A Phase 1/2 Study of VX15/2503 in Children, Adolescents, or Young Adults With Recurrent or Relapsed Solid Tumors
Phase: PHASE1
Conditions: Recurrent Malignant Solid Neoplasm, Recurrent Osteosarcoma, Refractory Malignant Solid Neoplasm, Refractory Osteosarcoma
Sponsor: Children's Oncology Group

                             
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Activated: 
January 16, 2018 
 
Version Date: 01/31/2019 
Closed: 
April 24, 2020 
 
Amendment #: 3 
 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
ADVL1614 
 
 
A PHASE 1/2 STUDY OF VX15/2503 
 in Children, Adolescents, or Young Adults 
with Recurrent or Relapsed Solid Tumors 
 
 
 
Lead Organization: COG Pediatric Early Phase Clinical Trials Network (PEP-CTN) 
 
 
 
 
 
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 
 
 
  
 
 
 
 
 
 
 
For PEP-CTN Operations and Data/Statistics Contacts see: http://members.childrensoncologygroup.org 
 
 

                             
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TABLE OF CONTENTS 
SECTION 
PAGE 
 
CHILDREN’S ONCOLOGY GROUP 
1 
STUDY COMMITTEE 
5 
STUDY COMMITTEE, CONT. 
6 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1. 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
 
Primary Aims 
9 
 
Secondary Aims 
9 
 
Exploratory Aim 
9 
 
BACKGROUND 
9 
 
Introduction/Rationale for Development 
9 
 
Preclinical Studies 
11 
 
Adult Studies 
17 
 
Pediatric Studies 
18 
 
Overview of Proposed Pediatric Study 
18 
 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
20 
 
Current Study Status 
20 
 
IRB Approval 
20 
 
Patient Registration 
21 
 
Reservation and Contact Requirements 
21 
 
Informed Consent/Assent 
21 
 
Screening Procedures 
21 
 
Eligibility Checklist 
21 
 
Institutional Pathology Report 
22 
 
Study Enrollment 
22 
 
Dose Assignment 
22 
 
PATIENT ELIGIBILITY 
22 
 
Inclusion Criteria 
23 
 
Exclusion Criteria 
26 
 
TREATMENT PROGRAM 
27 
 
Overview of Treatment Plan 
27 
 
Criteria for Starting Subsequent Cycles 
27 
 
Dose Confirmation Schema (Completed) 
27 
 
Part B 
28 
 
Grading of Adverse Events 
28 
 
Definition of Dose-Limiting Toxicity (DLT) 
28 
 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
29 
 
Dose Modification for Day 1 Dosing 
29 
 
Dose Modifications for Day 15 Dosing due to Toxicity on Day 15. 
30 
 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
32 
 
Concurrent Anticancer Therapy 
32 
 
Investigational Agents 
32 

                             
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Supportive Care 
32 
 
Growth Factors 
32 
 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
33 
 
Required Clinical, Laboratory and Disease Evaluation 
33 
 
Radiology Studies 
34 
 
Pharmacology (Required) 
35 
 
Immunogenicity Study (Required) 
36 
 
Pharmacodynamics:  T-lymphocyte saturation (Required) 
37 
 
Pharmacodynamics: Total soluble SEMA4D (Required) 
38 
 
Tumor Assessment (archival-required and biopsy-optional) 
39 
 
AGENT INFORMATION 
40 
 
VX15/2503 
40 
 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
43 
 
Criteria for Removal from Protocol Therapy 
43 
 
Off Study Criteria 
43 
 
STATISTICAL AND ETHICAL CONSIDERATIONS 
44 
 
Sample Size and Study Duration 
44 
 
Definitions 
44 
 
Determination of MTD 
45 
 
Inclusion of Children, Women and Minorities 
46 
 
Pharmacokinetic and Correlative Studies and Response Analysis 
47 
 
Study Design - Part B 
47 
 
Method of Analysis – Phase 2 
49 
 
EVALUATION CRITERIA 
50 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
50 
 
Response Criteria for Patients with Solid Tumors 
50 
 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
55 
 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
56 
 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
58 
 
Best Response 
58 
 
ADVERSE EVENT REPORTING REQUIREMENTS 
59 
 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
60 
 
When to Report an Event in an Expedited Manner 
62 
 
Expedited Reporting Methods 
62 
 
Definition of Onset and Resolution of Adverse Events 
63 
 
Other Recipients of Adverse Event Reports 
63 
 
Reporting Secondary AML/MDS 
63 
 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
64 
 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
65 
 
Categories of Research Records 
65 
 
CDUS 
65 
 
Data and Safety Monitoring Plan 
66 
REFERENCES 
67 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
68 
APPENDIX II: CORRELATIVE STUDIES GUIDE 
69 

                             
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APPENDIX III: TOXICITY-SPECIFIC GRADING 
70 
APPENDIX IV: PHARMACOKINETIC STUDY FORM FOR PATIENTS > 10KG 
71 
APPENDIX V: IMMUNOGENICITY STUDY FOR PATIENTS > 10KG 
73 
APPENDIX VI: PHARMACODYNAMICS T-LYMPHOCYTE SATURATION (FOR ALL 
PATIENTS) 
74 
APPENDIX VII: PHARMACODYNAMICS TOTAL SOLUBLE SEMA4D FOR                        
PATIENTS > 10KG 
75 
APPENDIX VIII: TISSUE STUDIES FORM 
76 
APPENDIX IX: PHARMACOKINETIC STUDY FORM FOR PATIENTS ≤ 10KG 
77 
APPENDIX X: IMMUNOGENICITY STUDY FOR PATIENTS ≤ 10KG 
78 
APPENDIX XI: PHARMACODYNAMICS TOTAL SOLUBLE SEMA4D FOR PATIENTS  ≤ 10KG 79 
APPENDIX XII: YOUTH INFORMATION SHEETS 
80 
APPENDIX XIII: YOUTH INFORMATION SHEETS 
81 
 

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STUDY COMMITTEE, CONT. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IND Sponsor: COG 
 
 
 
 
For PEP-CTN Operations and Data/Statistics Contacts   see: http:members.childrensoncologygroup.org 
 
SEE SECTION 8.3.6, 8.4.6, 8.5.6, 8.6.6, and 8.7.3 FOR SPECIMEN SHIPPING ADDRESSES 

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This trial is covered by 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 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 
 
Semaphorins consist of a family of soluble and transmembrane proteins, originally defined as axonal-
guidance factors1.  Binding of Semaphorin 4D (SEMA4D, CD100) to cells expressing the cognate plexin 
B1/2 receptors can induce cytoskeletal changes in immune, endothelial, and tumors cells and regulate their 
migration and differentiation within the tumor microenvironment (TME).2-4 SEMA4D has been shown to 
regulate leukocyte infiltration into tumors and promote tumor growth.  Immunohistochemical analysis of 
SEMA4D expression on tissues from several human tumor types has shown that SEMA4D is overexpressed 
in multiple malignancies, including urogenital, ovarian, pancreatic, head and neck, prostate, colon, breast, 
and lung cancer and correlates with invasive disease and poor prognosis.5,6,7 Expression of SEMA4D by 
tumor and cells of the tumor microenvironment, including inflammatory cells and tumor-associated 
macrophages, may be regulated by hypoxia. Additionally, strong expression of SEMA4D at the invasive 
margins of actively growing tumors influences distribution of leukocytes in the tumor microenvironment.8 
Investigators have studied the expression of SEMA4D in a variety of soft tissue sarcomas; two separate 
analyses have shown high level expression to correlate with poor prognosis and overall disease free 
survival.6,7   Recently, through a Sleeping Beauty forward genetic screen that induced osteosarcoma in mice, 
analysis of common insertion site-associated genes found SEMA4D to be a strong candidate proto-
oncogene. Human osteosarcoma tumors demonstrated up-regulation of SEMA4D compared to normal 
human osteoblasts. Expression was confirmed in nearly all human osteosarcomas, with high level 
expression in over half of the tumors.9 Over-expression of SEMA4D in osteosarcoma cell lines led to 
activation of MET or ERBB2 and subsequent increased phosphorylation of AKT and/or ERK. In addition, 
overexpression of SEMA4D resulted in increased colony formation in soft agar and proliferation and 
xenograft tumor formation in immunodeficient mice. The oncogenic role of SEMA4D in osteosarcoma was 
further confirmed by shRNA knockdown which resulted in significantly decreased colony formation.9  
VX15/2503 is a humanized IgG4 monoclonal antibody that binds specifically to the SEMA4D (CD100) 
antigen, blocking the binding of SEMA4D to its high affinity receptor, plexin B1 (PLXNB1), plexin B2 
(PLXNB2), and a low-affinity receptor, CD72. It has strong affinity for SEMA4D with an antibody-antigen 
dissociation constant (Kd) ranging from 1-5 nM.10 Treatment of osteosarcoma cell lines with VX15/2503 
resulted in decreased cell migration and colony formation as compared to controls. Additionally, a 
syngeneic mouse model of osteosarcoma treated with MAb67-2, a mouse analog of VX15/2503, had 

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significantly reduced tumor growth compared to controls.10 
This is a parallel phase 1/2 study of VX15/2503 in children and adolescent/young adults with relapsed or 
refractory solid tumors and osteosarcoma, respectively.  The phase 1 study will employ a rolling six design, 
whereas the phase 2 study will employ a two-stage design.  The aims of the phase 1 study include to 
determine the maximum tolerated dose or recommended phase 2 dose of VX15/2503 in children, as well 
as defining the pharmacokinetic and pharmacodynamic activity of VX15/2503 in pediatric malignancies.  
The aim of the phase 2 study will be to determine the activity of VX15/2503 in treating relapsed or 
refractory osteosarcoma. 
 
 
EXPERIMENTAL DESIGN SCHEMA 
 
Part A & B Treatment Schedule Table  
Cycles- 28 day duration 
Agent 
 
 
 
 
 
Day 1                Day 15                Day 28 
VX15/2503 intravenous infusion 
over 60 minutes 
 
Treatment will be discontinued if there is evidence of progressive disease or drug-related dose-
limiting toxicity that requires removal from therapy. Patients with stable disease or greater response 
may continue receiving protocol therapy provided that the patient meets the criteria for starting 
subsequent cycles (Section 5.2) and does not meet any of the criteria for removal from protocol 
therapy or off study criteria (Section 10.0). 
 
Infusion 
Infusion 
Evaluation 

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1. 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
 
Primary Aims 
 
 
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 
dose of VX15/2503 administered as an intravenous infusion every 14 days to 
children with recurrent or refractory solid tumors (Part A) 
 
 
To define and describe the toxicities of VX15/2503 administered on this schedule 
(Parts A-B) 
 
 
To characterize the pharmacokinetics of VX15/2503 in children with recurrent or 
refractory cancer (Parts A-B) 
 
 
To preliminarily define the antitumor activity of VX15/2503 for the treatment of 
relapsed or refractory osteosarcoma (Part B)  
 
 
To determine if VX15/2503 either improves the disease control rate at 4 months 
in patients with recurrent measurable osteosarcoma or produces an objective 
response rate in patients with relapsed or refractory osteosarcoma (Part B) 
 
 
Secondary Aims 
 
 
To assess the pharmacodynamics of VX15/2503 through VX15/2503 saturation 
of T-lymphocytes 
 
 
To assess the immunogenicity of VX15/2503 in pediatric patients with recurrent 
or refractory cancer. 
 
Exploratory Aim 
 
 
To evaluate potential biomarkers of VX15/2503 sensitivity including SEMA4D, 
PlexinB1, and other markers of immune cell infiltration in archival tumor tissues.   
 
 
 
BACKGROUND 
 
 
Introduction/Rationale for Development 
 
Semaphorins consist of a family of soluble and transmembrane proteins, originally defined 
as axonal-guidance factors.1 Binding of Semaphorin 4D (SEMA4D, CD100) to cells 
expressing the cognate plexin B1/2 receptors can induce cytoskeletal changes in immune, 
endothelial, and tumors cells and regulate their migration and differentiation within the 
tumor microenvironment (TME).2-4 SEMA4D has been shown to regulate leukocyte 
infiltration into tumors and promote tumor growth. 
 
Immunohistochemical analysis of SEMA4D expression on tissues from several human 
tumor types has shown that SEMA4D is overexpressed in multiple malignancies, including 
urogenital, ovarian, pancreatic, head and neck, prostate, colon, breast, and lung cancer and 
correlates with invasive disease and poor prognosis.5,6,7 Expression of SEMA4D by tumor 

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and cells of the tumor microenvironment, including inflammatory cells and tumor-
associated macrophages, may be regulated by hypoxia. Additionally, strong expression of 
SEMA4D at the invasive margins of actively growing tumors influences distribution of 
leukocytes in the tumor microenvironment.8 Investigators have studied the expression of 
SEMA4D in a variety of soft tissues sarcomas; two separate analyses have shown high 
level expression to correlate with poor prognosis and overall disease free survival.6,7  
 
Recently, through a Sleeping Beauty forward genetic screen that induced osteosarcoma in 
mice, analysis of common insertion site-associated genes found SEMA4D to be a strong 
candidate proto-oncogene. Human osteosarcoma tumors demonstrated up-regulation of 
SEMA4D compared to normal human osteoblasts. Expression was confirmed in nearly all 
human osteosarcomas, with high level expression in over half of the tumors.9 Over-
expression of SEMA4D in osteosarcoma cell lines led to activation of MET or ERBB2 and 
subsequent increased phosphorylation of AKT and/or ERK. In addition, overexpression of 
SEMA4D resulted in increased colony formation in soft agar and proliferation and 
xenograft tumor formation in immunodeficient mice. The oncogenic role of SEMA4D in 
osteosarcoma was further confirmed by shRNA knockdown which resulted in significantly 
decreased colony formation.9   
 
The role of SEMA4D and potential application of an anti-SEMA4D antibody is likely 
much broader than osteosarcoma. SEMA4D is expressed on cells within the tumor stroma 
and modulates the activity of the immune system. Expression of SEMA4D by tumor 
associated macrophages (TAMs) can be regulated by hypoxia and contribute to aggressive 
tumor growth. High levels of SEMA4D positively correlate with the presence of 
immunosuppressive TAMs and myeloid-derived suppressor cells (MDSCs) with 
concomitant exclusion of activated antigen presenting cells (APCs) and CD8+ cytotoxic T 
lymphocytes (CTLs) from the tumor. Antibody neutralization of SEMA4D results in a 
marked redistribution of immune cells at the tumor invasive margins in multiple tumor 
models. This includes an increased frequency of activated tumor-infiltrating macrophages, 
a significant increase in intratumoral CD8+ T cells and dispersion of M2 TAMs and 
MDSCs. Increased levels of interferon γ (IFNγ) and tumor necrosis factor α (TNFα) are 
also seen, indicating a shift to a pro-inflammatory environment. Treatment with anti-
SEMA4D antibody also increases Teffector:Tregulatory (Teff:Treg) cell ratios within the 
tumor and tumor-specific cytotoxic T-cell activity. This immunologic response is localized 
to the tumor, with minimal T-cell and cytokine activity in the peripheral lymphoid organs. 
This is important because it has been reported that efficient entry of functional tumor-
specific T-cells into the tumor correlated with improved survival and response to 
immunotherapy.12,15 
 
The combined role of SEMA4D in tumorigenesis from both the tumor cells and tumor 
microenvironment and the fact that it is a cell surface and soluble ligand makes it an 
attractive therapeutic target. Similar to checkpoint inhibitors, its role in controlling the 
tumor microenvironment by modulating interactions with key players in the immune 
system make it an attractive target for many pediatric malignancies, however, its additional 

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roles in osteosarcoma tumorigenesis make it particularly applicable to this disease. 
 
VX15/2503 is a humanized IgG4 monoclonal antibody that binds specifically to the 
SEMA4D (CD100) antigen, blocking the binding of SEMA4D to its high affinity receptor, 
plexin B1 (PLXNB1), plexin B2 (PLXNB2), and a low-affinity receptor, CD72. It has 
strong affinity for SEMA4D with an antibody-antigen dissociation constant (Kd) ranging 
from 1-5 nM.10 Treatment of osteosarcoma cell lines with VX15/2503 resulted in decreased 
cell migration and colony formation as compared to controls. Additionally, a syngeneic 
mouse model of osteosarcoma treated with MAb67-2, a mouse analog of VX15/2503, had 
significantly reduced tumor growth compared to controls.10 
 
 
 
Preclinical Studies 
 
 
Antitumor Activity 
 
VX15/2503 and the surrogate mouse MAb67-2 have demonstrated activity in both in vitro 
and in vivo tumor models. In vitro studies have demonstrated the agent’s ability to block 
the functional effects of SEMA4D binding to PLXNB1.11 In preclinical models, anti-
SEMA4D antibody blockade regulates the balance and activity of inflammatory and 
tolerance inducing cells and cytokines. This results in specifically increasing cytotoxic T-
cell infiltration and activity resulting in delayed tumor growth and durable tumor rejection 
in syngeneic murine tumor models.12 
 
 
 
Treatment with a murine monoclonal antibody to SEMA4D (MAb67-2) was evaluated in 
a syngeneic murine model of colorectal cancer using Colon26 cells. Mice were treated 
weekly with 10 mg/kg of MAb67-2 (aSEMA4D) or isotype control (Control Ig) 
intraperitoneally for 30 days. Treatment with anti-SEMA4D antibody promoted infiltration 
of activated macrophage and cytotoxic T-cells, with a reduction in infiltration of immune-
suppressive T-regulatory and Myeloid Derived Suppressor Cells (MDSC) (Figure 2).  
 
Figure 1. rSEMA4D (1 µg/ml) added 
to the lower chamber of a transwell 
inhibits spontaneous migration of 
mouse macrophage cell line, 
RAW264.7 
 

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Preclinical models have demonstrated the importance of saturation of SEMA4D in that loss 
of saturation on circulating T-cells correlates with the minimal drug concentration needed 
for efficacy. 
 
Through work at the University of Minnesota, SEMA4D expression has been extensively 
evaluated in osteosarcoma. The majority of human osteosarcoma cell lines tested express 
high amounts of SEMA4D transcript as evaluated by RT-qPCR (Figure 3). In addition, 
SEMA4D expression was analyzed in human tumor tissue microarrays of synovial 
sarcoma, neuroblastoma, and rhabdomyosarcoma. There was low level expression in 8/30 
neuroblastoma tumors, 2/50 synovial sarcoma tumors, and 1/104 rhabdomyosarcoma 
tumors, while SEMA4D was strongly expressed on immune infiltrate in these samples. 
 
A  
B  
C  
D  
Figure 2. Changes in immune function after treatment with infiltration and rSEMA4D. 

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The effect of treatment with anti-SEMA4D (VX15/2503) on osteosarcoma growth, 
migration, and proliferation has been studied in three human osteosarcoma cell lines 
(143B, MG-63, and HOS), one Ewing sarcoma (RD-ES), and two murine osteosarcoma 
cell lines (K12, K7M2) with encouraging results. Treatment with increasing 
concentrations of anti-SEMA4D (VX15/2503) in 143B and MG-63 osteosarcoma cells 
reduces cellular migration as compared to anti-CD20 isotype control antibody (Figure 
4). Treatment of 143B and HOS cells with 5 microgram/mL and 1 microgram/mL of 
VX15/2503 respectively demonstrated statistically significant decreases in colony 
formation as compared to control treatment. Similarly, treatment with 5 
micrograms/mL also reduced colony formation in a human Ewing sarcoma cell line 
RD-ES when compared to anti-CD20 isotype control antibody (Figure 5). Finally, 
cellular proliferation was evaluated via the MTS proliferation assay in MG-63 and 143B 
osteosarcoma cell lines. Treatment of 5 micrograms/mL and 1 microgram/mL in MG-
63 and 143B cells significantly reduced cellular proliferation on day 3 and days 2 and 
3 post-plating, respectively (Figure 6). Interestingly, exposure to soluble SEMA4D 
(CD100) markedly increased migration in three osteosarcoma cell lines (Figure 7) (data 
courtesy of Dr. Branden Moriarity, University of Minnesota). 
 
Figure 3. RT-PCR analysis of 
SEMA4D transcript levels in 
osteosarcoma cell lines, PDXs, and 
immortalized osteoblasts. 

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                               Figure 4.  Osteosarcoma cell migration assays 
                 Figure 5. Osteosarcoma colony formation assays 
            Figure 6.  Osteosarcoma proliferation (MTS) assay 

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Downstream signaling mediators as well as a co-receptor of SEMA4D, MET, were 
probed in 143B (Figs. 8A & B) and HOS (Fig. 8C) osteosarcoma cell lines following 
30’ of treatment with either CD20 isotype control or VX15/2503 anti-SEMA4D 
antibody. Treatment with VX15/2503 reduced total AKT, activated ERK as well as total 
MET levels in 143B cells 30’ post administration (A &B). Similarly, treatment with 
Figure 7. Osteosarcoma cell migration in response to soluble SEMA4D exposure 
 
Figure 8. Reduced expression of SEMA4D signaling pathway members following 
treatment with VX15. 

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VX15 in HOS cells also reduced total MET levels (C).  
 
 
 
 
 
 
 
 
 
 
Rho family GTPases such as RAC1 are thought to play a role in PLXNB receptor 
localization to the surface in the presence of ligand. Activated RAC1 expression was 
probed in 143B osteosarcoma cell lines over a 30’ time course. Treatment of 143B 
osteosarcoma cells with VX15, but not CD20 control reduced activated RAC1 levels 
(Figure 9).  
 
 
 
 
 
 
 
 
 
 
 
 
Treatment with a murine monoclonal antibody to Sema4D (MAb67-2) was evaluated in 
a syngeneic murine model of osteosarcoma using K7M2 cells. Mice were injected with 
2.5x105 cells intra-calcaneally and treated with 1 mg/kg of MAb67-2 (anti-sema4D) or 
isotype control intraperitoneally every 2 days for 30 days (Fig. 10A) or were injected 
with 1x106 and treated with 10 mg/kg of MAb67-2 (anti-sema4D) or isotype control 
intraperitoneally weekly for 30 days (Fig. 10B). Treatment with MAb67-2 resulted in 
reduced tumor growth beginning at post-implantation day 7 (PID 7) with continued 
effects observed at PID 30 when compared to control antibody (Figure 10A). Similarly, 
mice treated with 10 mg/kg experienced similar reductions in tumor growth (Figure 
A 
B 
Figure 9. Reduction in Rho family GTPase activation (RAC1) following VX15 
treatment. 
 
Figure 10. Treatment of osteosarcoma syngeneic mouse model with 
mAb67-2, murine anti-sema4D antibody 

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10B). 
 
 
Animal Toxicology 
 
No significant toxicological findings have been observed in single dose, one 
month, and six month GLP toxicology studies in Sprague Dawley rats and 
Cynomolgus macaques regardless of dose level.  The no observed adverse effect 
level (NOAEL) was 100 mg/kg to 200 mg/kg.  Immunophenotypic analysis of rat 
lymphocyte subsets performed prior to and at the end of the dosing regimen in the 
one-month study detected a statistically significant reduction in absolute and 
related NK levels in all treated animals.8 Due to lack of clinical signs or 
histopathologic changes in the animals, decreases in NK cell levels were not 
considered adverse.   In addition, a host-resistance study using rats challenged with 
flu virus after five weekly doses showed that antibody treatment was not 
immunosuppressive.   
13 
Additional studies exploring whether the absence of SEMA4D alters the 
development of fetal mice demonstrated functional defects in their immune 
system, without apparent abnormalities in other tissues.13  Furthermore, Vaccinex 
has bred CD100-deficient mice and has not noted any bony malformations.  
(personal communication from Vaccinex) 
 
 
Preclinical Pharmacokinetic Studies 
 
Formal pharmacokinetic analyses have been conducted through both single and 
multiple dose studies in Sprague Dawley rats and Cynomolgus macaques.  In 
general, longer half-lives were estimated for higher doses and the apparent volume 
of distribution estimated the serum volume for each species.  The half-life at 100 
mg/kg was about 10 days whereas that at 10 mg/kg was about 4 days.  AUC did 
not increase linearly with dose but rather increased more rapidly.8  
 
 
Adult Studies 
 
 
Phase 1 Studies 
 
A phase 1 trial of VX15/2503 in adults with advanced solid tumors demonstrated 
the antibody to be well tolerated as weekly infusions up to and including doses of 
20 mg/kg. All treatment related adverse events were Grade 1 or 2 with the 
exception of one Grade 3 GGT elevation at 15 mg/kg in a patient with progressive 
disease who had elevated GGT levels at baseline. The most common treatment 
related adverse events were nausea and fatigue.   
 
In terms of anti-tumor response, the progression free survival (PFS) was 7.82 
weeks (range: 0.57 to 54.8 weeks). One patient with papillary thyroid cancer 
treated at the 20 mg/kg dose level achieved a partial response. Nineteen patients 
(45.2%) exhibited stable disease for ≥ 8 weeks, with the longest durations of stable 
disease observed for patients with colorectal (48 weeks) and breast cancer (55 
weeks).14 
 
 

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Phase 2 Studies 
 
Phase 2 studies of VX15/2503 in adults with malignancies are in development. 
 
 
 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
 
The most accurate pharmacokinetic studies to date integrate the results of the 
Vaccinex phase 1 oncology and multiple sclerosis (MS) studies. Pharmacokinetic 
studies in adult oncology were limited due to inability to collect samples over a 
prolonged period of time. However, more extensive data collection points were 
obtained in the MS study allowing for more accurate assessment of T1/2 and 
AUC0-infinity. Based on data collected from the MS study, the half-life appears 
to increase with dose (t1/2, 20 days +/- 5 for 20 mg/kg dose, 15 days +/- 5 days for 
10 mg/kg/dose) and clearance appears to decrease with dose (0.0201 L/hr +/- 
0.0053 for 20 mg/kg dose). This may be explained by target-mediated drug 
disposition, which is commonly observed with monoclonal antibodies (MAbs).  
 
Saturation of human T-cells with cSEMA4D was analyzed in the adult phase 1 
study, with the threshold estimated to be approximately 0.3 microgram/mL. The 
extent of T lymphocyte associated SEMA4D saturation was dose independent, 
with weekly doses of VX15/2503 of 1 mg/kg or above producing complete, 
sustained cSEMA4D saturation. The time required for T-lymphocytes to become 
desaturated was dose dependent.  Cellular SEMA4D desaturation occurred with 
VX15/2503 clearance from the periphery.  The mean cSEMA4D saturation value 
at the end of infusion for all doses studied was 88% (range 68.5 to 98.7%). At the 
1 mg/kg dose level, cSEMA4D saturation fell to approximately 20% at roughly 30 
days post-infusion whereas full desaturation took greater than 155 days for the 20 
mg/kg dose level.  Cellular SEMA4D expression levels decreased approximately 
50% following VX15/2503 binding to the cell surface receptor and its 
internalization, and returned to baseline expression levels with antibody 
clearance.11,14   
 
 
Pediatric Studies 
 
 
Prior Experience in Children  
There have been no pediatric trials of VX15/2503. 
 
 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
There have been no pediatric trials of VX15/2503. 
 
 
Overview of Proposed Pediatric Study 
 
This is a phase 1/2 study of VX15/2503 in pediatric patients. The goal of Part A is to 
determine whether the adult recommended phase 2 dose (RP2D) of 20 mg/kg is both 
tolerated and deemed to be an optimal biologic dose, defined by adequate and sustained 
T-lymphocyte saturation by VX15/2503 (≥ 80% saturation).  Part A will enroll patients 
with relapsed/refractory solid tumors, excluding brain tumors, with either measurable or 
evaluable disease. Using a rolling 6 design, patients on Part A will receive 20 mg/kg of 
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interruption. If this dose is found to be tolerable and T-lymphocyte saturation is adequate 
and sustained through dosing, this will be the RP2D.  If this dose is tolerated but T-
lymphocyte saturation is not adequate or sustained, the study will be suspended while 
further dose escalation is considered. If at any time the dose level is determined to be 
intolerable, T-lymphocyte saturation will be assessed and if T-cell saturation is adequate, 
the dose will be de-escalated.  Part B will open concurrent to Part A for older patients 
with relapsed or refractory osteosarcoma. Once Part A is complete, Part B will expand to 
enroll patients of all ages with relapsed or refractory osteosarcoma and PK expansion 
cohort will open to further evaluate the pharmacokinetics of VX15/2503 in children of all 
ages with relapsed or refractory solid tumors. 
Measurable disease is required for Part B. 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 (1) disease control success and (2) RECIST 
response (CR or PR versus not CR or PR). Stage 2 will open if there are 5 or more 
disease control successes or 2 or more RECIST responders. Stage 2 will enroll 10 
evaluable patients. 
   
Dose Rationale:  In adult phase 1 studies, doses up to 20 mg/kg weekly were well 
tolerated, so we will start the study at 20 mg/kg. Modeling from adult trials suggest that 
lower doses, including 10 mg/kg, maintain saturation of SEMA4D on circulating T-cells 
throughout the dosing and follow-up periods, thus a lower dose may be biologically 
active.  Thus, if 20 mg/kg is deemed intolerable and T-lymphocyte saturation was 
adequate at 20 mg/kg, we will dose de-escalate to 10 mg/kg. This is important in 
choosing the dose as pre-clinical studies demonstrate that loss of saturation of SEMA4D 
on T-cells correlates with the minimal drug concentration needed for efficacy. The dosing 
interval is chosen based on the half-life determined in the MS study of 15 days +/- 5 days 
for the 10 mg/kg dose. Dosing on the half-life, or once every 2 weeks, should achieve a 
steady-state in 5-6 doses. Although steady-state will not be achieved until dose 5 or 6, 
based on experience from Vaccinex, we anticipate T-cell saturation to occur after the first 
dose and be maintained throughout the dosing periods. If the half-life or T-cell saturation 
is determined to be different in children, we will adjust the dosing interval accordingly.10 
 
At the time of Amendment #2A, the first 6 patients on Part A have completed the first 
cycle of treatment and no dose limiting toxicities were observed.  In addition, 5 of the 6 
patients had sufficient samples to be evaluable for T-cell saturation and all 5 patients had 
adequate and sustained saturations with ≥ 80% saturation at all time points evaluated 
after the first infusion.  Thus, the RP2D is 20 mg/kg IV every 14 days.  Given this, with 
Amendment #2A we will open Part B to patients > 12 months and < 30 years of age with 
relapsed and refractory osteosarcoma once the initial 6 adult patients complete toxicity 
assessments per Section 11.6, and we will open the PK expansion cohort to patients > 12 
months and < 21 years of age with relapsed/refractory solid tumors. 
 
 
 
 

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SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in 
conjunction with the Oncology Patient Enrollment Network (OPEN), a web-based registration 
system available on a 24/7 basis. It is integrated with the NCI Cancer Trials Support Unit (CTSU) 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
position in the RAVE database. 
 
Access requirements for OPEN:  
Investigators and site staff will need to be registered with CTEP and have a valid and active Cancer 
Therapy Evaluation Program-Identity and Access Management (CTEP-IAM) account (check at  
<https://ctepcore.nci.nih.gov/iam/index.jsp>). This is the same account (user id and password) used 
for credentialing in the CTSU members' web site. To perform registrations in OPEN, the site user 
must have been assigned the 'Registrar' role on the relevant Group or CTSU roster. 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. 
 
Current Study Status  
Investigators should refer to the COG website to determine if the study is currently open 
for accrual.  If the study is listed as active, investigators should then access the Studies 
Requiring Reservations page to ensure that a reservation for the study is available. To 
access the Studies Requiring Reservations page:  
1. Log in to https://open.ctsu.org/open/ 
2.  Click the Slot Reservation Tab. The Site Patient page opens.  
3.  Click the Report Tab. The Slot Reservation Report opens. Available Slots are 
detailed per study strata. 
 
 
IRB Approval 
NCI Pediatric CIRB approval or local IRB approval of this study must be obtained by a 
site prior to enrolling patients. Sites must submit CIRB/IRB approvals to the NCI’s Cancer 
Trials Support Unit (CTSU) Regulatory Office and allow 3 business days for processing. 
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 (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 Regulatory Tab. 
 
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. 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
 
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab 
→ Regulatory Submission 

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When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
For general (non-regulatory) questions, call the CTSU General Helpdesk at 1-888-823-
5923 or contact CTSU by email at ctsucontact@westat.com. 
 
Study centers can check the status of their registration packets by accessing the Site 
Registration Status page on the CTSU Member’s Website under the Regulatory Tab. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory 
Office.) 
 
 
Patient Registration 
Prior to enrollment on study, patients must be assigned a COG patient ID number. This 
number is obtained via the COG Registry in the OPEN system once authorization for the 
release of protected health information (PHI) has been obtained. 
 
 
Reservation and Contact Requirements 
Before enrolling a patient on study, a reservation must be made through the OPEN website 
and the Study Chair or Vice Chair should be notified. (The patient will need a COG patient 
ID number in order to obtain a reservation). Patients must be enrolled within 7 calendar 
days of making a reservation.  
 
Reservations may be obtained 24-hours a day through the OPEN website.  
 
 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
 
 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent.  This can be accomplished 
through one of the following mechanisms: a) the COG screening protocol, b) an IRB-
approved institutional screening protocol or c) the study-specific protocol.  Documentation 
of the informed consent for screening will be maintained in the patient’s research chart. 
Studies or procedures that were performed for clinical indications (not exclusively to 
determine eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be uploaded 
into RAVE immediately following enrollment. 
 

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Institutional Pathology Report 
Immediately following enrollment, the institutional pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into RAVE. The report must 
include the associated study number and COG patient registration and accession numbers. 
Personal identifiers, including the patient’s name and initials must be removed from the 
institutional pathology report prior to submission. 
 
 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have 
been met. Patients who give informed consent for the protocol in order to undergo 
screening for eligibility are not considered enrolled and should not be enrolled until the 
screening is completed and they are determined to meet all eligibility criteria. Study 
enrollment is accomplished by going to the CTSU OPEN (Oncology Patient Enrollment 
Network) https://open.ctsu.org/open/. For questions, please contact the COG Study 
Research 
Coordinator, 
or 
the 
CTSU 
OPEN 
helpdesk 
at 
https://www.ctsu.org/CTSUContact.aspx.  Patients must be enrolled before treatment 
begins.  The date protocol therapy is projected to start must be no later than five (5) calendar 
days after the date of study enrollment. Patients must not receive any protocol therapy 
prior to enrollment. 
 
 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
 
 
PATIENT ELIGIBILITY 
 
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 older than 7 days, 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, bone marrow biopsy and/or aspirate must be obtained within 14 days prior to start of 
protocol therapy (repeat the tumor imaging if necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01).  All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient’s 
medical or research record which will serve as the source document for verification at the 
time of audit. 
 
 
 
 
 

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Inclusion Criteria 
 
 
Age:   
• 
Part A: Patients must be ≥ 12 months and ≤ 21 years of age at the time of study 
enrollment. 
• 
Part B: Patients must be ≥ 22 years and ≤ 30 years of age at the time of study 
enrollment until part A is complete.  Part B will expand to include patients ≥ 
12 months and ≤ 30 years of age once Part A is complete and once the initial 
6 adult patients complete toxicity assessments per Section 11.6. 
 
 
Diagnosis:  
• 
Part A: Patients with recurrent or refractory solid tumors are eligible, 
excluding CNS tumors. Patients must have had histologic verification of 
malignancy at original diagnosis or relapse.  
• 
Part B:  Patients with recurrent or refractory osteosarcoma are eligible. Patients 
must have had histologic verification of malignancy at original diagnosis or 
relapse. 
 
 
Disease Status:  
• 
Part A: Patients must have either measurable or evaluable disease (see Sections 
12.2 and 12.3 for definitions).  
• 
Part B:  Patients must have measurable disease (see Section 12.2 for 
definition). 
 
 
Therapeutic Options: Patient’s current disease state must be one for which there 
is no known curative therapy or therapy proven to prolong survival with an 
acceptable quality of life. 
  
 
Performance Level:  Karnofsky ≥ 50% for patients > 16 years of age and Lansky 
≥ 50 for patients ≤ 16 years of age (See Appendix I).  Patients who are unable to 
walk because of paralysis, but who are up in a wheelchair, will be considered 
ambulatory for the purpose of assessing the performance score. 
 
 
Prior Therapy 
 
4.1.6.1 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the numerical eligibility criteria are met, e.g. blood count 
criteria, the patient is considered to have recovered adequately. 
 
a. Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive. See DVL homepage for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 
of this interval must be discussed with the study chair and the study-
assigned Research Coordinator prior to enrollment. 
 
≥ 21 days after the last dose of cytotoxic or myelosuppressive 
chemotherapy (42 days if prior nitrosourea).  
 
 
 

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b. Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥ 7 days after the 
last dose of agent. See DVL homepage for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 
of this interval must be discussed with the study chair and the study-
assigned Research Coordinator prior to enrollment.  
 
c. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1. 
 
d. Corticosteroids: See Section 4.2.2. If used to modify immune adverse 
events related to prior therapy, ≥ 14 days must have elapsed since last 
dose of corticosteroid. 
 
e. Hematopoietic growth factors: ≥ 14 days after the last dose of a long-
acting growth factor (e.g. pegfilfrastim) or 7 days for short-acting 
growth factor. For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur.  The 
duration of this interval must be discussed with the study chair and the 
study-assigned Research Coordinator. 
 
f. Interleukins, Interferons and Cytokines (other than Hematopoetic 
Growth Factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than Hematopoetic Growth Factors ) 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥ 84 
days after infusion and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion:  ≥ 42 
days. 
 
h. Cellular Therapy: ≥ 42 days after the completion of any type of 
cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.) 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days after 
local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to 
≥ 50% of the pelvis; ≥ 42 days if other substantial BM radiation. 
 
j. 
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-
MIBG): ≥ 42 days after systemically administered 
radiopharmaceutical therapy. 
 
k. Patients must not have received prior exposure to VX15/2503 
 
 
 
 

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Organ Function Requirements 
 
 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 
- 
Platelet count ≥ 100,000/mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
- 
Hemoglobin ≥ 8.0 g/dL at baseline (may receive RBC 
transfusions) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in 4.1.7.1.a 
(may receive transfusions provided they are not known to be 
refractory to red cell or platelet transfusions). These patients will 
not be evaluable for hematologic toxicity. At least 5 of every 
cohort of 6 patients must be evaluable for hematologic toxicity for 
the dose-confirmation part of the study. If dose-limiting 
hematologic toxicity is observed, all subsequent patients enrolled 
must be evaluable for hematologic toxicity. 
 
 
 Adequate Renal Function Defined as: 
 
- 
Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or 
- 
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 GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 
 Adequate Liver Function Defined as: 
 
- 
Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of 
normal (ULN) for age  
- 
(ALT) (SPGT)  ≤ 135 U/L.  For the purpose of this study, the ULN 
for ALT is 45 U/L.  
- 
Serum albumin ≥ 2 g/dL. 
. 
 

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 Adequate Pulmonary Function Defined as: 
 
a. No clinical indications such as evidence of dyspnea at rest, or 
exercise intolerance due to pulmonary insufficiency. 
b. If clinical indications, pulse oximetry >94% on room air.  
 
 
 
Informed Consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional guidelines.  
 
 
Tissue blocks or slides must be sent per Section 8.7. If tissue blocks or slides are 
unavailable, the study chair must be notified prior to enrollment. 
 
 
Exclusion Criteria 
 
 
Pregnancy or Breast- Feeding 
Pregnant or breast-feeding women will not be entered on this study. Pregnancy 
tests must be obtained in girls who are post-menarchal. Males or females of 
reproductive potential may not participate unless they have agreed to use two 
effective methods of birth control, including a medically accepted barrier or 
contraceptive method (e.g., male or female condom) for the duration of the study. 
Abstinence is an acceptable method of birth control. 
 
 
Concomitant Medications 
 
a) 
Corticosteroids:  Patients receiving systemic corticosteroids who have not 
been on a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. If used to modify immune adverse events related to 
prior therapy, ≥ 14 days must have elapsed since last dose of systemic 
corticosteroid (See Section 4.1.6.1.d). Note: patients who are using topical or 
inhaled corticosteroids are eligible. 
 
b) 
Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
 
c) 
Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible [except leukemia patients receiving hydroxyurea, which 
may be continued until 24 hours prior to start of protocol therapy]. 
 
d) 
Anti-GVHD agents post-transplant:  
Patients who are receiving cyclosporine, tacrolimus or other agents to prevent 
graft-versus-host disease post bone marrow transplant are not eligible for this trial. 
 
 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
 
Patients who have received a prior solid organ transplantation are not eligible. 
 
 
Patients who in the opinion of the investigator may not be able to comply with 
the safety monitoring requirements of the study are not eligible. 
 
 

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TREATMENT PROGRAM 
 
 
Overview of Treatment Plan 
 
Day 1 
Day 15 
Day 28 
VX15/2503 IV 
VX15/2503 IV 
End of Cycle/Evaluation 
 
VX15/2503 will be administered intravenously over 60 minutes on Days 1 and 15 of a 28 
day cycle. Patients should be monitored for signs and symptoms of infusion reactions 
during the drug infusion and for 4 hours after completion of post-infusion flush (e.g., 
monitor vital signs every 15 minutes during VX15/2503 infusion and every 30 minutes 
thereafter). Precautions for anaphylaxis should be observed during VX15/2503 
administration. Emergency resuscitation equipment and medications should be present 
for immediate use in the immediate area where patients are receiving their infusions. If a 
patient develops a ≥ Grade 2 infusion related reaction, the infusion should be stopped and 
standard institutional guidelines for management of infusion reactions should be 
followed. Note: If the initial dose is well tolerated subsequent doses will required patients 
to be monitored for 1 hour after completion of post-infusion flush.  
See Section 6.2.3 for management and dose modification guidelines for infusion related 
reactions. If there is no evidence of an infusion related reaction during the initial 2 
infusions of VX15/2503, then no observation period is required for subsequent treatment 
cycles. In the event an infusion related reaction occurs thereafter, the four-hour 
observation period should be reinstituted.   
A cycle of therapy is considered to be 28 days. A cycle may be repeated for a total of 13 
cycles, up to a total duration of therapy of approximately 12 months. As some of the 
correlatives require same-day shipping (see Section 8.5), caution should be paid to the day 
of the week therapy should start and drug infusion should occur so that correlative samples 
are able to be sent out for analysis without delay.  
 
Drug doses should be adjusted based on weight measured within 7 days prior to the 
beginning of each cycle.   
 
Update: With the release of Amendment #2A, the dose confirmation portion of 
the study is complete. Given this, Part B will be open to patients > 12 months and 
< 30 years of age with relapsed and refractory osteosarcoma once the initial 6 adult 
patients complete toxicity assessments per Section 11.6.  
 
 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease and has 
again met laboratory parameters as defined in the eligibility section, Section 4.0, and is 
eligible to continue agent administration per the requirements in Section 6.0.  
 
 
Dose Confirmation Schema (Completed) 
 
 
Inter-Patient Escalation 
The starting dose will be 20 mg/kg (dose level 1)  
 
 
Dose Level 
Dose (mg/kg) 

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-1 
10 
1* 
20 
* Starting Dose Level 
 
If the MTD has been exceeded at the first dose level, then the subsequent cohort 
of patients will be treated at a dose of 10 mg/kg (dose level -1). If dose level -1 is 
not well tolerated, further de-escalation will not occur. The study will be closed to 
accrual. 
 
 
Update: The RP2D was determined to be 20 mg/kg.  
 
 
Intra-Patient Escalation 
Intra-patient dose escalation is not allowed.  
 
 
PK Expansion Cohort and Part B 
VX15/2503 will be administered intravenously over 60 minutes on Days 1 and 15 of a 28 
day cycle at the RP2D of 20 mg/kg.  
 
 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). Any 
suspected or confirmed dose-limiting toxicity should be reported immediately (within 24 
hours) to the Study Chair. 
 
 
 
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.  The DLT observation period for the purposes of dose-
confirmation will be the first cycle of therapy. 
 
Dose limiting hematological and non-hematological toxicities are defined differently.   
 
 
Non-hematological dose-limiting toxicity 
a) Any Grade 3 or greater non-hematological toxicity attributable to protocol 
therapy with the specific exclusion of: 
 
• Grade 3 nausea and vomiting < 3 days duration 
• Grade 3 liver enzyme elevation, including ALT,that returns to Grade ≤ 1 
or baseline prior to the time for the next treatment cycle. See Appendix III 
for values that represent thresholds between CTCAE grades. Note:  For 
the purposes of this study the ULN for ALT is defined as 45 U/L. 
• Grade 3 fever  
• Grade 3 infection 
• Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to supplementation. 
 
b) Non-hematological toxicity that causes a delay of ≥ 14 days between treatment 

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cycles. 
 
c) Note: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
 
 
Hematological dose limiting toxicity 
a) In patients evaluable for hematological toxicity (see section 4.1.7.1), 
hematological dose limiting toxicity is defined as: 
• 
Day 15:  
o Grade 4 neutropenia or Grade 3 thrombocytopenia (platelets < 
50,000/mm3 ) that does not resolve to ANC ≥ 500/mm3 and platelets 
≥ 50,000/mm3 (transfusion independent) by Day 18 will be considered 
dose-limiting (See Section 6.2.1). 
• 
Platelet count < 25,000/mm3 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.  
 
b) Note:  Grade 3 or 4 febrile neutropenia will not be considered a dose-limiting 
toxicity. 
 
 
 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. 
 
Dose Modification for Day 1 Dosing 
 
 
Dose Modifications for Hematologic Toxicity 
 
 Patients who have dose-limiting thrombocytopenia should receive 
subsequent cycles at the next lower dose level.  
 
 Patients who have dose-limiting neutropenia with no other dose-limiting 
toxicity should receive the same dose in the next cycle with myeloid 
growth factor support or receive study drug at the next lower dose level.  
[Note: Patients MUST NOT receive prophylactic myeloid growth factor 
in the first cycle of therapy (See Section 7.4).] If dose-limiting neutropenia 
recurs after myeloid growth factor is added, then the patient should be 
given the next lower dose level for subsequent cycles. If dose-limiting 
neutropenia recurs in a patient that has received a dose level reduction but 
has not received myeloid growth factor, then myeloid growth factor should 
be administered. If, per the treating physician, addition of myeloid growth 
factor is not in the best interest of the patient, the patient should be 
removed from protocol therapy. In the case where myeloid growth factor 
is used, it should be initiated 24 hours after the dose.  If the day 15 dose is 
delayed to allow for recovery, the myeloid growth factor should not be 
given until 24 hours after the day 15 dose is given. If the day 15 dose is 
omitted, myeloid growth factor can be given at the time the decision is 
made to omit the dose.  
 

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 Patients who experience dose-limiting thrombocytopenia after one dose 
reduction or dose-limiting neutropenia after addition of myeloid growth 
factor and one dose reduction must be removed from protocol therapy. 
 
 Patients who have a dose-limiting hematological toxicity that does not 
resolve to eligibility parameters within 21 days after the planned start of 
the next treatment cycle must be removed from protocol therapy. 
 
 
Dose Modifications for Non-Hematological Toxicity 
 
 Patients who have any dose-limiting non-hematological toxicity (as 
defined in Section 5.5.1) may continue on protocol therapy upon meeting 
eligibility lab requirements or baseline but should receive subsequent 
doses at the next lower dose level.  
 
 If the patient experiences non-hematological dose-limiting toxicity after 
one dose reduction, the patient must be removed from protocol therapy. 
 
 Patients who have a dose-limiting non-hematological toxicity that does not 
resolve to baseline or eligibility (whichever is higher) within 21 days after 
the planned start of the next treatment cycle must be removed from 
protocol therapy. 
 
 
 
Dose Modifications for Day 15 Dosing due to Toxicity on Day 15.  
 
 
Dose Modifications for Hematological Toxicity: 
 
 Patients who have Grade 4 neutropenia or Grade 3 thrombocytopenia 
(platelets < 50,000/mm3) on Day 15 will have their dose withheld. If the 
toxicity resolves to ANC ≥ 500/mm3 and platelets ≥ 50,000/mm3 
(transfusion independent) by Day 18, the dose may be given. Platelets 
cannot be given to achieve a platelet count >50,000/mm3 to receive the 
day 15 dose. If the toxicity does not resolve to ANC ≥ 500/mm3 and 
platelets ≥ 50,000/mm3 by Day 18, the dose will be omitted and this will 
be considered a DLT. Patients who require that their Day 15 dose be 
omitted for Grade 4 neutropenia or Grade 3 platelets (< 50,000/mm3) after 
a dose reduction for any reason must be removed from protocol therapy.  
  Patients who meet hematological DLT criteria as defined in Section 5.5.2 
on Day 15 will have their Day 15 dose omitted. Patients should receive 
subsequent cycles of drug per Section 6.2 after their toxicity resolves, no 
sooner than the planned start of the subsequent cycle. Patients who require 
that their Day 15 dose be omitted for hematologic DLT as defined in 
Section 5.5.1 after one dose reduction must be removed from protocol 
therapy. 
 
 
Dose Modifications for Non-Hematologic Toxicity:  
 
  Patients who have Grade 3 or Grade 4 non-hematological toxicity 
attributable to the study drug prior to the Day 15 dose (with the exception 

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of the DLT exclusions in Section 5.5.1) will be considered to have had a 
DLT. If the toxicity resolves to meet eligibility or ≤ Grade 2 (if not part of 
eligibility criteria) by Day 15, the dose may be given but at the next lower 
dose level. 
 
  Patients who have Grade 3 or Grade 4 non-hematological toxicity 
attributable to the study drug on Day 15 prior to dosing (with the exception 
of the DLT exclusions in Section 5.5.2) will have their dose withheld and 
this will be considered a DLT. If the toxicity resolves to meet eligibility or 
≤ Grade 2 (if not part of eligibility criteria) by Day 18, the dose may be 
given but at the next lower dose level. If the toxicity does not resolve by 
Day 18, the dose will be omitted. Patients should receive subsequent 
cycles of drug but with dose modifications according to Section 6.2. 
 
6.2.2.3  If the patient experiences non-hematological dose-limiting toxicity after 
 
one dose reduction, the patient must be removed from protocol therapy.  
 
 
 
Dose Modifications for Infusion-Related Reactions: 
 
For patients who have allergic or acute infusion reactions to VX15/2503, therapy 
modifications based on grade should be as follows 
 
 
                                       
Grade (CTCAE v.5) 
Infusion 
Related 
Reaction 
Action 
Grade 1 
Transient flushing 
or rash, drug fever 
< 38° C 
 
• Monitor patient until recovery from symptoms; infusion rate 
may be slowed. 
• If the infusion is interrupted, then restart the infusion at 50% 
of the original infusion rate when symptoms resolve. Monitor 
patient closely. 
 
The following prophylactic premedications are recommended: 
diphenhydramine 1 mg/kg with max 50 mg (or equivalent) and/or 
acetaminophen 10-15 mg/kg (max 1000 mg) at least 30 minutes 
before additional VX15/2503 administrations, slowing infusion 
rate as above. Note: Prophylactic premedications should be 
administered upon restart of infusion, when symptoms resolve.   
Grade 2 
Rash, flushing, 
urticaria, dyspnea, 
drug fever ≥ 38°C 
• Stop infusion, begin an IV infusion of normal saline, and 
treat the subject with diphenhydramine 1 mg/kg with max 50 
mg IV (or equivalent) and/or acetaminophen 10-15 mg/kg 
(max 1000 mg); remain at bedside and monitor patient until 
resolution of symptoms. Corticosteroid or bronchodilator 
therapy may also be administered as appropriate. 
• If the infusion is interrupted, then restart the infusion at 50% 
of the original infusion rate when symptoms resolve. Monitor 
patient closely. 
•  If symptoms recur, then no further VX15/2503 will be 
administered at that visit. Administer diphenhydramine 1 
mg/kg with max 50 mg IV (or equivalent), and remain at 

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bedside and monitor the patient until resolution of symptoms.  
 
The following prophylactic premedications are recommended: 
diphenhydramine 1 mg/kg with max 50 mg IV (or equivalent) 
and acetaminophen (10-15 mg/kg, max 1000 mg) should be 
administered at least 30 minutes before additional VX15/2503 
administrations. If clinically indicated, corticosteroids 
(recommended dose: 1-2 mg/kg/day methylprednisolone IV or 
equivalent) may be used. 
Grade 3 or 4 
Symptomatic 
bronchospasm with 
or without urticaria, 
allergy-related 
edema/angioedema, 
hypotension; 
Anaphylaxis 
• Immediately discontinue infusion of VX15/2503.  
• Begin an IV infusion of normal saline, and treat the subject as 
follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg 
of a 1 mg/ml solution for subcutaneous administration, 0.1 to 
0.25 mg of a 0.1 mg/ml solution injected slowly for IV 
administration, 0.01 mg/kg of 1:1000 dilution (0.01 
ml/kg/dose) 
for 
intramuscular 
administration, 
and/or 
diphenhydramine 1 mg/kg with max 50 mg IV with 1-2 
mg/kg/day methylprednisolone IV (or equivalent), as needed. 
• Patient should be monitored until the investigator is 
comfortable that the symptoms will not recur. 
• VX15/2503 will be permanently discontinued. 
 
Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor patient 
until recovery from symptoms. In the case of late-occurring 
hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritis within 1 week after treatment), symptomatic 
treatment may be given (e.g., oral antihistamine, or 
corticosteroids).  
 
 
 
 
 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy. 
 
 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. See COG Supportive Care Endorsed Guidelines 
at https://childrensoncologygroup.org/index.php/cog-supportive-care-endorsed-guidelines 
for more information. 
 
 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 

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administered in accordance with Section 6.1.1.2 or for culture proven bacteremia or 
invasive fungal infection. The Study Chair should be notified before growth factors are 
initiated. 
 
 
 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
Required Clinical, Laboratory and Disease Evaluation 
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 
(see Section 4.0) 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 older than 7 days, 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, bone 
marrow aspirate and/or biopsy, must be obtained within 14 days prior to start of protocol 
therapy (repeat the tumor imaging if necessary). 
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Prior to 
Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam with vital signs12 
X 
Weekly 
X 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
 
CBC, differential, platelets 
X 
Twice Weekly 
(every 3 to 4 days)3 
Every 
subsequent 
cycle on D14 
and D154 
Pharmacokinetics1 
X 
X 
X 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Albumin 
X 
 
X 
Tumor Disease Evaluation 
X 
End of Cycle 1 
Every other 
cycle x 2 
then q 3 
cycles 5 
Tumor Disease Evaluation- Part B 
Phase 2 
X 
 
After cycles 
2,4 and 6 and 
then q 3 
cycles 5 
Bone Marrow Evaluation7 
X 
End of Cycle 18 
Every other 
cycle x 2 
then q 3 
cycles 8 
Pregnancy Test2 
X 
With tumor 
disease 
With tumor 
disease 

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evaluation2 
evaluation 2 
Oxygen Saturation6  
X 
 
 
Immunogenicity Study 
X 
X9 
X9 
T Lymphocyte Saturation 
X 
X10 
X10 
Total Soluble SEMA4D 
X 
X11 
X11 
Tumor Tissue 
X13 
X14 
X14 
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
See Section 8.3 for timing of PK studies. 
2 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; 
sexually active patients must use an acceptable method of birth control for the duration of the 
study.  Abstinence is an acceptable method of birth control. Pregnancy testing is required prior 
to tumor imaging per institutional guidelines. 
3 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until 
recovery to Grade 3 or until meeting the criteria for dose limiting toxicity. 
4 
If patients develop Grade 4 neutropenia then CBCs should be checked every 3 to 4 days until 
recovery to Grade 3 
5 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial 
documentation of either a PR or CR.  Subsequent scans may restart 2 cycles after the 
confirmatory scan. Please note that for solid tumor patients, if the institutional investigator 
determines that the patient has progressed based on clinical or laboratory evidence, he/she may 
opt not to confirm this finding radiographically. 
6 
Only if there is clinical indication of inadequate pulmonary function. See Section 4.1.7.4. 
7 
Patients with known bone marrow disease should have baseline bone marrow evaluation 
8 
If bone marrow evaluation pre-study is positive for metastatic disease 
9 
Immunogenicity Study see section 8.4 for timing of Immunogenicity studies 
10 
T Lymphocyte Saturation see section 8.5 for timing of T Lymphocyte Saturation studies 
11 
Total Soluble SEMA4D Solubility Assay see section 8.6 for timing of SEMA4D solubility 
studies. 
12     Monitor vital signs every 15 minutes during VX15/2503 infusion and every 30 minutes 
thereafter for 4 hours.  
13     Tumor tissue should be obtained if available. If a patient does not have tissue available, the 
study chair must be notified prior to enrollment. See Section 8.7. 
14     In the event a subject requires a biopsy for surgery and tumor tissue is removed, tumor tissue 
will be requested for analysis. Tumor biopsies will not be performed solely for research 
purposes. See Section 8.7. 
 
 
 
Radiology Studies 
 
 
Central Radiology Review for Response:  Patients who respond (CR, PR) to 
therapy or have long term stable disease (SD) (≥ 6 cycles) on protocol therapy 
will be centrally reviewed. COG Operations Center will notify the Imaging 
Center of any patient requiring central review. The Imaging Center will then 
request that the treating institution forward the requested images for central 
review. The central image evaluation results will be entered into RAVE for 
review by the COG Operations Center and for data analysis.  
 
The images are to be forwarded electronically to the Imaging Research Center at 
Children’s Hospital Los Angeles via the ImageInBox.   
 
COG institutions that are not connected via the ImageInBox can send the images 
on CD ROM or USB flash drive. Submitted imaging studies should be clearly 

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marked with the COG patient ID, study number (ADVL1614) and date and shipped 
to 
 
 
 
 
 
 
 
 
 
Pharmacology (Required) 
 
 
Description of Studies and Assay 
Pharmacokinetics (PK) will be performed to determine the PK of VX15/2503 in 
children. Serum will be collected and VX15/2503 concentration will be determined 
by a qualified ELISA assay. Samples will be analyzed by Covance Laboratories. 
 
 
Sampling Schedule (See Appendix IV and Appendix IX) 
 
a. For patients ≤ 10kg, blood samples will be obtained prior to drug 
administration and at the following time points:  
-     Cycle 1, Day 1: prior to start of infusion [3.5 ml], at the end of infusion 
[2.5 ml], and 2 hours following the end of infusion [2.5 ml] 
 
 
 
       -  Cycle 1, Day 15: prior to start of infusion [2.5 ml] 
   
       -     Cycle 2, Day 1: prior to start of infusion [3.5 ml] 
   
       -     Cycle 2, Day 15: prior to start of infusion [2.5 ml] 
 
 
 
       -      Each subsequent cycle, Day 1: These samples are collected in conjunction 
 
 
 
 
with the immunogenicity study samples for patients ≤ 10kg. No extra  
 
 
 
 
blood draws or sample tubes for PK are required for these time points. See 
 
 
 
 
Section 8.4.2 for timing and blood volume.  
 
b. For patients > 10kg, blood samples will be obtained prior to drug 
administration and at the following time points. Blood sample volumes are 2.5 
ml unless otherwise indicated:  
- 
Cycle 1, Day 1: prior to start of infusion, at the end of infusion, and 2 
hours following the end of infusion.  
 
Note: The PK samples collected prior to infusion and at 
the end of infusion are collected in conjunction with the 
immunogenicity study samples for patients > 10kg on 
Cycle 1 Day 1. No extra blood draws or sample tubes for 
PK are required for these time points. See Section 8.4.2 
for timing and blood volume.  
- 
Cycle 1, Days 4 (±1), 8 (±1)  
- 
Cycle 1, Day 15: prior to start of infusion and at the end of infusion. 
- 
Cycle 2, Day 1: prior to start of infusion, at the end of infusion, and 2 
hours following the end of infusion.  
 
Note: The PK sample collected prior to start of infusion 
is collected in conjunction with the immunogenicity 
study sample for patients > 10kg on Cycle 2 Day 1. No 

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extra blood draws or sample tubes for PK are required 
for this time point. See Section 8.4.2 for timing and 
blood volume.  
- 
Cycle 2, Day 15: prior to start of infusion. 
- 
Each subsequent cycle, Day 1: These samples are collected in 
conjunction with the immunogenicity study samples for patients > 10kg. 
No extra blood draws or sample tubes for PK are required for these time 
points. See Section 8.4.2 for timing and blood volume.  
 
 
Sample Collection and Handling Instructions 
Please refer to the lab manual.  Briefly, blood samples will be collected in SST 
tubes at a site distant from the infusion for pharmacokinetic evaluation. Please note 
above which samples are 2.5 ml and which samples are 3.5 ml. For blood samples 
that are to be used for both pharmacokinetic analysis and immunogenicity analysis, 
3.5 ml of blood will be drawn total for both analyses. See Section 8.4.2 and Section 
8.4.3 for details. Samples cannot be drawn from the 2nd lumen of a multi-lumen 
catheter through which drug is being administered. Record the exact time that the 
sample is drawn along with the exact time that the drug is administered.  Please 
include the infusion start and stop times. 
 
 
Sample Processing 
Refer to lab manual for sample processing details. 
 
 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn.  Data should be recorded on the 
Pharmacokinetic Study Form (see Appendix IV and Appendix IX), which must 
accompany the sample(s). Additional details will be provided in the Covance lab 
manual. 
 
 
Sample Shipping Instructions 
Samples should be batched per patient and shipped frozen on dry ice in opaque 
containers at the end of cycle 1 to the lab processing the samples. Primary and 
backup samples should not be shipped at the same time, please refer to lab manual 
for detailed shipping information. 
 
Samples should be shipped to the following address:  
Covance Central Laboratory Services, Inc. 
8211 SciCor Dr. 
Indianapolis, IN 46214-2985 
 
 
 
Immunogenicity Study (Required) 
 
 
Description of Studies 
Serum samples will be evaluated for Anti-Drug Antibodies through a qualified 
ELISA assay.  
 
 
Sampling Schedule (See Appendix V and Appendix X) 

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a) For patients ≤ 10kg, samples will be collected at: 
- 
Cycle 3, Day 1 and each subsequent cycle, Day 1: prior to start of 
infusion. 
o  Note: 3.5 ml of blood will be drawn and will be used for both 
the immunogenicity analyses and the pharmacokinetic 
analyses.  
b) For patients > 10kg, samples will be collected at: 
- 
Cycle 1, Day 1: prior to start of infusion and at the end of infusion.  
o Note: 3.5 ml of blood will be drawn and will be used for both 
the immunogenicity analyses and the pharmacokinetic 
analyses. 
- 
Each subsequent cycle, Day 1: prior to start of infusion. 
o Note: 3.5 ml of blood will be drawn and will be used for both 
the immunogenicity analyses and the pharmacokinetic 
analyses.  
 
 
 
Sample Collection and Handling Instructions 
Please refer to the lab manual.  Briefly, blood samples (3.5 ml) will be collected 
in SST tubes at a site distant from the infusion for both immunogenicity 
evaluation and pharmacokinetic evaluation. Record the exact time that the 
sample is drawn along with the exact time that the drug is administered. 
 
 
Sample Processing 
Please refer to lab manual 
 
 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn.  Data should be recorded on 
the Correlative Study Form, which must accompany the sample(s). Please refer 
to the Covance lab manual for additional information. 
 
 
Sample Shipping Instructions 
Samples should be shipped to the following address:  
Covance Central Laboratory Services, Inc. 
8211 SciCor Dr. 
Indianapolis, IN 46214-2985 
 
 
Pharmacodynamics:  T-lymphocyte saturation (Required) 
 
 
Description of Studies 
Blood samples will be evaluated for T-lymphocyte saturation by VX15/2503 
utilizing a validated flow-cytometry based assay. 
 
 
Sampling Schedule (See Appendix VI) 
c) For all patients, samples will be collected at: 
- 
Cycle 1, Day 1: prior to start of infusion and at the end of infusion 
- 
Cycle 1, Day 15: prior to start of infusion and at the end of infusion 
- 
Cycle 1, Day 28: prior to Cycle 2, Day 1 dose for all patients regardless 
of whether or not patient is proceeding to Cycle 2  

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- 
Each subsequent cycle, Day 1: prior to start of infusion 
 
 
Sample Collection and Handling Instructions 
Blood samples:  
- 
Cycle 1 Day 1: 2 x 4mL 
- 
Cycle 1 Day 15: 2 x 4mL 
- 
Cycle 1 Day 28: 1 x 4mL 
- 
Subsequent Cycles: prior to start of infusion, Day 1: 1 x 4mL 
 
Blood samples will be collected in cyto-chex tubes at a site distant from the infusion 
for pharmacodynamic evaluation. Record the exact time that the sample is drawn along 
with the exact time that the drug is administered. 
 
 
Sample Processing 
Please refer to lab manual 
 
 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn.  Data should be recorded on the 
Correlative Study Form, which must accompany the sample(s). Please refer to the 
Covance lab manual for additional information. 
 
 
Sample Shipping Instructions 
Please note that these samples are very time-sensitive and that samples are to be 
sent the day of collection. 
 
Samples should be shipped to the following address:  
Covance Central Laboratory Services, Inc. 
8211 SciCor Dr. 
Indianapolis, IN 46214-2985 
 
 
Pharmacodynamics: Total soluble SEMA4D (Required) 
 
 
Description of Studies 
Blood and serum samples will be evaluated for total soluble SEMA4D through a 
qualified ELISA assay.   
 
 
Sampling Schedule (See Appendix VII and Appendix XI) 
d) For patients ≤ 10kg, samples will be collected at: 
- 
Cycle 3, Day 1 and each subsequent cycle, Day 1: prior to start of 
infusion 
 
e) For patients > 10kg, samples will be collected at: 
- 
Cycle 1, Day 1: prior to start of infusion and at the end of infusion 
- 
Each subsequent cycle, Day 1: prior to start of infusion 
 
 
 
Sample Collection and Handling Instructions 
Please refer to lab manual.  Briefly, blood samples (3.5mL) will be collected in 
SST tubes at a site distant from the infusion for pharmacodynamic evaluation. 
Record the exact time that the sample is drawn along with the exact time that the 

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drug is administered. 
 
 
Sample Processing 
Please refer to lab manual 
 
 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn.  Data should be recorded on the 
Correlative Study Form, which must accompany the sample(s). 
 
 
Sample Shipping Instructions 
Samples should be batched per patient and shipped frozen on dry ice in opaque 
containers at the end of cycle 1 to the lab processing the samples. Primary and 
backup samples should not be shipped at the same time, please refer to lab manual 
for detailed shipping information. 
 
Samples should be shipped to the following address:  
Covance Central Laboratory Services, Inc. 
8211 SciCor Dr. 
Indianapolis, IN 46214-2985 
 
 
 
Tumor Assessment (archival-required and biopsy-optional) 
 
 
Description of Studies 
Tumor Expression: SEMA4D, PlexinB1, and other markers of immune cell 
infiltration will be performed by Immunohistochemistry.  Archival tumor tissue 
should be submitted for all patients.  If a patient does not have tissue available, the 
study chair must be notified prior to enrollment.   
 
 
Sampling Schedules (See Appendix VIII) 
a) Archival tumor tissue (Archival Formalin-Fixed Paraffin-Embedded (FFPE)) will 
be requested to be sent when available. Please submit a redacted copy of the 
pathology report along with the specimen. 
b) In the event a subject requires a biopsy or surgery and tumor tissue is removed, 
tissue will be requested for the analysis of SEMA4D, PlexinB1, and other markers 
of immune cell infiltration (optional). Tumor biopsies will not be performed solely 
for research purposes. 
 
 
Sample Shipping Instructions: 
Samples should be shipped to the following address:  
Immunochemistry Services 
Covance Laboratories, Inc.  
3635 Concorde Parkway, Suite# 100 
Chantilly, VA 20151 
  
 
 
Sample Labeling 
Each specimen must be labeled with the patient’s study registration number, the 
study I.D., and must be accompanied by a pathology report.  Data should be 

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recorded on the Tissue Studies Form (see Appendix VIII), which must accompany 
the sample(s). 
 
 
 
AGENT INFORMATION 
 
 
VX15/2503 
(Mab2503) NSC# 795997 IND#136181  
 
 
Structure and molecular weight: 
VX15/2503 is a humanized, IgG4 kappa monoclonal antibody that binds 
specifically to the semaphorin 4D (SEMA4D; CD100) antigen, a member of the 
semaphorin family that normally functions to regulate the motility and 
differentiation of multiple cell types, including those of the immune, vascular, and 
nervous systems. It bears a proline at position 228 of the core hinge sequence 
(instead of a serine) to stabilize the hinge region and prevent chain recombination 
from occurring. SEMA4D blockade represents a novel mechanism and therapeutic 
strategy to promote immune infiltration into the tumor microenvironment and 
inhibit tumor progression.   
 
VX15/2503 has a molecular weight of approximately 148 kDa. 
 
 
Supplied by: Vaccinex, Inc 
 
 
Formulation 
The agent is supplied as a sterile solution of 20 mg/ml antibody in 20 mM sodium 
acetate, pH5.4, containing 130 mM sodium chloride and 0.02% polysorbate 80. 
The formulation contains no preservatives. Each 10 mL vial of VX15/2503 
contains 10 mL (200 mg) of antibody; each vial is intended for single use. The 
product packaging consists of 10 mL USP Type I Schott glass vials with West 
Pharmaceutical Services FluroTec grey butyl rubber stoppers and a blue plastic 
cap with aluminum overseal. Each 10 mL product vials is packaged in a cardboard 
box that provides protection from light. 
 
 
Storage 
VX15/2503 is to be kept dry and refrigerated at 2-8°C (36-46ºF) until use.  It 
should be protected from light. 
 
 
Solution Preparation 
 
Using aseptic technique, prepare the solution for infusion as follows:  
 
• 
Drug vials should be carefully inspected for discoloration and for particulates. 
The solution of VX15/2503 are normally clear to slightly opalescent, colorless or 
faintly yellow, and may contain a small amount of visible particulates. If the 
solution is discolored or otherwise does not meet this description the drug should 
not be administered and instead the study sponsor be contacted. The solution 
vials contains no preservatives. 
  
• 
Do not shake the solution vials.  

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• 
To prepare infusion solution, withdraw the required amount of VX15/2503 and 
dilute the solution with 0.9% sodium chloride injection, USP, as needed. The 
final concentration should be between 1-10 mg/mL after dilution. Doses of 2,000 
mg and above should be diluted to a total volume of 250 mL with 0.9% sodium 
chloride injection, USP. Mix the diluted solution by gentle inversion; do not 
shake. Inspect the prepared solution visually for particulates prior to 
administration.  
 
• 
Destroy any unused vialed material according to organizational procedures for 
the destruction of biologic agents. If no appropriate procedure exists, return the 
unused vialed solution to the study drug distributor for destruction.  
 
 
Stability 
Refer to the package labeling for vials expiration dating.  
 
Administration of VX15/2503 should occur as soon as possible following dilution 
(see Section 9.1.5). If a delay is anticipated, the prepared solution may be kept at 
room temperature for no more than 8 hours prior to infusion, or for no more than 
24 hours after dilution if stored at 2-8 ºC (36 to 46ºF). Do not freeze the diluted 
solution 
 
 
 
Administration  
See Treatment (Section 5.0) and Dose Modification (Section 6.0) of the protocol 
for complete details.  
 
Administration of VX15/2503 should occur as soon as possible following dilution.  
 
Use one of the following (or comparable) infusion sets:  
•  Hospira product number 12030-12 (polyvinyl chloride composition) (with 
or without in-line filter)  
• 
Baxter product number 2C8875 (polyvinyl chloride composition with 
polyethylene lined tubing) (with or without in-line filter)  
Administer the prepared intravenous solutions using an infusion pump. Infuse all 
doses of VX15/2503 over the time interval specified in the study protocol using a 
peripheral intravenous line or indwelling intravenous catheter. Flush the line with 
0.9% sodium chloride injection, USP, after study drug infusion.  
 
Do not administer VX15/2503 as an infusion with intravenous solutions of other 
medicinal products. Do not add other medications to solutions containing 
VX15/2503. 
 
 
Toxicities 
 
The table below lists the expected toxicity profile of VX15/2503. This list may not be 
comprehensive; VX15/2503 may result in events which have never been previously 
reported. Note: An adverse event is unexpected for sponsor IND reporting purposes if 
it is not listed in bold font in the table below. Please refer to Section 13.1 for protocol-

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specific exceptions to CTEP-AERS expedited reporting.  
 
 
 
Incidence 
Toxicities 
Common 
(>20% of patients) 
None 
Occasional 
(4-20% of patients) 
• 
Nausea 
• 
Fatigue 
• 
Arthralgia 
• 
Decreased appetite 
• 
Infusion-related reaction 
• 
Fever 
• 
Myalgia 
• 
Pruritus 
Rare 
(<3% of patients) 
• 
Elevated gamma glutamyl transferase 
• 
Lipase increased 
• 
Neutrophil count decreased 
• 
White blood cell count decreased 
• 
Abdominal pain 
• 
Hepatitis E 
• 
Lymphadenopathy 
• 
Lymphedema 
• 
Eye pain, decreased visual acuity 
• 
Rash 
• 
Pericardial effusion 
Pregnancy 
& 
Lactation 
No reproductive toxicology, genotoxicity, or mutagenicity studies have been 
conducted with VX15/2503. Pregnant or breast-feeding women will not be entered 
on this study. Pregnancy tests must be obtained in girls who are post-menarchal. 
Males or females of reproductive potential may not participate unless they have 
agreed to use an effective contraceptive method for the duration of study therapy. 
 
 
 
Agent Accountability  
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all agents received 
using the appropriate NCI Drug Accountability Record Form (DARF) available on 
the CTEP forms page. Accountability records will include dates, quantities, 
batch/serial numbers, expiration dates (if applicable), and patient numbers.   
 
 
 
Upon completion of preparation of an injection, used or partially used vials should 
be discarded per institutional standard operating procedures. Unused vials should 
be stored in the original carton under refrigeration at 2°C to 8°C (36°F to 46°F) 
protected from light in a secure, limited access area. Do not freeze. If there are 
unused vials remaining at the end of the study, the pharmacist or designee should 
destroy unused or expired vials per institutional standard operating procedures. All 
material containing study drug will be treated and disposed of as hazardous waste 
in accordance with governing regulations. Appropriate disposal confirmation will 

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be provided to Vaccinex. 
 
 Agent Ordering 
VX15/2503 will be supplied by Vaccinex, Inc. Information on drug supply and 
management is posted on the protocol web site. VX15/2503 is for investigational 
use only, and is to be used only within the context of this study. Under no 
circumstances should the investigator or other site personnel supply study drug to 
other investigators, subjects, or clinics, or allow supplies to be used other than 
directed by this protocol. 
 
 
 Useful Links and Contacts  
• CTEP Forms, Templates, Documents:   
 
http://ctep.cancer.gov/forms/ 
 
 
 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12.0). 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6.0). 
c) 
Refusal of protocol therapy by patient/parent/guardian 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Completion of 13 cycles of therapy. 
f) 
Physician determines it is not in the patient’s best interest. 
g) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of VX15/2503 (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
 
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent. Patients who are removed from protocol therapy in subsequent cycles should 
have the necessary observations to ensure adequate clinical care.  
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Ongoing adverse events, or adverse events that emerge after the patient 
is removed from protocol therapy, but within 30 days of the last dose of investigational 
agent, must be followed and reported via RAVE and CTEP-AERS (if applicable).  Follow-
up data will be required unless consent is withdrawn. 
 
 
Off Study Criteria 
 

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a) 
Thirty days after the last dose of the investigational agent. 
b) 
Death 
c) 
Lost to follow-up 
d) 
Withdrawal of consent for any required observations or data submission. 
e) 
Enrollment onto another COG therapeutic (anti-cancer) study  
f) 
The patient does not receive protocol treatment after study enrollment.  
 
 
 
 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
 
Sample Size and Study Duration 
 
A minimum of 4 evaluable patients will be required for Part A. The expected maximum 
number of evaluable patients required to complete part A is 12. Once the MTD or 
recommended Phase 2 dose has been defined, up to 6 additional patients with recurrent or 
refractory solid tumors without restrictions on heme evaluability may be enrolled to acquire 
PK data in a representative number of young patients (i.e. patients < 12 years old). 
Therefore, the maximum number of patients anticipated to be enrolled into Part A is 23 
patients which allows for 6 patients at each of 2 dose levels, 6 additional patients for PK, 
and 20% inevaluability. Review of the enrollment rate into previous COG new agent 
studies indicates that 4 patients per month are expected. Therefore, the study is expected 
to be completed within about 6 months. In the unlikely event that both dose levels are 
expanded to 12 patients due to DLTs of different classes, the absolute maximum number 
of patients enrolled into Part A would be 38. The absolute maximum would be expected to 
be completed within 10 months. 
 
Additionally once the MTD/or RP2D has been determined in Part A, the Phase 2 portion 
of the study (Part B) will use a Simon’s optimal two-stage design. 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 in Section 11.6.  A maximum of 37 patients are expected to be enrolled to 
allow for 20% inevaluability. This is expected to be completed within about 10 months. 
Overall, a maximum of 60 patients are expected to be enrolled into the study, and this 
should be completed within about 16 months. An absolute maximum of 75 patients would 
take up to 19 months to complete enrollment. 
 
Strata: 
a) 
Part A-Determination of the MTD 
b) 
Part B- Osteosarcoma Phase 2 cohort.  
 
 
 
Definitions 
 
 Evaluable For Adverse Events 
Any patient who receives at least one dose of the study drug(s) or who experiences a 
dose-limiting toxicity is considered evaluable for Adverse Events. Patients who do not 
have DLT and are not considered evaluable for toxicity will be replaced. 
 
 Maximum Tolerated Dose 
• 
The MTD will be the maximum dose at which fewer than one-third of 
patients experience DLT (See Section 5.5) during Cycle 1 of therapy.  

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• 
In the unlikely event that two DLTs observed out of 6 evaluable patients are 
different classes of Adverse Effects (e.g. hepatotoxicity and 
myelosuppression), AND all of the following conditions are met, expansion 
of the cohort to 12 patients will be considered:  
 
•  One of the DLTs does not appear to be dose-related 
•  The Adverse Effects are readily reversible 
•  The study chair, DVL statistician, DVL committee chair or vice chair, 
and IND sponsor all agree that expansion of the cohort is acceptable 
 
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting 
toxicities, the dose escalation will be considered. 
 
• 
The DLTs observed in the pharmacokinetic (PK) expansion cohort will be 
counted towards the total number of DLTs observed at the MTD during the 
dose escalation portion of the study. If ≥ 1/3 of the cohort of patients at the 
MTD (during the dose escalation plus the PK phase 2) experience DLT then 
the MTD will be exceeded.  
 
 
 Determination of MTD 
 
The rolling six phase 1 trial design will be used for the conduct of this study15.  Two to six 
patients can be concurrently enrolled onto a dose level, dependent upon (1) the number of 
patients enrolled at the current dose level, (2) the number of patients who have experienced 
DLT at the current dose level, and (3) the number of patients entered but with tolerability 
data pending at the current dose level.  Accrual is suspended when a cohort of six has 
enrolled or when the study endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in the 
cohort, the number of DLTs observed, and the number of participants at risk for developing 
a DLT (i.e., participants enrolled but who are not yet assessable for toxicity). For example, 
when three participants are enrolled onto a dose cohort, if toxicity data is available for all 
three when the fourth participant entered and there are no DLTs, the dose is escalated and 
the fourth participant is enrolled to the subsequent dose level. If data is not yet available 
for one or more of the first three participants and no DLT has been observed, or if one DLT 
has been observed, the new participant is entered at the same dose level. Lastly, if two or 
more DLTs have been observed, the dose level is de-escalated. This process is repeated for 
participants five and six. In place of suspending accrual after every three participants, 
accrual is only suspended when a cohort of six is filled. When participants are inevaluable 
for toxicity, they are replaced with the next available participant if escalation or de-
escalation rules have not been fulfilled at the time the next available participant is enrolled 
onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the current dose 
level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the study 
is suspended to accrual: 
 
 
# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 

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2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
3 
0 
3 
0 
Escalate** 
 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
 
4 
0 
4 
0 
Escalate** 
 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
 
5 
0 
5 
0 
Escalate** 
 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
* If six patients already entered at next lower dose level, the MTD has been defined. 
**If final dose level has been reached, the recommended dose has been reached. 
 
If two or more of a cohort of up to six patients experience DLT at a given dose level, then 
the MTD has been exceeded and dose escalation will be stopped (see Section 11.2.2 for 
exception to rule). 
 
In addition to determination of the MTD, a descriptive summary of all toxicities will be 
reported. 
 
 
 
 
Inclusion of Children, Women and Minorities 
 
CTEP PLANNED ENROLLMENT REPORT 
Race Categories 
Ethnicity Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
0 
1 
0 
0 
1 
Asian 
1 
2 
0 
0 
3 
Native Hawaiian or 
Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
5 
5 
0 
0 
10 

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White 
20 
29 
4 
4 
57 
More Than One Race 0 
0 
0 
0 
0 
Total 
26 
37 
4 
4 
71 
 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual 
to past COG studies of new agents demonstrates the accrual of both genders and all NIH-
identified ethnicities to such studies.  Efforts will be made to extend the accrual to a 
representative population, but in a Phase 1 trial which will accrue a limited number of 
patients, a balance must be struck between patient safety considerations and limitations on 
the number of individuals exposed to potentially toxic or ineffective treatments on the one 
hand and the need to explore gender, racial, and ethnic aspects of clinical research on the 
other. If differences in outcome that correlate to gender, racial, or ethnic identity are noted, 
accrual may be expanded or additional studies may be performed to investigate those 
differences more fully. 
 
 
Pharmacokinetic and Correlative Studies and Response Analysis 
 
A descriptive analysis of pharmacokinetic (PK) parameters of VX15/2503 will be 
performed to define systemic exposure, drug clearance, and other pharmacokinetic 
parameters. The PK parameters will be summarized with simple summary statistics, 
including means, medians, ranges, and standard deviations (if numbers and distribution 
permit).   
 
While the primary aim of this study is to evaluate the toxicity of VX15/2503, patients will 
have disease evaluations performed as indicated in Section 8.1. Disease response will be 
assessed according to RECIST criteria for patients with solid tumors, and will be reported 
descriptively. 
 
All these analyses will be descriptive and exploratory and hypotheses generating in nature. 
 
 
Study Design - Part B  
 
Data collected from patients from the dose determining portion (Part A) treated at the 
MTD/RP2D and who meet eligibility criteria for Part B of the study will be counted in the 
Phase 2 evaluation. The following Simon’s optimal two stage design will be used in each 
stratum. 
 
The two stage design is illustrated below: 
 
Stage 
Number of patients 
enrolled in stage 
Cumulative response 
results 
Decision 
1 
19 
4 or fewer disease control 
successes and 1 or fewer 
RECIST responders 
Terminate the trial with the 
conclusion that VX15/2503 is 
not associated with sufficient 
activity for further 
investigation 
 
 
5 or more disease control 
success or 2 or more 
RECIST responders 
Continue to stage 2 

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2 
10 
8 or fewer disease control 
successes and 4 or fewer 
RECIST responders 
Terminate the trial with the 
conclusion that VX15/2503 is 
not associated with sufficient 
activity for further 
investigation 
 
 
9 or more disease control 
successes or 5 or more 
RECIST responders 
Terminate the trial with the 
conclusion that VX15/2503 is 
associated with sufficient 
activity for further 
investigation 
Part B will be initially opened to 6 adult patients. The Rolling 6 design logic will be 
applied for assessing toxicity in the initial cohort of 6 adults. If 2 or more patients in this 
cohort experience a DLT in Cycle 1, then enrollment to Part B will be suspended pending 
study committee discussion. If Part A is complete and the initial cohort of 6 adult patients 
in Part B is deemed safe, up to 19 patients will be enrolled into Stage 1 with a maximum 
of 12 adult patients. However, if at any point the percentage of patients experiencing a 
Cycle 1 DLT is >33%, then the study will be suspended pending internal review. This will 
include DLTs observed for all younger patients from Part A that were assigned to the 
MTD/RP2D used in Part B of the study. 
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 (S | R) = 0.90. 
 
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 
 
We will concurrently enroll on the Phase 1 and Phase 2 studies. While the Phase 1 study is 
accruing we will limit the Phase 2 enrollment to osteosarcoma patients greater than 21 
years of age to ensure the completion of the phase 1 portion of this study. After the Phase 
1 study is complete, patients less than or equal to 21 will be enrolled into the Phase 2 

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portion of this study. The Phase 2 study will cap the number of older patients (>21 years) 
enrolled into Stage 1 at 12 patients to ensure a representative number of patients in both 
age groups. Without this cap, it may be possible to open Stage 2 of the Phase 2 study 
without having enrolled any younger patients and stage 2 would have opened based on 
information collected solely in older patients. Osteosarcoma patients enrolled in Phase 1 
will also be included in the Phase 2 part of the study. 
 
 
Method of Analysis – Phase 2  
 
Response in Part B osteosarcoma patients will be determined as defined in Section 12.0. A 
report on the efficacy assessment will be posted on the completed disease stratum as part 
of the semi-annual study committee meeting book report.  
 
Toxicities for patients will be described separately.  Every effort will be made to accrue 
the number of patients needed to evaluate efficacy according to the schema in Section 11.6. 
For strata not appropriately filled, descriptive statistics will be employed to describe 
outcomes.  
 
Which Patients will be Considered Evaluable for RECIST Response: 
Any eligible patient who receives at least one dose of VX15/2503 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 VX15/2503 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 VX15/2503 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 considered not to have experienced disease control success. Also, any patient who 
is eligible, receives one dose of VX15/2503 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 

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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. 
 
 
EVALUATION CRITERIA 
 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
 
Response Criteria for Patients with Solid Tumors  
See the table in section 8.0 for the schedule of tumor evaluations. In addition to the 
scheduled scans, a confirmatory scan should be obtained on the next consecutive cycle 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009].  Key points are that 5 target lesions are identified and that changes in the largest 
diameter (unidimensional measurement) of the tumor lesions but the shortest diameter of 
malignant lymph nodes are used in the RECIST v 1.1 criteria. 
 
 Definitions 
 
a) 
 Evaluable for objective response: Eligible patients who receive at least 
one dose of protocol therapy will be considered evaluable for response. Evaluable 
patients who demonstrate a complete or partial response confirmed by central 
review before receiving non-protocol anti-cancer therapy will be considered a 
responder. All other evaluable patients will be considered non-responders.  
 
b) 
 Evaluable Non-Target Disease Response: Eligible patients who have 
lesions present at baseline that are evaluable but do not meet the definitions of 
measurable disease and have received at least one dose of protocol therapy will be 
considered evaluable for non-target disease. The response assessment is based on 
the presence, absence, or unequivocal progression of the lesions. 
 Disease Parameters 
 
12.2.2.1 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). 
 
Note:  Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable. If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 

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12.2.2.2 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 no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
12.2.2.3 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. 
 
12.2.2.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions 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 that 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. 
 
12.2.2.5 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.  
 
 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  

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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. 
 
12.2.3.1 Clinical lesions: Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
12.2.3.2 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.  
 
12.2.3.3 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 (e.g. for body 
scans). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  
 
12.2.3.4 PET-CT:  At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
12.2.3.5 Tumor markers: Tumor markers alone cannot be used to assess response.  
If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.  
 
12.2.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.2.3.7 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 

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scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
 
 Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
12.2.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
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 progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 

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discontinuation of therapy 
 
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 
 
12.2.4.2 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) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
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.     
 
 Overall Response Assessment 
 
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥ 28 days Confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
≥ 28 days 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 ≥ 
28 days from baseline 
PD 
Any 
Yes or No 
PD 
 

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Any 
PD** 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  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. 
 
 
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Table 4: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.6 from a sequence of overall response assessments. 
 
 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
 Evaluable Disease 
The presence of at least one lesion, with no lesion that can be accurately measured 
in at least one dimension.  Such lesions may be evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers or other reliable 
measures.  
 
 Complete Response 
Disappearance of all evaluable disease. 

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 Partial response 
Partial responses cannot be determined in patients with evaluable disease 
 
 Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), 
or Progressive Disease. 
 
 Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, clinical, or 
radiographic progression. 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.6 from a sequence of overall response assessments. 
 
 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
 MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  
Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease:  Development of new MIBG positive lesions 
 
 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess efficacy 
for study endpoint. See Section 8.2 for details on transferring images to the Imaging 
Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  

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The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 
 
 
The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
 
 Overall Response Assessment 
 
Table 5: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly 
identified lesion by CT/MRI that occurs during therapy would be considered progressive 
disease. 
 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 

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CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Table 3 in Section 12.6. 
 
 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
 Bone Marrow Involvement  
Bone marrow obtained within 28 days prior to study enrollment with tumor cells 
seen on routine morphology (not by immunohistochemical staining only) of 
bilateral aspirate or biopsy on one bone marrow sample. 
 
Bone Marrow responses are determined by H&E Staining of bilateral bone marrow 
biopsies and aspirates. 
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there 
is a doubling in the amount of tumor in the marrow AND 
a minimum of 25% tumor in bone marrow by 
morphology. (For example, a patient entering with 5% 
tumor in marrow by morphology must increase to ≥ 25% 
tumor to have progressive disease; a patient entering with 
30% tumor must increase to > 60%). 
 
In patients who enroll without evidence of neuroblastoma 
in bone marrow will be defined as progressive disease if 
tumor is detected in 2 consecutive bone marrow biopsies 
or aspirations done at least 21 days apart. 
 
Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.6. 
 
 
Best Response 
 
 Evaluation of Best Overall Response 
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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. 
 
Table 3.  Sequences of overall response assessments with corresponding best 
response. 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
 Duration of Response 
 
 Duration of overall response:  The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is 
objectively documented. 
 
 
 Duration of stable disease:  Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the treatment 
started, including the baseline measurements.  
 
 
 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  Adverse events are reported in a routine manner at scheduled times 
during a trial.  (Please follow directions for routine reporting provided in the Case Report Forms 
for this protocol).  Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  The following sections provide information 
about expedited reporting. 
 
 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered serious; 
3) the grade (severity); and 4) whether or not hospitalization or prolongation of hospitalization was 

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associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source.  The NCI, rather than a commercial distributor, may on some occasions 
distribute commercial agents for a trial. 
 
 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the NCI CTCAE version 5.0. All 
appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
Note:  This includes all events that occur within 30 days of the last dose of protocol 
treatment.  Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the 
agent(s) must also be reported according to the instructions in the table 
below. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
Table A: Phase 1 and Early Phase 2 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, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 

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ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported via CTEP-AERS within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be 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 report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific 
expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 
birth defects must be reported via CTEP-AERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 1 
Trials Utilizing an Agent under a CTEP-IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not clearly due 
to progressive disease must be reported via CTEP-AERS for an agent under a CTEP or non-CTEP 
IND agent per the timelines outlined in the table above. 
 
• Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), does 
not require expedited reporting, unless it is associated with hospitalization. 

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Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD/LYMPHATICS DISORDERS 
Anemia 
 
• 
Grade 1 and 2 adverse events listed in the table below do not require expedited reporting via 
CTEPAERS, unless it is associated with hospitalization 
   
Category 
Adverse Events 
GASTROINTESTINAL DISORDERS 
Nausea 
GENERAL DISORDERS AND 
ADMINISTRATION SITE CONDITIONS 
Fatigue 
MUSCULOSKELETAL AND 
CONNECTIVE TISSUE DISORDERS  
Arthralgia 
GASTROINTESTINAL DISORDERS 
Decreased appetite 
IMMUNE SYSTEM DISORDERS 
Infusion-related reaction  
INFECTIONS AND INFESTATIONS  
Fever  
MUSCULOSKELETAL AND 
CONNECTIVE TISSU DISORDERS 
Myalgia  
SKIN AND SUBCUTANEOUS 
DISORDERS 
Pruritus 
 
As referenced in the CTEP Adverse Events Reporting Requirements, an AE that resolves and then recurs 
during a subsequent cycle does not require CTEP-AERS reporting unless (1) the Grade increases; or (2) 
hospitalization is associated with the recurring AE. 
 
 
When to Report an Event in an Expedited Manner  
 
• 
Some adverse events require notification within 24 hours (refer to Table A to NCI via 
the web at http://ctep.cancer.gov (email the ADVL1614 COG assigned study Research 
Coordinator within 24 hours of becoming aware of the event if the CTEP-AERS 24-Hour 
Notification web-based application is unavailable) and by telephone call to the Study 
Chair. Once internet connectivity is restored, a 24-hour notification phoned in must be 
entered electronically into CTEP-AERS by the original submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 
• 
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page https://eapps-
ctep.nci.nih.gov/ctepaers. 
 
 
Expedited Reporting Methods  
 
 CTEP-AERS Reporting 
To report adverse events in an expedited fashion use the NCI’s Adverse Event 
Expedited 
Reporting 
System 
(CTEP-AERS) 
that 
can 
be 
found 
at 
http://ctep.cancer.gov. 
 
A CTEP-AERS report must be submitted electronically via the CTEP-AERS Web-

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based application located at https://eapps-ctep.nci.nih.gov/ctepaers/.  If prompted 
to 
enter 
a 
sponsor 
email 
address, 
please 
type 
in: 
PEPCTNAERS@childrensoncologygroup.org. 
 
Send supporting documentation by email to the ADVL1614 COG study assigned 
Research Coordinator.  ALWAYS include the ticket number on all faxed and 
emailed documents. 
 
 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG case report 
forms and do not alter the guidelines for CTEP-AERS reporting. 
 
 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
 If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported. 
 
 The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects.  
 
 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than or equal to Grade 1, whichever level is higher (note that the 
resolution date may therefore be different from the date at which the grade of the 
AE decreased from its highest grade).  If the AE does not return to baseline the 
resolution date should be recorded as "ongoing."   
 
 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
 
Other Recipients of Adverse Event Reports 
 
 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.3) 
should be reported at the end of each cycle using the forms provided in the CRF 
packet (See Section 14.1). 
 
 COG will forward reports and supporting documentation to the Study Chair, to 
the FDA (when COG holds the IND) and to the pharmaceutical company (for 
industry sponsored trials). 
 
 Adverse events determined to be reportable must also be reported according to 
the local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
 
Reporting Secondary AML/MDS 
All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that 
occur in patients following their chemotherapy for cancer must be reported via CTEP-
AERS and included as part of the second malignant neoplasm reporting requirements for 

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this protocol (see data submission packet).  Submit the completed CTEP-AERS report 
within 14 days of an AML/MDS diagnosis occurring after protocol treatment for cancer. 
 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
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. 
 
 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and emailed to the 
ADVL1614 COG Study Assigned Research Coordinator along with any additional medical 
information. The potential risk of exposure of the fetus to the investigational agent should 
be documented in the “Description of Event” section of the CTEP-AERS report. 
 
 Pregnancy 
• 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic. For this reason, pregnancy 
occurring on study or within 6 months following the last dose of study 
therapy should 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” System Organ Class (SOC). 
 
• 
Pregnancy should 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.  
 
 Pregnancy Loss (Fetal Death) 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
 
• 
Any pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 

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since CTEP-AERS recognizes any Grade 5 event as a patient death.   
 
 Death Neonatal 
• 
Neonatal death, defined in CTCAE as “Newborn deaths occurring during 
the first 28 days after birth” that is felt by the investigator to be at least 
possibly due to the investigational agent/intervention, should be reported 
expeditiously. 
 
• 
A neonatal death should be reported expeditiously as Grade 4 “Death 
neonatal” under the “General disorders and administration” SOC 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 as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death. 
 
Pregnancy should be followed up until the outcome of the pregnancy is 
known at intervals deemed appropriate by her physicians. The “Pregnancy 
Information Form” should be used for all follow-ups. This form is 
available 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs
/PregnancyReportForm.pdf.  
 
 
 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
entered in RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the case report form (CRF) 
packet. 
 
See separate CRF Packet, which includes submission schedule. 
 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, July 
31, and October 31.  Instructions for submitting data using the CDUS can be found on the 
CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
 
 

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Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
2. 
Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the PEP-CTN scientific 
committee; and a member from the NCI. The DSMC meets at least every 6 months 
to review current study results, as well as data available to the DSMC from other 
related studies. Approximately 6 weeks before each meeting of the Phase 1 and 2 
DSMC, study chairs will be responsible for working with the study statistician to 
prepare study reports for review by the DSMC. The DSMC will provide 
recommendations to the COG PEP-CTN Chair and the Group Chair for each study 
reviewed to change the study or to continue the study unchanged. Data and Safety 
Committee reports for institutional review boards can be prepared using the public 
data monitoring report as posted on the COG Web site. 
 
3. 
Monitoring by the Study Chair and Developmental Therapeutics Leadership  
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the COG 
PEP-CTN Chair, Vice Chair and Statistician on a weekly conference call. 

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REFERENCES 
1. 
Giraudon P, Vincent P, Vuaillat C: T-cells in neuronal injury and repair: semaphorins and 
related T-cell signals. Neuromolecular Med 7:207-16, 2005 
2. 
Worzfeld T, Offermanns S: Semaphorins and plexins as therapeutic targets. Nat Rev Drug 
Discov 13:603-21, 2014 
3. 
Takamatsu H, Takegahara N, Nakagawa Y, et al: Semaphorins guide the entry of dendritic 
cells into the lymphatics by activating myosin II. Nat Immunol 11:594-600, 2010 
4. 
Mendes-da-Cruz DA, Lepelletier Y, Brignier AC, et al: Neuropilins, semaphorins, and their 
role in thymocyte development. Ann N Y Acad Sci 1153:20-8, 2009 
5. 
Basile JR, Castilho RM, Williams VP, et al: Semaphorin 4D provides a link between axon 
guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci U S A 103:9017-22, 
2006 
6. 
Campos M, SG DEC, Ribeiro GG, et al: Ki-67 and CD100 immunohistochemical expression 
is associated with local recurrence and poor prognosis in soft tissue sarcomas, respectively. 
Oncol Lett 5:1527-1535, 2013 
7. 
Ch'ng E, Tomita Y, Zhang B, et al: Prognostic significance of CD100 expression in soft tissue 
sarcoma. Cancer 110:164-72, 2007 
8. 
Leonard JE, Fisher TL, Winter LA, et al: Nonclinical Safety Evaluation of VX15/2503, a 
Humanized IgG4 Anti-SEMA4D Antibody. Mol Cancer Ther 14:964-72, 2015 
9. 
Moriarity BS, Otto GM, Rahrmann EP, et al: A Sleeping Beauty forward genetic screen 
identifies new genes and pathways driving osteosarcoma development and metastasis. Nat 
Genet 47:615-24, 2015 
10. 
Vaccinex: VX15/2503 Investigator's Brochure v. 3, 2015 
11. 
Fisher TL, Reilly CA, Winter LA, et al: Generation and preclinical characterization of an 
antibody specific for SEMA4D. MAbs:1-13, 2015 
12. 
Evans EE, Paris M, Smith ES, et al: Immunomodulation of the tumor microenvironment by 
neutralization of Semaphorin 4D. Oncoimmunology 4:e1054599, 2015 
13. 
Shi W, Kumanogoh A, Watanabe C, et al: The class IV semaphorin CD100 plays 
nonredundant roles in the immune system: defective B and T cell activation in CD100-
deficient mice. Immunity 13:633-42, 2000 
14. 
Patnaik A, Weiss GJ, Leonard JE, et al: Safety, Pharmacokinetics, and Pharmacodynamics 
of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with 
Advanced Solid Tumors. Clin Cancer Res 22:827-36, 2016 
15. 
Skolnik JM, Barrett JS, Jayaraman B, et al: Shortening the timeline of pediatric phase I 
trials: the rolling six design. J Clin Oncol 26:190-5, 2008 

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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
 
Karnofsky 
Lansky 
Score 
Description 
Score Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time spent 
in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet 
play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to very 
passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 
 
 
 

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APPENDIX II: CORRELATIVE STUDIES GUIDE  
 
FOR PATIENTS ≤ 10KG 
 
 
 
FOR PATIENTS > 10KG 
 
 
 
Correlative Study 
 
 
 
 
 
Appx 
Sample volume 
 
 
Tube Type 
Volume per 
sample 
Total  
Cycle 1 
Total Cycle 2 
 
Subsequent 
Cycles 
 
Pharmacokinetic Study 
IV 
2.5ml 
12.5ml 
7.5ml 
Included with 
Immunogenicity 
Samples 
SST Tubes 
Immunogenicity Study 
(Anti-Drug Antibody) 
V 
3.5ml 
7ml 
3.5ml 
3.5ml 
SST Tubes 
Pharmacodynamics-           
T lymphocyte 
saturation/cellular 
SEMA4D assay  
VI 
4ml 
20ml 
4ml 
4ml 
Cyto-Chex 
Tubes 
Pharmacodynamics- Total 
Soluble  SEMA4D 
VII 
3.5ml 
7ml 
3.5ml 
3.5ml 
SST Tubes 
Total Blood Volume 
 46.5ml 
18.5ml 
11ml 
 
 
 
Correlative Study 
 
 
 
 
 
Appx 
Sample volume 
 
 
Tube Type 
Volume per 
sample 
Total  
Cycle 1 
Total Cycle 2 
 
Subsequent 
Cycles 
 
Pharmacokinetic Study 
IX 
2.5-3.5ml 
11ml 
6ml 
Included with 
Immunogenicity 
Samples 
SST Tubes 
Immunogenicity Study 
(Anti-Drug Antibody) 
X 
3.5ml 
0ml 
0ml 
3.5ml 
SST Tubes 
Pharmacodynamics-           
T lymphocyte 
saturation/cellular 
SEMA4D assay  
VI 
4ml 
20ml 
4ml 
4ml 
Cyto-Chex 
Tubes 
Pharmacodynamics- Total 
Soluble  SEMA4D 
XI 
3.5ml 
0ml 
0ml 
3.5ml 
SST Tubes 
Total Blood Volume 
 31ml 
10ml 
11ml 
 

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APPENDIX III: TOXICITY-SPECIFIC GRADING 
 
Bilirubin 
 
Grade 1: 
> ULN - ≤ 1.5 x ULN 
Grade 2: 
> 1.5 x ULN - 3.0 x ULN  
Grade 3: 
> 3.0 x ULN - 10.0 x ULN 
Grade 4: 
> 10.0 x ULN 
 
ALT: For the purpose of this study, the ULN for SGPT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
> 45 U/L - ≤ 135 U/L 
Grade 2: 
136 U/L - 225 U/L 
Grade 3: 
226 U/L - 900 U/L 
Grade 4: 
> 900 U/L 
 
AST: For the purpose of this study, the ULN for SGOT is 50 U/L regardless of baseline. 
 
Grade 1: 
> 50 U/L - ≤ 150 U/L 
Grade 2: 
151 U/L - 250 U/L 
Grade 3: 
251 U/L - 1000 U/L 
Grade 4: 
> 1000 U/L 
 
GGT: 
 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5 x ULN - 5.0 x ULN 
Grade 3: 
> 5.0 x ULN - 20.0 x ULN 
Grade 4: 
> 20.0 x ULN 

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APPENDIX IV: PHARMACOKINETIC STUDY FORM FOR PATIENTS > 10KG 
 
COG Pt ID # _______________ 
 
 
 
Cycle # ______ Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg  VX15/2503 Dose Level: ______mg/kg    VX15/2503 Total Daily Dose: ______mg 
 
Blood samples (2.5 ml) will be collected in SST tubes at the following time points during Cycle 1: Day 1 (2 hrs. after 
the infusion), Day 4 (at any time point), Day 8 (at any time point), and Day 15 (pre-infusion, and at the end of infusion). 
For cycle 2, blood samples (2.5 ml) will be collected in SST tubes at the following time points: Day 1 (at the end of 
infusion, and 2 hrs. after the infusion), and Day 15 (pre-infusion). On Cycle 1 Day 1 (pre-infusion, and at the end of 
infusion), and Cycle 2 Day 1 (pre-infusion), pharmacokinetic blood samples (3.5 ml) will be collected in conjunction 
with immunogenicity samples in SST tubes. For subsequent cycles pharmacokinetic samples (3.5 ml) will be collected 
in conjunction with immunogenicity samples in SST tubes on Day 1 prior to infusion. 
 
Record the exact time the sample is drawn along with the exact time VX15/2503 is given on Days 1 and 15. 
 
Blood Sample 
No. 
Cycle 1 
Timepoint 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time Sample Collected 
(24-hr clock) 
1 
Day 1 
Prior to Cycle 1 Day 1 VX15/2503 
infusion 
___/___/___ 
|__|__| : |__|__| 
VX15/2503 on Cycle 1 Day 1   Date:___/___/___   Infusion Start Time: |__|__| : __|__| |__|__| End Time: |__|__| : |__|__| 
2 
Day 1 
At the end of infusion on Cycle 1 Day 1 
VX15/2503  
___/___/___ 
|__|__| : |__|__| 
3 
Day 1 
2 hrs. following infusion on Cycle 1 
Day 1 VX15/2503  infusion 
___/___/___ 
|__|__| : |__|__| 
4 
Day 4      
(+/ - 1 Day) Any time point 
___/___/___ 
|__|__| : |__|__| 
5 
Day 8     
(+/ - 1 Day) Any time point 
___/___/___ 
|__|__| : |__|__| 
6 
Day 15 
Prior to Day 15 VX15/2503  infusion 
 
 
VX15/2503  on Cycle 1 Day 15    Date:___/___/___     Infusion Start Time: |__|__| : |__|__| End Time: |__|__| : |__|__| 
7 
Day 15 
At the end of infusion on Cycle 1 Day 
15 VX15/2503 
___/___/___ 
|__|__| : |__|__| 
Blood Sample 
No. 
Cycle 2 
Timepoint 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time Sample Collected 
(24-hr clock) 
8 
Day 1 
Prior to Day 1 VX15/2503 infusion 
___/___/___ 
|__|__| : |__|__| 
VX15/2503 on Cycle 2 Day 1   Date:___/___/___     Infusion Start Time: |__|__| : |__|__| End Time: |__|__| : |__|__| 
9 
Day 1 
At the end of infusion on Cycle 2 Day 1 
VX15/2503  
___/___/___ 
|__|__| : |__|__| 
10 
Day 1 
2 hrs. following infusion on Cycle 2 
Day 1 VX15/2503  infusion 
___/___/___ 
|__|__| : |__|__| 
11 
Day 15 
Prior to Cycle 2 Day 15 VX15/2503  
infusion 
 
 
VX15/2503 on Cycle 2 Day 15    Date:___/___/___    Infusion Start Time: |__|__| : |__|__| End Time: |__|__| : |__|__| 
 
 

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Subsequent Cycles (cycle 3 onwards) 
Blood 
Sample 
No. 
Timepoint 
Scheduled Collection Time 
Actual Date 
Sample Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle #_____________ 
 
Prior to VX15/2503 infusion 
 
|__|__| : |__|__| 
VX15/2503 Infusion on Day 1  Date:___/___/___   Infusion Start Time: |__|__| : |__|__| End Time: |__|__| : |__|__| 
 
 
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should be sent with the samples 
to the address listed in Section 8.3.6.  See Section 8.3 for detailed guidelines for packaging and shipping PK samples. 
 
Signature: _________________________________________                    Date:___________________  
               (site personnel responsible for collection of samples) 
 
 
 

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APPENDIX V: IMMUNOGENICITY STUDY FOR PATIENTS > 10KG 
COG Pt ID # _______________ 
 
 
 
 
Cycle # ______ Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg VX15/2503 Dose Level: ______mg/kg  VX15/2503 Total Daily Dose: _____mg 
 
Blood samples (3.5 ml) will be collected in consenting patients in SST tubes during Cycle 1 at the following time 
points: Day 1 (pre-infusion and at the end of infusion) and each subsequent cycle on Day 1 prior to infusion. All of 
these blood draws will be used for both immunogenicity and pharmacokinetic analysis.  
 
Record the exact time the sample is drawn along with the exact time VX15/2503 is given on Days 1 and 15. 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time 
Actual 
Date 
Sample 
Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle 1, Day 1 
Prior to VX15/2503 infusion 
 
|__|__| : |__|__| 
VX15/2503 Infusion on Day 1       Date:___/___/___       Infusion Start Time: |__|__| : |__|__| 
Infusion End Time: |__|__| : |__|__| 
2 
Cycle 1, Day 1 
At the end of VX15/2503 infusion 
 
|__|__| : |__|__| 
 
Subsequent Cycles (Cycle 2 onwards) 
Blood 
Sample 
No. 
Time Point/Cycle 
Number 
Scheduled Collection Time 
Actual Date 
Sample 
Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle #_____________ 
 
Prior to VX15/2503 infusion 
 
|__|__|:|__|__| 
VX15/2503 Infusion on Day 1       Date:___/___/___       Infusion Start Time: |__|__| : |__|__| 
Infusion End Time: |__|__| : |__|__| 
One copy of this Immunogenicity Study Form should be uploaded into RAVE. A second copy should be sent with the 
samples to the address listed in Section 8.4.6 . See Section 8.4 for detailed guidelines for packaging and shipping PD 
samples. 
 
Record any notes for Sample Storage Conditions below. 
 
Notes_______________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________
_______________________________________________________________ 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this 
form below: 
Signature: _________________________________________                    Date:___________________ 
  
(site personnel responsible for collection of samples) 

                         ADVL1614 
 
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APPENDIX VI: PHARMACODYNAMICS T-LYMPHOCYTE SATURATION (FOR ALL 
PATIENTS) 
COG Pt ID # _______________ 
 
 
 
 
 Cycle # ______    Date: _____________ 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg             VX15/2503 Dose Level: ______mg/kg VX15/2503              Total Daily Dose: _____mg 
 
Blood samples (4 ml) will be collected in consenting patients in cyto-chex tubes during Cycle 1 at the following time 
points: Day 1 (pre-infusion and at the end of infusion), Day 15 (pre-infusion and at the end of infusion), and Day 28 (at 
any time point). Blood samples (4 ml) will be collected in consenting patients prior to infusion on Day 1 for each 
subsequent cycle. 
 
Record the exact time the sample is drawn along with the exact time VX15/2503 is given on Day 1 and Day 15. 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time 
Actual Date 
Sample 
Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle 1, Day 1 
Prior to VX15/2503 infusion 
 
|__|__| : |__|__| 
VX15/2503 on Day 1      Date:___/___/___    Infusion Start Time: |__|__| : |__|__|    End Time: |__|__| : |__|__| 
2 
Cycle 1, Day 1 
At the end of VX15/2503 infusion 
 
|__|__| : |__|__| 
 
3 
Cycle 1, Day 15 
Prior to VX15/2503 infusion 
 
|__|__| : |__|__| 
VX15/2503 on Day 1    Date:___/___/___    Infusion Start Time: |__|__| : |__|__|     End Time: |__|__| : |__|__| 
4 
Cycle 1, Day 15 
At the end of VX15/2503 infusion 
 
|__|__| : |__|__| 
5 
Cycle 1, Day 28 
Any time point 
 
|__|__| : |__|__| 
 
One copy of this Pharmacodynamic T-Lymphocyte Saturation Study Form should be uploaded into RAVE. A second 
copy should be sent with the samples to the address listed in Section 8.5.6. See Section 8.5 for detailed guidelines for 
packaging and shipping PD samples. 
 
Record any notes for Sample Storage Conditions below. 
Notes: 
_____________________________________________________________________________________________
_____________________________________________________________________________________________ 
_____________________________________________________________________________________________ 
_____________________________________________________________________________________________ 
_____________________________________________________________________________________________ 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this 
form below: 
 
 
Signature: _________________________________________                    Date:___________________ 
 
   (site personnel responsible for collection of samples) 
 
Subsequent Cycles (Cycle 2 onwards) 
Blood 
Sample 
No.  
Time 
Point/Cycle 
Number 
Scheduled Collection Time 
Actual Date 
Sample 
Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle #_______ 
Prior to VX15/2503 infusion 
 
 
 
|__|__| : |__|__| 
 
VX15/2503 on Day 1    Date:___/___/___  Infusion Start Time: |__|__| : |__|__| End Time: |__|__| : |__|__| 

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APPENDIX 
VII: 
PHARMACODYNAMICS 
TOTAL 
SOLUBLE 
SEMA4D 
FOR                        
PATIENTS > 10KG 
 
COG Pt ID # _______________ 
 
 
 
 
Cycle # ______ Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg   
 
VX15/2503 Dose Level: ______mg/kg 
 
VX15/2503 Total Daily Dose: _____mg 
 
Blood samples (3.5 ml) will be collected in consenting patients in SST tubes during Cycle 1 at the following time 
points: Day 1 (pre-infusion and at the end of infusion) and each subsequent cycle on Day 1 prior to infusion. 
 
Record the exact time the sample is drawn along with the exact time VX15/2503 is given on Days 1 and 15. 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time 
Actual Date 
Sample 
Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle 1, Day 1 
Prior to VX15/2503 infusion 
 
|__|__| : |__|__| 
   VX15/2503 on Day 1   Date:___/___/___   Infusion Start Time: |__|__| : |__|__|  End Time: |__|__| : |__|__| 
2 
Cycle 1, Day 1 
At the end of VX15/2503 infusion 
 
|__|__| : |__|__| 
 
 
 
 
One copy of this Pharmacodynamic Total Soluble SEMA4D Study Form should be uploaded into RAVE. A second 
copy should be sent with the samples to the address listed in Section 8.6. See Section 8.6.6 for detailed guidelines for 
packaging and shipping PD samples. 
 
Record any notes for Sample Storage Conditions below. 
 
Notes_______________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________ 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this 
form below: 
 
Signature: _________________________________________                    Date:___________________ 
 
    (site personnel responsible for collection of samples) 
 
 
 
Subsequent Cycles (cycle 2 onwards) 
Blood 
Sample 
No.  
Time 
Point/Cycle 
Number 
Scheduled Collection Time 
Actual Date 
Sample 
Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle #_______ 
Prior to VX15/2503 infusion 
 
 
 
|__|__| : |__|__| 
 
 
VX15/2503 on Day 1    Date:___/___/___  Infusion Start Time: |__|__| : |__|__| End Time: |__|__| : |__|__| 

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APPENDIX VIII: TISSUE STUDIES FORM 
 
COG Pt ID # _______________ 
ACC # ______________ Date:________     Part of Study # ____  
(Please do not write patient names on this form or on samples) 
 
Sample Labeling: 
Samples should be labeled with the following information: 
Protocol number:    ADVL1614 
Institution:        _________________ 
Patient ID #:     _________________ 
Accession #:     _________________  
Sample Date:    _________________ 
Site of Acquired Tissue:  __________________ 
 
Tissue obtained at (check one option below): 
Diagnosis            Relapse         Subsequent Resection/Biopsy 
 
Tissue sample is from a: 
    Resection     or       Biopsy 
Shipment of Tumor Tissue: 
Tissue is requested from original diagnosis, relapse, or any subsequent resection or biopsy prior to treatment with 
VX15/2503. Archived tissue samples should be in the form of a paraffin-embedded tissue block or 8-10 unstained 
slides from the tissue block accompanied by a copy of the pathology report. Fine needle aspirate samples or other 
cytology samples are not acceptable and tumor samples obtained from bone metastases are generally not considered 
acceptable. 
 
All blocks or slides must be labeled with the patient’s study registration number (COG Patient ID #), the study I.D. 
(ADVL1614), and the sample collection date. Data should be recorded on this Tissue Studies Form, which must 
accompany the sample(s) to the address provided in Section 8.7.3.  
 
1. If sending paraffin block (PREFERRED): 
a. 
Place appropriate sample ID label on back of cassette 
b. Place labeled cassette in a Zipper lock bag  
c. 
Paraffin blocks are shipped to the lab at ambient temperature. It is acceptable to send blocks 
refrigerated if sending blocks and slides together. 
 
2. If sending slides: 
If slides will be cut from tissue block, recommended thickness of tissue sections for slides is 4 
microns. Positively charged slides are required (Superfrost Plus is recommended). After cutting, 
the slides should be kept in refrigerator (2-5°C). 
a. 
Place slides in the plastic slide holder and place sample ID label provided on the slide holder 
b. Place the slide holder in the Zipper lock bag and eliminate as much air (and therefore moisture) as 
possible prior to sealing the Zip-lock bag 
c. 
Slides are shipped to the lab at refrigerated temperature on a cold gel pack. It is acceptable to send 
blocks refrigerated if sending blocks and slides together. 
 
One copy of this form should be uploaded into RAVE.   
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this 
form below: 
 
Signature: _________________________________________          Date:________________________________ 
                (site personnel responsible for collection of samples) 

                         ADVL1614 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
77 
Version Date: 01/31/19 
APPENDIX IX: PHARMACOKINETIC STUDY FORM FOR PATIENTS ≤ 10KG 
 
COG Pt ID # _______________ 
 
 
 
Cycle # ______ Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg  
VX15/2503 Dose Level: ______mg/kg    
VX15/2503 Total Daily Dose: ______mg 
 
Blood samples will be collected in SST tubes at the following time points during Cycle 1: Day 1 (pre-infusion [3.5 ml], at 
the end of infusion [2.5 ml], and 2 hrs. after the infusion [2.5 ml]), and Day 15 (pre-infusion [2.5 ml]). For Cycle 2, blood 
samples will be collected in SST tubes at the following time points: Day 1 (pre-infusion [3.5 ml]) and Day 15 (pre-infusion 
[2.5 ml]). For subsequent cycles pharmacokinetic blood samples (3.5 ml) will be collected in conjunction with 
immunogenicity samples in SST tubes on Day 1 prior to infusion. 
 
Record the exact time the sample is drawn along with the exact time VX15/2503 is given on Days 1 and 15.  
Blood Sample 
No. 
Cycle 1 
Timepoint 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time Sample Collected 
(24-hr clock) 
1 
Day 1 
Prior to Cycle 1 Day 1 VX15/2503 
infusion 
___/___/___ 
|__|__| : |__|__| 
VX15/2503 on Cycle 1 Day 1   Date:___/___/___   Infusion Start Time: |__|__| : __|__| |__|__| End Time: |__|__| : |__|__| 
2 
Day 1 
At the end of infusion on Cycle 1 Day 1 
VX15/2503 
___/___/___ 
|__|__| : |__|__| 
3 
Day 1 
2 hrs. following infusion on Cycle 1 
Day 1 VX15/2503  infusion 
___/___/___ 
|__|__| : |__|__| 
4 
Day 15 
Prior to Day 15 VX15/2503  infusion 
 
 
VX15/2503  on Cycle 1 Day 15    Date:___/___/___     Infusion Start Time: |__|__| : |__|__| End Time: |__|__| : |__|__| 
Blood Sample 
No. 
Cycle 2 
Timepoint 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time Sample Collected 
(24-hr clock) 
5 
Day 1 
Prior to Day 1 VX15/2503 infusion 
___/___/___ 
|__|__| : |__|__| 
VX15/2503 on Cycle 2 Day 1   Date:___/___/___     Infusion Start Time: |__|__| : |__|__| End Time: |__|__| : |__|__| 
6 
Day 15 
Prior to Cycle 2 Day 15 VX15/2503  
infusion 
 
 
VX15/2503 on Cycle 2 Day 15    Date:___/___/___    Infusion Start Time: |__|__| : |__|__| End Time: |__|__| : |__|__| 
 
Subsequent Cycles (cycle 3 onwards) 
Blood 
Sample 
No. 
Timepoint 
Scheduled Collection Time 
Actual Date 
Sample Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle #_____________ 
 
Prior to VX15/2503 infusion 
 
|__|__| : |__|__| 
VX15/2503 Infusion on Day 1  Date:___/___/___   Infusion Start Time: |__|__| : |__|__| End Time: |__|__| : |__|__| 
 
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should be sent with the samples 
to the address listed in Section 8.3.6.  See Section 8.3 for detailed guidelines for packaging and shipping PK samples. 
 
Signature: _________________________________________                    Date:___________________  
               (site personnel responsible for collection of samples) 

                         ADVL1614 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
78 
Version Date: 01/31/19 
APPENDIX X: IMMUNOGENICITY STUDY FOR PATIENTS ≤ 10KG 
COG Pt ID # _______________ 
 
 
 
Cycle # ______ Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg VX15/2503 Dose Level: ______mg/kg  VX15/2503 Total Daily Dose: _____mg 
 
Blood samples (3.5 ml) will be collected in consenting patients in SST tubes during Cycle 3 and each 
subsequent cycle on Day 1 prior to infusion. All of these blood draws will be used for both immunogenicity 
and pharmacokinetic analysis.  
 
Record the exact time the sample is drawn along with the exact time VX15/2503 is given on Day 1 of Cycle 
3 and each subsequent cycle.  
 
One copy of this Immunogenicity Study Form should be uploaded into RAVE. A second copy should be 
sent with the samples to the address listed in Section 8.4.6 . See Section 8.4 for detailed guidelines for 
packaging and shipping immunogenicity samples. 
 
Record any notes for Sample Storage Conditions below. 
 
Notes______________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________ 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
Signature: _________________________________________                    Date:___________________ 
 
    (site personnel responsible for collection of samples) 
 
 
 
 
 
 
 
 
Cycle 3 Onwards 
Blood 
Sample 
No. 
Time Point/Cycle 
Number 
Scheduled Collection Time 
Actual Date 
Sample 
Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle #_____________ 
 
Prior to VX15/2503 infusion 
 
|__|__|:|__|__| 
VX15/2503 Infusion on Day 1       Date:___/___/___       Infusion Start Time: |__|__| : |__|__| 
Infusion End Time: |__|__| : |__|__| 

                         ADVL1614 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
79 
Version Date: 01/31/19 
APPENDIX XI: PHARMACODYNAMICS TOTAL SOLUBLE SEMA4D FOR PATIENTS  ≤ 10KG 
 
COG Pt ID # _______________ 
 
 
 
Cycle # ______ Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg 
VX15/2503 Dose Level: ______mg/kgVX15/2503  
 
Total Daily Dose: _____mg 
 
Blood samples (3.5 ml) will be collected in consenting patients in SST tubes during Cycle 3 and each 
subsequent cycle on Day 1 prior to infusion. 
 
Record the exact time the sample is drawn along with the exact time VX15/2503 is given on Day 1 of Cycle 
3 and each subsequent cycle. 
 
 
One copy of this Pharmacodynamic Total Soluble SEMA4D Study Form should be uploaded into RAVE. 
A second copy should be sent with the samples to the address listed in Section 8.6. See Section 8.6.6 for 
detailed guidelines for packaging and shipping PD samples. 
 
Record any notes for Sample Storage Conditions below. 
 
Notes______________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________ 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
 
Signature: _________________________________________                    Date:___________________ 
 
    (site personnel responsible for collection of samples) 
 
 
 
 
 
 
 
 
 
 
 
Cycle 3 Onwards 
Blood 
Sample 
No.  
Time 
Point/Cycle 
Number 
Scheduled Collection Time 
Actual Date 
Sample 
Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle #_______ 
Prior to VX15/2503 infusion 
 
 
 
|__|__| : |__|__| 
 
 
VX15/2503 on Day 1    Date:___/___/___  Infusion Start Time: |__|__| : |__|__| End Time: |__|__| : |__|__| 

                         ADVL1614 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
80 
Version Date: 01/31/19 
APPENDIX XII: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ADVL1614 
(for children from 7 through 12 years of age) 
A study of VX15/2503 in children 
with a cancer that has come back after treatment or is difficult to treat 
 
 
1. We have been talking with you about your cancer. You have had treatment for the cancer already 
but the cancer did not go away or it came back after treatment.  
 
2. We are asking you to take part in a research study because other treatments did not get rid of the 
cancer. 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 the kind of cancer that you have. 
We will do this by trying a new medicine to treat your cancer.  
 
3. Children who are part of this study will be treated with a cancer-fighting medicine called 
VX15/2503. You will also have regular tests and exams done more often while you are in this 
study. The doctors want to see if VX15/2503 will make children with your type of cancer get better. 
We don’t know if VX15/2503 will work well to get rid of your cancer. That is why we are doing 
this study.  
 
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 VX15/2503 
may cause your cancer to stop growing or to shrink for a period of time 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.” The risks to you from this study are that you may have more problems, or side 
effects, from VX15/2503 than other treatments. 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. As part of your regular care, your doctor may have removed some tissue to see if you have cancer. 
If you take part in this study, we will keep some of the tissue that is left over to do special tests. 
These tests may help us learn more about how VX15/2503 works.  
 
 
 
 
 
 
 
 
 
 
 
 

                         ADVL1614 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
81 
Version Date: 01/31/19 
APPENDIX XIII: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ADVL1614 
(for teens from 13 through 17 years of age) 
A study of VX15/2503 in children 
with a cancer that has come back after treatment or is difficult to treat 
 
1. We have been talking with you about your cancer. You have had treatment for the cancer already but 
the cancer did not go away or it came back after treatment.  
 
2. We are asking you to take part in a research study because other treatments did not get rid of the cancer. 
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 the kind of cancer that you have. 
 
3. Children and teens who are part of this study will be given a cancer-fighting medicine called 
VX15/2503. VX15/2503 is an antibody (a protein that makes up part of the immune system) that binds 
to an antigen (a substance that activates the immune system) and therefore blocks the antigen from 
working to increase tumor growth. We are using VX15/2503 in this study because it seems to work 
against certain types of cancer cells in test tubes and animals. VX15/2503 is considered experimental 
because the Food and Drug Administration (FDA) has not approved this drug. The dose of VX15/2503 
used in this study was found to be well-tolerated in adults. 
 
4. You will get VX15/2503 by IV on Days 1 and 15 of a 28-day period. This entire 28-day period is called 
a cycle. You may continue to receive VX15/2503 for up to about 12 months (up to 13 cycles) as long 
as you do not have bad effects from it and your cancer does not get any worse. You will also have 
exams and tests done that are part of normal cancer care. But, the exams and tests will be done more 
often while you are being treated with VX15/2503. The doctors want to see if VX15/2503 will make 
children with your type of cancer get better. We don’t know if VX15/2503 is better than other 
medicines. That is why we are doing this study.  
 
5. 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 VX15/2503 may cause 
your cancer to stop growing or to shrink for a period of time but we don’t know for sure if there is any 
benefit of being part of this study. 
 
6. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study are that you may have more problems, or side effects, 
from VX15/2503 than other treatments. Other things may happen to you that we don’t yet know about. 
 
7. 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.  
 
8. As part of your regular care, your doctor may have removed some tissue to see if you have cancer. If 
you take part in this study, we will keep some of the tissue that is left over to do special research tests. 
These tests may help us learn more about how VX15/2503 works. The samples will come from leftover 
tissue so there would be no extra procedures.