requires 
expedited reporting within 24 hours.  
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  
 


  
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Any medical documentation supporting an expedited report (eg, H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to 
the NCI. NOTE: English is required for supporting documentation submitted to the 
numbers listed below in order for the NCI to meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents supplied under 
a CTEP IND to: 301-230-0159 (back-up: 301-897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax# 310-640-
9193; 
email: 
COGAERS@childrensoncologygroup.org; 
Attention: 
COG 
AERS 
Coordinator).  
 
•
ALWAYS include the ticket number on all faxed documents. 
 
•
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
 
 


  
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11.8 
Reporting Table for 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 Investigational 
Agent/Intervention 1 
 
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) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours. This does not include hospitalizations that are part of routine medical practice. 
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 CTEP-AERS within the timeframes detailed in the table below.   
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
7 Calendar Days 
 
 
24-Hour 
Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 
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. Additional 
Special Situations as Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE.  
 
1SAEs 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 7 calendar day reports for:  
•
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
•
Grade 3 adverse events  


  
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11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
•
Grades 1- 4 myelosuppression (anemia, neutropenia, thrombocytopenia) do not 
require expedited reporting.  
•
Grades 1-2 peripheral neuropathy do not require expedited reporting.  
 
11.10 Routine Reporting of Adverse Events 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting will include all CTEP-AERS 
reportable events and Grade 3 and higher non-hematologic and Grade 4 and higher 
hematologic Adverse Events 
 
 
12.0 
STUDY REPORTING AND MONITORING  
The Case Report Forms and the submission schedule are posted on the COG web site with each 
protocol under “Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31 and October 31. This is not a responsibility of institutions 
participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (eg, termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released prior to the release of study results at the time specified 
in the protocol document. 
 
12.3 
CRADA/CTA 
NCI/DCTD Standard Language to Be Incorporated into All Protocols Involving 
Agent(s) Covered by a Clinical Trials Agreement (CTA), a Cooperative Research and 
Development Agreement (CRADA) or a Clinical Supply Agreement, hereinafter referred 
to as Collaborative Agreement: 


  
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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 
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. 
 


  
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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-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. 
 
 
13.0 
SURGICAL GUIDELINES 
See COG Surgical Guidelines for osteosarcoma at:  
https://members.childrensoncologygroup.org/_files/Disc/surgery/handbooks/OsteoBoneHandboo
k.pdf 
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
All patients enrolling on this protocol require institutional histological confirmation of 
osteosarcoma at the time of original diagnosis or relapse. Patients are required to submit archival 
tumor samples (collected at original diagnosis or at relapse or at any subsequent resections or 
biopsies) for immunohistochemical analysis. 
 
Please note: At enrollment, all patients must have adequate tumor specimen available for submission 
as detailed in Section 3.2.3.  
 
Autopsy  
In the event of patient death on AOST1521, a complete unrestricted postmortem examination is 
strongly encouraged. For patients enrolled on AOST06B1at COG sites, tissue submission at 
autopsy is requested. (See AOST06B1 protocol.) 


  
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15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
15.1 
Tumor GPNMB Expression (mandatory participation) 
15.1.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


  
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Participation in the PK studies is limited to COG member institutions. Serial blood samples 
for the assessment of CDX-011, CR011 antibody and MMAE are required for the first 
6 evaluable patients ≤ 14 years of age enrolled at a COG member site. Serial blood samples 
for the assessment of CDX-011, CR011 antibody and MMAE are optional for patients 
> 14 years of age and ≤ 21 years of age enrolled at a COG member site. 
 
Blood samples will be obtained in Cycle 1 on Days 1, 4 (+/- 1 day), 7 and 21 at 
the following 10 time points related to CDX-011 dosing: 
•
Time 0 (pre-dose) 
•
End of infusion 
•
1 hour post infusion 
•
2 hours post infusion 
•
4 hours post infusion 
•
8 hours post infusion 
•
24 hours (+/- 4 hours) post infusion 
•
4 days (+/- 1 day) post infusion 
•
7 days post infusion 
•
21 days post infusion 
 


  
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16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except where 
explicitly prohibited within the protocol). 
 
16.1 
Required and Recommended Osteosarcoma Imaging  
 
Site 
Anatomic Imaging Functional 
Imaging 
Timing 
Primary tumor 
and bone 
metastases 
AP and lateral 
radiographs 
 
At presentation, following 
Cycles 2, 4, 6, and 
following every third cycle 
thereafter. 
Primary tumor 
and bone 
metastases 
CT or MRI with 
gadolinium 
 
 
At presentation, following 
Cycles 2, 4, 6*, and 
following every third cycle 
thereafter. 
Chest 
CT 
 
At presentation, following 
Cycles 2, 4, 6, and 
following every third cycle 
thereafter. 
Whole body 
 
18FDG PET or 
MDP bone 
scintigraphy 
(recommended, 
not required)  
 
Recommended at 
presentation.  
If a bone scan or 18FDG 
PET is positive, it should 
be repeated following 
Cycles 2, 4, 6 and 
following every third cycle 
thereafter. 
*For patients who undergo a surgical resection following Cycle 6, either a CT scan or MRI 
post-surgery to establish a new baseline is strongly recommended before re-initiating 
CDX-011 therapy.   
 
NOTE: patients who have a RECIST response (CR or PR) at Cycle 6 will have 
confirmatory imaging after Cycle 8. 
 
16.2 
Technical Guidelines for Imaging Studies 
16.2.1 CT and MRI guidelines are available on the COG Member site at: 
http://members.childrensoncologygroup.org/_files/reference/RefMaterial/Diagno
sticImagingGuidelines_MRI&CT.pdf 
 
16.2.2 X-ray 
AP and lateral radiographs of primary tumor and bone metastases 


  
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16.2.3 Bone Scan (Recommended)  
MDP bone scintigraphy  
•
Whole body bone scintigraphy should be performed and include 
planar images of the skeleton, including anterior and posterior views 
of the axial skeleton. Anterior and/or posterior views should be 
obtained of the appendicular skeleton. 
•
Delayed (skeletal phase) images should be performed in all cases with 
flow and blood pool images as per local custom and clinical need. 
•
Dose Administration: Dose administered should be according to 
standard weight-based protocols. Injection site should be away from 
lesion extremity or contralateral extremity if flow imaging is to be 
performed. Three-phase imaging is not required unless warranted by 
symptoms for a focal lesion to assess hyperemia. 
•
Imaging Parameters: Whole body delayed imaging is acquired 2-
3 hours after injection of the radiopharmaceutical. Spot views should 
be acquired of specific sites of symptoms or of any sites of 
abnormality as warranted by the whole body views. 
•
Single-photon 
emission 
computed 
tomography 
(SPECT) 
is 
recommended, but not required, particularly in cases with suspicion of 
lung metastases. 
•
SPECT Imaging: SPECT should be performed of the lesion site. 
SPECT imaging should be performed as recommended by the camera 
manufacturer. Typical acquisition and processing parameters are 360° 
circular orbit, 60–120 stops, 64 ´ 64 ´ 16 or greater matrix, and 10–
40 s/stop. An equivalent total number of counts should be acquired if 
continuous acquisition is used. 
•
Special Consideration: Imaging of pelvis can be difficult due to 
overlying bladder activity. To lessen this problem, repeat imaging can 
be 
performed 
immediately 
after 
patient 
voiding. 
Bladder 
catheterization may be used, but should be reserved for patients in 
whom visualization of the pelvis is essential. For SPECT acquisition 
of the pelvis: Single or multiple rapid (5-10 min/acquisition) SPECT 
acquisition(s) are preferred to avoid artifacts caused by changing 
activity in the bladder. Bladder artifacts are exaggerated in the plane 
in which the SPECT acquisition begins and ends. Beginning SPECT 
acquisition with the camera heads in the left and right lateral positions 
(for dual-head camera) or posterior position (for single-head camera) 
will help reduce bladder filling artifact.  
 
16.2.4 [18F]–Fluorodeoxyglucose Positron Emission Tomography (FDG PET) Imaging 
(Recommended) 
FDG PET imaging is optional, but is encouraged for all patients. The primary 
lesion must be ≥ 1 cm on baseline anatomic imaging in order for a FDG PET scan 
to be performed. If done, FDG PET imaging should be performed prior to the start 
of therapy and following Cycle 2, Cycle 4, Cycle 6 and following every 3rd cycle 
thereafter.  


  
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Patient Guidelines 
The patient should fast for at least 4 hours prior to injection of FDG. FDG PET 
imaging may follow a MUGA study on the same day, or FDG PET imaging may 
be performed on the day preceding this study. Plasma glucose should be checked 
and, if the patient is hyperglycemic (plasma glucose > 250 mg/dL), appropriate 
treatment with small doses of insulin may be given to bring the plasma glucose 
into the normal range prior to FDG PET imaging. However, insulin administration 
may result in excessive muscle uptake of FDG and consequent tumor non-
visualization. If possible, the study should be postponed until the plasma glucose 
is under better control. 
 
Good hydration is required, as the primary route of FDG excretion is renal. The 
patient should drink water or receive intravenous fluids (not containing dextrose) 
after FDG injection to promote urinary excretion of the radioactive substrate. After 
injection, the patient must be kept in a resting state for 45-60 minutes prior to 
imaging. The patient should empty the bladder immediately prior to imaging. 
 
Imaging Technique 
The technique will vary by local institutional guidelines. In general, FDG is 
administered intravenously at a dose of 0.125-0.200 mCi/kg or by algorithms that 
adjust the dose by body surface area, with a minimum total dose of 2.0 mCi and 
maximum total dose of 20.0 mCi.  
 
The body should be imaged from the top of the ears to the bottom of the feet. If 
there is suspicion of involvement of the skull or skull contents, the volume that is 
imaged should be expanded.  
 
Imaging with a dedicated positron emission tomograph/computed tomography 
(PET/CT) camera is standard.   
 
The length of time needed to perform head to toe CT will depend on the patient’s 
height but will be approximately 45 seconds. Contiguous axial images should be 
obtained at 5 mm thickness using 90 mA and 120 Kv and adjusted for local 
institutional protocol. No oral or IV contrast is required but either or both are 
permissible and may be of benefit in cases where intraabdominal or pelvic 
pathology is a specific concern. With regard to patient positioning, the arms can 
be placed in a comfortable position at the patient’s sides as long as they fit into the 
field of view. If the patient is large it may be necessary to lay the arms across the 
abdomen and hold in position with a stabilizing device. 
 
Study Processing 
The FDG PET study is processed for display by an iterative reconstruction 
algorithm. FDG activity should be corrected for attenuation, scatter, and 
radioactive decay. Attenuation correction is necessary, as apparent uptake will 
otherwise vary with depth of the lesion in the body and the nature of surrounding 
tissues. The procedure used for attenuation correction should be recorded. The 
level of tumor uptake is assessed subjectively by visual inspection and semi-
quantitatively by determination of standardized uptake values (SUV). Uptake time, 
glucose levels, and partial volume effects influence both methods. The SUV 


  
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method is also dependent on body weight, and correction of SUV by normalizing 
for body surface area (BSA) reduces this dependency on body weight. SUVs 
should be calculated for lesions known to be 1.2 cm or larger in diameter. Smaller 
lesions may have underestimated SUVs due to partial volume averaging effects at 
typical scanner resolutions (0.6-1.2 cm). 
 
To calculate the SUV, a region of interest (ROI) should be carefully drawn around 
as much of the area of elevated FDG uptake as can be done. The SUV should be 
calculated as SUVBSA = ROI activity concentration (nCi/cc) x BSA / injected 
activity (nCi). SUVMAX is obtained by determining the activity of the pixel with 
the highest FDG uptake. 
 
The BSA is calculated from body mass (kg) and height (cm) using an appropriate 
algorithm. The SUVBSA for each measured lesion should be recorded and the 
technique for assessing SUVBSA should be consistent on follow-up studies. 
 
 
 


  
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RELATIONSHIP BETWEEN CHANGE IN SINGLE DIAMETER (RECIST), PRODUCT OF 
TWO DIAMETERS (WHO), AND THREE PERPENDICULAR DIAMETERS (“VOLUME”) 
 
Target lesions at baseline must measure greater than 1 cm; if these target lesions decrease in size to below 
1 cm, care should be taken in measuring and inadvertently progressing a patient due to minimal changes in 
measurement from a nadir value below 1 cm, which may be within measurement error. When multiple 
primary or metastatic masses are present, all masses will be described. However, up to 5 target masses 
should be measured, using the same method in subsequent follow ups.  
 
 
 
 
 
 
Diameter, 2R 
Product, (2R)2 
Volume, 4/3R3 
 
Response 
 
Decrease 
Decrease 
Decrease 
 
 
 
30% 
 
    50%   
65% 
 
 
 
50% 
 
   75%  
87% 
 
Disease Progression 
   Increase 
Increase 
Increase 
 
 
 
12% 
 
    25%  
  40% 
 
 
 
20% 
                   44%                  73% 
 
 
 
25% 
                   56%                  95% 
 
 
 
30% 
                   69%               120% 
 
Z
AXIS
W
T
A
B
C
D
E
COG GUIDELINE: TUMOR SIZE 
MEASUREMENT BASED ON CROSS-
SECTIONAL IMAGING
A, B, C, D, & E are contiguous parallel slices     
in the X-Y plane (usually axial) showing the 
tumor
W and T are the maximal perpendicular 
diameters on the slice (C in this example) 
showing the largest surface area
Tumor length in the Z-axis (L) (perpendicular 
to X-Y plane) can be obtained either by the [a] 
(difference in table position of the first and last 
slices showing the tumor plus one slice
thickness), or [b] the product of ([slice 
thickness + gap] and the number of slices 
showing the tumor) minus one gap distance
• WHO criteria: TxW is used
• RECIST: the larger of the two (T & W) is      
used (W in this example)
• Elliptical model volume=0.5 LxWxT
• The same modality and measurement method 
used in the initial imaging should be used in 
follow ups
X-Y
PLANE
L


  
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APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
CTEP INVESTIGATOR 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, 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 
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 will be needed to access all CTEP and CTSU (Cancer Trials 
Support Unit) websites and applications, including the CTSU members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>. For questions, please contact 
the CTEP Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 


  
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Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the AOST1521 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
▪Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
▪Click on the Protocols tab in the upper left of your screen 
▪Click on the COG link to expand, then select trial protocol AOST1521 
▪Click on the Site Registration Documents link 
 
Requirements for AOST1521 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI 
CIRB)  
 
Submitting Regulatory Documents: 
 
Submit completed forms along with a copy of your IRB Approval 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) 
 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS site registration status page 
of the members’ section of the CTSU website. (Note: Sites will not receive formal notification of 
regulatory approval from the CTSU Regulatory Office.) 
▪Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪Click on the Regulatory tab at the top of your screen 
▪Click on the Site Registration tab 
▪Enter your 5-character CTEP Institution Code and click on Go 
 
 
 


  
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APPENDIX II:  YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY AOST1521 
(for subjects from 7 to 12 years of age) 
 
A trial using a new drug, CDX-011, to treat osteosarcoma that has not responded to treatment or that has 
come back 
 
 
1. 
We have been talking with you about your illness, osteosarcoma. Osteosarcoma is a type of cancer 
that grows in the cells that produce bones. After doing tests, we have found that you have this type of 
cancer and it has not gotten better with treatment or it has come back.  
 
2. 
We are asking you to take part in a research study because you have osteosarcoma and it has not gotten 
better with treatment or it has come back. A research study is when doctors work together to try out 
new ways to help people who are sick. In this study we are trying to learn more about how to treat 
osteosarcoma that has come back. We will do this by giving a new drug to treat osteosarcoma. We do 
not know how well the new drug will work in children, teens and young adults. That is why we are 
doing this study.  
 
3. 
Children who are part of this study will be given an experimental new drug called CDX-011. You will 
also have scans to see if the cancer is getting worse, staying the same or getting better. There is a 
possibility that you will also have surgery or radiation therapy (high energy x-rays to kill cancer cells) 
while you are part of this study. Surgery and radiation therapy are often used to treat osteosarcoma 
and they are not experimental. 
 
4. 
Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that you are able to get 
rid of the cancer. But we don’t know for sure if there is any benefit of being part of this study. 
 
5. 
Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” Being in this study may involve special risks, which your doctor will discuss with you. 
Other things may happen to you that we don’t yet know about. 
 
6. 
Your family can choose to be part of this study or not. Your family can also decide to stop being in 
this study at any time once you start. There may be other treatments for your illness that your doctor 
can tell you about. Make sure to ask your doctors any questions that you have.  
 
7. 
We are trying to learn about how children’s bodies handle the new drug CDX-011. If you are getting 
treatment at certain hospitals, we will take extra blood samples from you for research tests. These 
samples will be drawn through your central line if you have one. 
 
If you are getting treatment at a different hospital, we are asking your permission to collect additional 
blood. We are trying to learn how child and teenage bodies handle the new drug. These additional 
blood tests may help children, teens and adults who take this drug in the future. These blood tests will 
require additional blood draws, which will be drawn through your central line if you have one. You 
can still be treated on this study even if you don't allow us to collect the extra blood samples for 
research.  


  
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INFORMATION SHEET REGARDING RESEARCH STUDY AOST1521 
(for subjects from 13 to 17 years of age) 
 
A trial using a new drug, CDX-011, to treat osteosarcoma that has not responded to treatment or that has 
come back 
 
 
1. 
We have been talking with you about your illness, osteosarcoma. Osteosarcoma is a type of cancer 
that grows in the cells that produce bones. Recurrent means that the cancer has come back after 
treatment. After doing tests, we have found that you have this type of cancer.  
 
2. 
We are asking you to take part in a research study because you have recurrent osteosarcoma. A 
research study is when doctors work together to try out new ways to help people who are sick. In this 
study we are trying to learn more about how to treat osteosarcoma that has come back. We will do this 
by giving a new drug to treat recurrent osteosarcoma. We do not know how well the new drug will 
work in children, teens and young adults. That is why we are doing this study.  
 
3. 
Children and teens and young adults who are part of this study will be given an experimental new drug 
called CDX-011. You will also have scans to see if the cancer is getting worse, staying the same or 
getting better. There is a possibility that you will also have surgery or radiation therapy (high energy 
x-rays) while you are part of this study. Surgery and radiation therapy are commonly used to treat 
osteosarcoma and they are not experimental. 
 
4. 
Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that you are able to get 
rid of the cancer. But we don’t know for sure if there is any benefit of being part of this study. 
 
5. 
Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” Being in this study may involve special risks, which your doctor will discuss with you. 
Other things may happen to you that we don’t yet know about. 
 
6. 
You or your family can choose to be part of this study or not. Your family can also decide to stop 
being in this study at any time once you start. Please talk this over with your parents. Together you 
can decide if you want to take part in the study or not. There may be other treatments for your illness 
that your doctor can tell you about. Make sure to ask your doctors any questions that you have.  
 
7. 
We are trying to learn about how children’s bodies handle the new drug CDX-011. If you are getting 
treatment at certain hospitals, we will take extra blood samples from you for research tests. These 
samples will be drawn through your central line if you have one. 
 
If you are getting treatment at a different hospital, we are asking your permission to collect additional 
blood. We are trying to learn how child and teenage bodies handle the new drug. These additional 
blood tests may help children, teens and adults who receive this drug in the future. These blood tests 
will require additional blood draws, which will be drawn through your central line if you have one. 
You can still be treated on this study even if you don't allow us to collect the extra blood samples for 
research.  


  
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APPENDIX III:  POSSIBLE DRUG INTERACTIONS  
The list below does not include everything that may interact with chemotherapy. Study Subjects and/or 
their Parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in diet. 
 
Drugs that may interact with CDX-011 (glembatumumab vedotin)* 
• 
Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• 
Antifungals  
o Itraconazole, ketoconazole, posaconazole, voriconazole) 
• 
Arthritis medications 
o Leflunomide, tofacitinib 
• 
Anti-rejection medications 
o Cyclosporine, sirolimus, tacrolimus 
• 
Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, 
fosamprenavir, indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, 
saquinavir, Stribild, telaprevir 
• 
Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• 
Heart medications  
o Nicardipine, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Many other drugs, including the following: 
o Aprepitant, 
bosentan, 
deferasirox, 
dexamethasone, 
lomitapide, 
natalizumab, nefazodone 
Food and supplements** that may interact with  CDX-011 (glembatumumab vedotin) 
• 
Echinacea 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
  
*Sometimes these drugs are used with CDX-011 (glembatumumab vedotin) on purpose.  Discuss 
all drugs with your doctor. 
**Supplements may come in many forms such as teas, drinks, juices, liquids, drops, capsules, 
pills, and dried herbs. All forms should be avoided.  


  
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APPENDIX IV:  PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions 
with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the experimental study 
drug, CDX-011. 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.  
 
These are the things that you as a healthcare provider need to know: 
  
CDX-011 (glembatumumab vedotin) interacts with certain specific enzymes in your liver* and certain 
transport proteins that help move drugs in and out of cells**.  
 
• *The enzyme in question is CYP3A4. CDX-011 (glembatumumab vedotin) is metabolized by 
CYP3A4. Patients must be closely monitored for adverse reaction if strong inhibitors or inducers 
are administered with CDX-011 (glembatumumab vedotin). 
• **The protein in question is P-glycoprotein (P-gp). CDX-011 (glembatumumab vedotin) requires P-
gp to move in and out of cells. Patients receiving P-gp inhibitors concomitantly with CDX-011 
(glembatumumab vedotin) should be closely monitored for adverse reactions. 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
CDX-011 (glembatumumab vedotin) may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you enroll onto 
this clinical trial. It is also very important to tell your doctors if you stop taking any regular medicines, or 
if you start taking a new medicine while you take part in this study. When you talk about your current 
medications with your doctors, include medicine you buy without a prescription (over-the-counter remedy), 
or any herbal supplements such as St. John’s Wort. It is helpful to bring your medication bottles or an 
updated medication list with you. 
 
Many health care providers can write prescriptions. You must tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
CDX-011 (glembatumumab vedotin) must be used very carefully with other medicines that use certain liver 
enzymes or transport proteins to be effective or to be cleared from your system. Before you enroll onto the 
clinical trial, your study doctor will work with your regular health care providers to review any medicines 
and herbal supplements that are considered “strong inducers/inhibitors or substrates of CYP3A4 or transport 
protein P-gp”. 
 
• Please be very careful! Over-the-counter drugs (including herbal supplements) may contain ingredients 
that could interact with your study drug. Speak to your doctors or pharmacist to determine if there could 
be any side effects.  
• Your regular health care provider should check a frequently updated medical reference or call 
your study doctor before prescribing any new medicine or discontinuing any medicine. Your 
study doctor’s name is __________________________________ and he or she can be 
contacted at _____________________________________. 
 


  
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CDX-011 (glembatumumab vedotin) interacts with a specific liver 
enzyme called CYP3A4 and transport protein P-gp and must be used 
very carefully with other medicines that interact with this enzyme or 
transporter.  
➢ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines  and herbal supplements that are considered “strong 
inducers/inhibitors or substrates of CYP3A4 or P-gp 
transporter.”  
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
CDX-011 (glembatumumab vedotin). This clinical trial is sponsored by 
the NCI. CDX-011 (glembatumumab vedotin) may interact with drugs 
that are processed by your liver or use certain transport proteins in 
your body. Because of this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 
 
 
 


  
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