Clinical trial NCT02564198
Conditions: Pediatric Solid Tumor Refractory Tumor Recurrent Tumor CNS Malignancies
Keywords: relapsed pediatric solid tumors unspecified childhood solid tumor brain and central nervous system tumors
Sponsor: Eli Lilly and Company
Start date: 2015-12-11; Completion date: 2019-07-16
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to evaluate the safety of the study drug known as ramucirumab in children with recurrent or refractory solid tumors including central nervous system (CNS) tumors.

Detailed description:

Arms: arm 1: (Part A-Non-CNS Solid Tumors) Escalating doses of 8 milligrams per kilogram (mg/kg) or 12 mg/kg Ramucirumab administered as an intravenous infusion every 2 weeks (Q2W) with 3 doses per 42 day cycle.

(Part B-CNS Tumors) Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
Interventions: intervention 1: Ramucirumab
Intervention descriptions: intervention 1: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol (3): I4T-MC-JVDA
A Phase 1 Study of Ramucirumab, a Humanized, Monoclonal Antibody Against the Vascular 
Endothelial Growth Factor-2 (VEGFR-2) Receptor in Children with Recurrent or Refractory 
Solid Tumors, including CNS Tumors
NCT02564198
Approval Date: 31-Jan-2019


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TABLE OF CONTENTS 
SECTION 
PAGE 
 
STUDY COMMITTEE 
5 
COG OPERATIONS STAFF 
6 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Aims 
8 
1.2 
Secondary Aims 
8 
1.3 
Exploratory Aims 
8 
2.0 
BACKGROUND 
8 
2.1 
Introduction/Rationale for Development 
8 
2.2 
Preclinical Studies 
11 
2.3 
Adult Studies 
13 
2.4 
Pediatric Studies 
18 
2.5 
Overview of Proposed Pediatric Study 
18 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
19 
3.1 
Current Study Status 
20 
3.2 
IRB Approval 
20 
3.3 
Patient Registration 
21 
3.4 
Reservation and Contact Requirements 
21 
3.5 
Informed Consent/Assent 
21 
3.6 
Screening Procedures 
21 
3.7 
Eligibility Checklist 
21 
3.8 
Institutional Pathology Report 
21 
3.9 
Study Enrollment 
22 
3.10 
Dose Assignment 
22 
4.0 
PATIENT ELIGIBILITY 
22 
4.1 
Inclusion Criteria 
22 
4.2 
Exclusion Criteria 
25 
5.0 
TREATMENT PROGRAM 
27 
5.1 
Overview of Treatment Plan 
27 
5.2 
Criteria for Starting Subsequent Cycles 
28 
5.3 
Dose Escalation Schema (Completed) 
28 
5.4 
Grading of Adverse Events 
29 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
29 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
32 
6.1 
Dose Modifications for Hematological Toxicity 
32 
6.2 
Dose Modifications for Non-Hematological Toxicity 
32 
6.3 
Dose Modifications for Infusion-Related Reactions 
33 
6.4 
Dose Modifications for Hypertension 
34 
6.5 
Dose Modifications for Proteinuria 
36 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
37 


                             
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7.1 
Concurrent Anticancer Therapy 
37 
7.2 
Investigational Agents 
37 
7.3 
Supportive Care 
37 
7.4 
Growth Factors 
37 
7.5 
Surgery 
37 
7.6 
Concomitant Medications 
37 
7.7 
Concurrent Anti-Hypertensive Therapy 
37 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
38 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
38 
8.2 
Monitoring for Specific Toxicities 
39 
8.3 
Radiology Studies 
40 
8.4 
Pharmacokinetics (Required) 
40 
8.5 
Immunogenicity Studies (Required) 
41 
8.6 
Circulating Plasma Molecular Marker Studies 
42 
8.7 
Pharmacogenomic Studies 
43 
8.8 
Peripheral Blood Flow-Cytometry (PBFC) Studies (Part A Only) 
44 
8.9 
Tissue Studies 
46 
9.0 
AGENT INFORMATION 
46 
9.1 
Ramucirumab 
46 
9.2 
Agent Accountability 
49 
9.3 
Obtaining the Agent 
49 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA50 
10.1 
Criteria for Removal from Protocol Therapy 
50 
10.2 
Off Study Criteria 
50 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
50 
11.1 
Sample Size and Study Duration 
50 
11.2 
Definitions 
51 
11.3 
Dose Escalation and Determination of MTD 
52 
11.4 
Inclusion of Children, Women and Minorities 
53 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
53 
11.6 
Statistical methods 
54 
12.0 
EVALUATION CRITERIA 
56 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
56 
12.2 
Response Criteria for Patients with Solid Tumors 
56 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
61 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
61 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
63 
12.6 
Response Criteria for Patients with CNS Tumors 
64 
12.7 
Best Response 
65 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
68 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
68 
13.2 
When to Report an Event in an Expedited Manner 
70 
13.3 
Expedited Reporting Methods 
71 
13.4 
Definition of Onset and Resolution of Adverse Events 
71 
13.5 
Other Recipients of Adverse Event Reports 
71 
13.6 
Reporting Secondary AML/MDS 
72 
13.7 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
72 


                             
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14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
74 
14.1 
Categories of Research Records 
74 
14.2 
Access to Rave for Data Submission/ Data Reporting 
74 
14.3 
CDUS 
74 
14.4 
Data and Safety Monitoring Plan 
75 
REFERENCES 
76 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
81 
APPENDIX II: CORRELATIVE STUDIES GUIDE 
82 
APPENDIX III: PHARMACOKINETIC STUDY FORM 
83 
APPENDIX IV: IMMUNOGENICITY FORM:  ANTI- RAMUCIRUMAB ANTIBODY STUDIES 
85 
APPENDIX V-A: CIRCULATING PLASMA MOLECULAR MARKER STUDIES FORM 
86 
APPENDIX V-B: PHARMACOGENOMICS STUDY FORM 
87 
APPENDIX VI: PERIPHERAL BLOOD FLOW CYTOMETRY SETUDIES FORM (PART A ONLY)88 
APPENDIX VII: TISSUE STUDIES FORM 
89 
APPENDIX VIII: BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT 
PERCENTILE 
90 
APPENDIX IX:  URINE PROTEIN TO CREATININE (UPC) RATIO 
92 
APPENDIX X: TOXICITY-SPECIFIC GRADING 
93 
APPENDIX XI: CTEP AND CTSU REGISTRATION PROCEDURES 
94 
 


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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 
This is a Phase 1 study of ramucirumab (IMC-1121B; LY3009806), a recombinant, human monoclonal 
antibody of the immunoglobulin G subclass 1 developed against the vascular endothelial growth factor-2 
receptor (VEGFR-2), to be conducted in children with recurrent or refractory solid tumors including CNS 
tumors. Ramucirumab specifically binds to the extracellular domain of human VEGFR-2 with high 
affinity and leads to a comprehensive inhibition of the signaling pathways activated by VEGF-A (VEGF) 
binding. In addition to VEGF, Ramucirumab also inhibits the binding of VEGF-C and VEGF-D to 
VEGFR-2. By virtue of its specificity for VEGFR-2, ramucirumab has less potential to induce “off-
target” toxicities seen with VEGFR-2 tyrosine kinase inhibitors. Preclinical studies have shown that 
ramucirumab is efficacious as either a single agent or in combination with doxorubicin across a series of 
pediatric patient-derived xenograft sarcoma models including synovial, osteosarcoma, Ewings, and 
undifferentiated histologies and in a cell-derived neuroblastoma xenograft. It has undergone Phase 1, 2, 
and 3 testing in adults and has been FDA approved for advanced gastro-esophageal carcinoma and 
metastatic non-small cell lung cancer. The adult recommended FDA approved doses are 8 mg/kg I.V. 
administered every other week in gastric indications and 10 mg/kg I.V. administered every 3 weeks in 
non-small cell lung cancer. In Part A, we will evaluate the maximum tolerated dose (MTD) and/or RP2D 
of ramucirumab given intravenously every other week in children with solid tumors, excluding CNS 
tumors. In Part B of the study we will evaluate the tolerability and/or RP2D of ramucirumab in children 
with recurrent or refractory CNS tumors. In addition to pharmacokinetic and immunogenicity studies, 
correlative biologic endpoints will include evaluation of angiogenic proteins and circulating 
hematopoietic and endothelial progenitor cells.  
 
EXPERIMENTAL DESIGN SCHEMA 
 
Ramucirumab         Ramucirumab 
Ramucirumab 
Tumor Disease Evaluation*  
 
Cycle:   
 
                         Day 1 
 
Day 15  
Day 29   
 
Day 42 
* Tumor Disease Evaluations will occur at the end of cycles 1 and 2, and then every other cycle. 
 
Therapy will be discontinued if there is evidence of progressive disease or drug related dose-limiting 
toxicity that requires removal from therapy. Therapy may otherwise continue up to 8 cycles or until one 
of the off protocol therapy criteria in Section 10.1 is met. 
 
 


                         
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 
dose (RP2D) of ramucirumab administered as an intravenous infusion over 60 
minutes, every 2 weeks, to children with recurrent or refractory solid tumors. 
 
1.1.2 
To determine the tolerability of the MTD and/or RP2D of ramucirumab in 
children with recurrent or refractory CNS tumors. 
 
1.1.3 
To define and describe the toxicities of ramucirumab administered on this 
schedule. 
 
1.1.4 
To characterize the pharmacokinetics and immunogenicity of ramucirumab in 
children with recurrent or refractory solid tumors including CNS tumors. 
 
1.2 
Secondary Aims 
 
1.2.1 
To preliminarily define the antitumor activity of ramucirumab within the 
confines of a Phase 1 study.  
 
1.3 
Exploratory Aims 
 
1.3.1 
To explore the pharmacodynamics (PD) effects of ramucirumab in this pediatric 
population. 
                  
1.3.2 
To explore potential predictive biomarkers relevant to pediatric cancers, cancer-
related conditions, ramucirumab and angiogenesis. 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
Angiogenesis, the generation of new blood vessels from existing ones, is an essential 
physiological process that is deregulated in various pathological conditions including 
cancer.1 Both adult and pediatric solid tumors rely on angiogenesis for growth and 
metastasis.2 As a result, the pathways that mediate tumor angiogenesis have been targeted 
for new anti-cancer drug development. This strategy has resulted in the approval of anti-
angiogenic agents with a variety of mechanisms for a number of human cancers in the 
last decade.3  
 
The vascular endothelial growth factor (VEGF)/vascular endothelial growth factor 
receptor (VEGFR-2) pathway (VEGF pathway hereafter) is considered the most 
important mediator of tumor angiogenesis.4  The pathway is activated by the binding of 
cognate ligands, VEGF-A, VEGF-C and VEGF-D to the VEGFR-2 receptor.  Activation 
of VEGFR-2 leads to receptor dimerization and transphosphorylation of key tyrosine 
residues in the cytoplasmic domain of the receptor. This event initiates several signal 
transduction cascades that mediate survival, migration and proliferation of endothelial 
cells as well as permeability of blood vessels.5  In situ hybridization studies have revealed 
that VEGF-A mRNA is upregulated in the vast majority of human tumors including 


                         
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breast, lung, thyroid, gastrointestinal tract, kidney, bladder, ovary, uterine, cervix, 
angiosarcoma, germ-cell, and several intracranial tumors, including glioblastoma 
multiforme.6 Multiple biological agents have been developed against the VEGF pathway. 
These VEGF pathway inhibitors have been designed to either neutralize VEGF-A, the 
principal VEGFR-2 ligand, or to antagonize the protein kinase activity that initiates the 
downstream 
pro-angiogenic 
intra-cellular 
signaling 
pathways. 
For 
example, 
bevacizumab, a monoclonal antibody against VEGF-A, improved overall survival when 
added to chemotherapy in patients with metastatic colorectal carcinoma, resulting in its 
approval as the first anti-angiogenic agent almost a decade ago.7 Several successful 
Phase-3 trials with bevacizumab have led to the expansion of its use in patients with 
advanced lung cancer,8 recurrent glioblastoma,9 renal cell carcinoma10 and metastatic 
breast cancer.11 Despite this initial success, there has been a lack of survival benefit in 
subsequent confirmatory trials among patients with breast cancer,12 and only marginal 
benefit among patients with colorectal cancer.13  
 
Aflibercept, a soluble decoy VEGF receptor that neutralizes VEGF-A, VEGF-B, and 
placental growth factor with high affinity represents an alternative approach to 
antagonize the VEGF pathway. While clinical benefit has not been universally 
demonstrated across several tumor types, the positive findings of prolonged overall 
survival (OS) and progression free survival (PFS) in the prospective, randomized, 
double-blind phase III VELOUR study (aflibercept versus placebo in combination with 
irinotecan and 5-FU [FOLFIRI] in the treatment of patients with metastatic colorectal 
cancer [mCRC] after failure of an oxaliplatin based regimen) led to the recent US 
approval of the aflibercept-FOLFIRI combination  for use  in this patient population.14 
However, the toxicity profile demonstrated that more patients on the aflibercept arm had 
grade 3 or 4 adverse events (83.5% vs. 62.5%). These events included not just those 
expected with anti-VEGF agents, such as hypertension, hemorrhage, and arterial and 
venous thromboembolic events, but also the potentiation of adverse effects associated 
with FOLFIRI.  
 
Another therapeutic modality to inhibit angiogenesis involves targeting the VEGF 
pathway by using tyrosine kinase inhibitors (TKIs) to block the intracellular tyrosine 
kinase activity triggered by VEGF/VEGFR-2 binding. TKIs impede the downstream 
signals necessary for endothelial proliferation, survival, and migration that are required 
for tumor growth and metastasis; however, lack of absolute specificity of TKIs for 
VEGFR-2 results in significant “off-target” inhibition. For example, although the specific 
pattern of kinase inhibition varies, the TKIs sorafenib,  sunitnib, cediranib, pazopanib, 
and motesanib all additionally inhibit VEGFRs 1 and 3, cKit and PDGFRb, while 
vandetanib also inhibits EGFR.15 The lack of specificity of TKIs result in a pattern of 
dose-limiting toxicities that have made this class of drugs difficult to combine with 
chemotherapeutic regimens.16 
 
The above discussion highlights the need for a novel, highly potent and selective anti-
angiogenic therapy with a distinct mechanism of action.   To this end, selective inhibition 
of the extracellular domain of VEGFR-2 has been explored.  Ramucirumab, (IMC-
1121B; LY3009806), is a recombinant human monoclonal, receptor-targeted antibody of 
the immunoglobulin G subclass 1 that specifically binds to the extracellular domain of 
human VEGFR-2 with high affinity (approximately 50 pM).17,18 The binding of 
ramucirumab to VEGFR-2 prevents its interaction with not just VEGF-A,15,19 the 
principal ligand that initiates the pro-angiogenic effects of the VEGF pathway, but also 
all other VEGFR-2 activating ligands including VEGF-C and VEGF-D (Preclinical, Eli 


                         
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Lilly and Company, data on file). Ramucirumab thus provides a highly specific and 
comprehensive inhibition of the VEGF pathway, effectively blocking the downstream 
intracellular signaling, which results in proliferation, survival, and migration of 
endothelial cells.20-23 Ramucirumab may further reduce signaling by inducing VEGFR-2 
internalization (Preclinical, Eli Lilly and Company, data on file). Finally, by virtue of its 
specificity for VEGFR-2, ramucirumab has less potential to induce “off-target” toxicities 
seen with VEGFR-2 TKIs.   
 
Rationale for Use in Pediatrics: Although survival for pediatric patients with solid 
tumors has improved with more than 75% cured, prognosis is still poor for patients with 
metastatic or recurrent disease. These patients need innovative therapies to combat tumor 
resistance. Similar to adult tumors, angiogenesis is upregulated in pediatric embryonal 
tumors making it an important pathway to target with novel anti-angiogenic agents. 
VEGF and its downstream signaling play a vital role in tumor growth and metastasis in 
children.  Studies have shown high levels of circulating VEGF levels in children with 
tumors at baseline.24,25 Neuroblastoma and Wilm’s tumor tissues express VEGF, and high 
expression is correlated with invasion, metastasis, and risk of recurrence. 26-28 VEGF 
expression drives tumor angiogenesis and in some instances tumor growth and metastasis 
among patients with Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma.29-31 
Among osteosarcoma patients, VEGF upregulation is associated with adverse clinical 
outcomes.32,33 
 
The pre-clinical testing of various anti-angiogenic agents in pediatric cancers has been 
investigated with VEGF ligand or intracellular VEGF receptor inhibition. VEGF ligand 
inhibition with bevacizumab and aflibercept suppresses tumor angiogenesis and growth 
in murine models of rhabdomyosarcoma, neuroblastoma, and hepatoblastoma. In 
addition, aflibercept decreased the tumor vasculature resulting in regression of 
established tumors and lung metastases in an orthotopic xenograft model of Wilm’s 
tumor.34 The anti-VEGF TKIs, cediranib, sorafenib, and sunitinib have been tested 
against a panel of pediatric solid tumor cell lines by the Pediatric Preclinical Testing 
Program (PPTP). Although complete responses were rare when tested in vivo, all 3 
agents exhibited growth inhibitory activity consistent with anti-angiogenic mechanisms 
leading to significant prolongation of the time to event, and their response activity was 
rated as intermediate.35  
 
Eight anti-angiogenic agents have completed Phase-1 clinical testing in children: 
bevacizumab,36 aflibercept,37 and several VEGFR-2 TKIs, including cediranib,38 
pazopanib,39 semaxanib,40 sorefenib,41 sunitinib,42 and vandetanib.43 Compared to adult 
recommended dosing, those for children have ranged from reduced dosing in pediatrics, 
due to MTDs seen in many of the TKIs and aflibercept, to pediatric dosing that is 
comparable to adult dosing, as is the case for bevacizumab where an MTD was never 
established in the pediatric population.16 Safety profiles of anti-angiogenics have been 
similar across age groups, with class effects including hypertension, proteinuria, and 
arterial thrombo-embolic events.16 For children, two potential toxicities of particular 
interest are growth plate abnormalities and cardiotoxicity, given the prevalent use of 
anthracyclines in pediatric regimens. Physeal widening was observed in a single anti-
angiogenic phase 1 trial with pazopanib; no other pediatric studies of VEGF pathway 
inhibitors have reported growth plate defects. Cardiotoxicities have been observed in 
some patients with prior anthracycline exposure who were treated with anti-angiogenic 
agents, though the pathogenesis of this cardiotoxicity and its association with VEGF 
pathway inhibition is not yet known.  Regarding efficacy, while there is minimal data on 


                         
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the anti-tumor activity of commonly used anti-angiogenic agents in children, single agent 
activity consisting of partial responses and stable disease have been reported in patients 
with 
soft-tissue 
sarcoma, 
Ewing’s 
sarcoma, 
osteosarcoma, 
Wilm’s 
tumor, 
hepatoblastoma, ependymoma, and gliomas.35  
 
Preclinical studies have shown that anti-VEGF therapies might modify the tumor 
vasculature and lead to better delivery of cytotoxic agents.44 This has prompted numerous 
ongoing Phase-2 combination therapy studies of bevacizumab and cytotoxic agents to 
assess efficacy of these novel strategies in specific types of cancer.  In adult studies there 
has been benefit for some cancers with the addition of bevacizumab to standard 
chemotherapy. Early results of bevacizumab combined with standard chemotherapy have 
shown promise in pediatric patients with low-grade gliomas.45 Utilizing a monoclonal 
antibody like ramucirumab to block not only VEGF-A but any ligand that might interact 
with VEGFR-2 to activate downstream angiogenic activity, offers the possibility of a 
more comprehensive inhibition of the VEGF pathway. For patients who acquire 
resistance to bevacizumab, this comprehensive blockade may prove particularly 
advantageous. Extrapolating from the experiences of Phase 2 and 3 studies that combined 
chemotherapy with various anti-VEGF therapies, monoclonal antibodies such as 
ramucirumab are also less likely to result in cumulative toxicities when given with 
cytotoxic agents, in contrast to VEGFR-2 TKIs known to have “off-target” toxicities.46,47 
Given the novel target of inhibition, and the specificity, potency, and potential for safely 
combining with other cytotoxic agents, ramucirumab may be an optimal candidate  to 
treat pediatric patients with solid tumors, particularly those with recurrent or metastatic 
disease.  
 
2.2 
Preclinical Studies 
 
2.2.1 
Antitumor Activity  
Pre-clinical studies in animal models using ramucirumab have been challenging 
due to its high species specificity for human VEGFR-2. Syngeneic and xenograft 
tumors engrafted into mice depend on expansion of murine vasculature within 
the host stroma precluding the use of ramucirumab in such studies. Therefore, 
DC101, a rat antibody targeting mouse VEGFR-2 has been used to validate the 
therapeutic utility of targeting VEGFR-2 in vivo. DC101 has pharmacological 
characteristics very similar to ramucirumab meeting the scientific criteria of a 
surrogate antibody. DC101 was evaluated in a pancreatic cancer BxPC-3 
xenograft model to establish an effective dose regimen and determine the 
associated plasma concentration to guide subsequent studies. 48 In this model, 
significant tumor growth inhibition was observed at doses which were on average 
associated with a minimum serum drug concentration of 18 µg/mL. DC101 has 
demonstrated anti-tumor effect in numerous mouse xenograft solid tumor models 
that include gastric, hepatic, breast, colorectal, and non-small cell lung 
cancers.49,50 Monotherapy with DC101 produced tumor growth inhibition (TGI) 
up to 59% (range: 27%-78%) and also produced additive effects when combined 
with chemotherapy in multiple tumor types.  Importantly, single agent DC101 
was active across a series of pediatric patient-derived xenograft (PDX) sarcoma 
models including synovial, osteo, Ewing’s, and undifferentiated histologies (TGI 
ranging from 52 % to 88%). Significant activity of DC101 was also observed in 
combination with doxorubicin in PDX models of Ewings sarcoma and in a mouse 
cell-derived xenograft model of human neuroblastoma (TGI >100% in both 
cases) (Preclinical, Eli Lilly and Company, data on file). Tumor growth 


                         
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inhibition in excess of 100% was also observed in a synovial sarcoma PDX 
model when treated with DC101 monotherapy following initial doxorubicin 
therapy and in combination with doxorubicin.  Since the affinity of ramucirumab 
to human VEGFR-2 is 10-fold higher than the affinity of DC101 to mouse 
VEGFR-2, the in vivo studies of DC101 may underestimate the anti-tumor 
potency of ramucirumab.21,49-51 Pre-clinical studies have shown that targeting 
VEGFR-2 with antibody produces tumor growth inhibition in xenografts that 
were resistant to the anti-VEGF TKIs.52 
 
2.2.2 
Animal Toxicology:  
The animal toxicology studies of ramucirumab were conducted in cynomolgus 
monkeys. A tissue cross-reactivity study was conducted with a full panel of 
cynomolgus monkey and human tissues that showed that the tissue reactivity of 
ramucirumab observed in both tissues was similar, indicating that the 
cynomolgus monkey is an appropriate animal model for toxicity testing of 
ramucirumab. In a 5-week, 4-dose study, cynomolgus monkeys were given 
ramucirumab I.V. weekly at dose levels 0, 4, 12, or 40 mg/kg on Days 1, 15, 22, 
and 29, with a subset of monkeys sacrificed after the last dose and a second 
subset of monkeys entering a 6-week recovery phase for toxicity assessments. 
The only significant findings were mild local injection site reactions. I.V. 
administration was well tolerated at all dose levels and the no-observable adverse 
effect level was 40 mg/kg, the highest dose administered. A second toxicology 
study assessed the long-term (chronic) administration of ramucirumab in 
cynomolgus monkeys who received doses of 0, 5, 16, or 50 mg/kg administered 
intravenously every week for 12 or 39 weeks. The results revealed nephrotoxicity 
consistent with multi-focal and marked glomerulonephritis in both kidneys in 
monkeys receiving doses of 16 and 50 mg/kg for 39 weeks. In addition, 
secondary changes were also observed in the tubules, collecting ducts and the 
renal interstitium. Osteochondropathy and thickening of the epiphyseal growth 
plate was noted at all doses administered.48 
 
In addition to toxicology studies, a wound healing study following a single dose 
of ramucirumab was also conducted at doses 5, 15, and 50 mg/kg since there is a 
strong role for VEGF pathway in wound healing. This study did not reveal a 
clinical or histological impairment of wound-healing in this cynomolgus monkey 
linear incision model after a single dose.48 
 
2.2.3 
Preclinical Pharmacokinetic Studies: Non-compartmental analysis of the 
concentration-vs-time data from the cynomolgus monkey studies mentioned 
above indicated that the PK behavior of ramucirumab was non-linear over the 4-
50 mg/kg dose range. Area under the concentration-vs-time curve extrapolated to 
infinity (AUC0-inf) and maximum concentration (Cmax) increased in a greater than 
dose-proportional manner. Ramucirumab half-life increased and clearance 
decreased with increasing dose. Mean ramucirumab AUC0-inf in the 50mg/kg 
group increased between the 1st and the 39th dose, indicating drug accumulation 
consistent with a saturation of receptor mediated clearance. 48 
 
 
 


                         
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2.3 
Adult Studies 
 
2.3.1 
Phase 1 Studies: Several adult Phase 1 trials have been completed using 
ramucirumab. They have been escalating, single-arm studies in which 
ramucirumab was administered as a single agent (Table 1). In addition, 3 
combination studies have also been completed where a fixed dose of 
ramucirumab has been used in combination with other cytotoxic agents to assess 
safety, tolerability and efficacy (Table 2). 
 
Table 1: Single-arm, Phase 1 Studies using escalating doses of Ramucirumab17,26-28,48,53 
Study name 
Study design 
Diagnosis 
Dose range 
     DLT 
MTD 
I4T-IE-
JVBM 
Open-label, 
single-arm 
Advanced 
solid tumors 
2-16 mg/kg qw X  4 
Hypertension; 
DVT 
13 
mg/kg 
I4T-IE-
JVBN 
Open-label, 
single-arm 
Advanced 
solid tumors 
Cohort 1-3: 6-10 mg/kg q2w X 4 
Cohort 4-5: 15-20 mg/kg  q3w X 4 
None 
None 
I4T-IE-JVBI 
Japanese 
Open-label, 
single-arm 
Advanced 
solid tumors 
Cohort 1: 6 mg/kg q2w  
Cohort 2: 8 mg/kg q3w 
Cohort 3: 10 mg/kg q3w 
None 
None 
DLT: dose-limiting toxicity; DVT: deep vein thrombosis. MTD: maximum tolerated dose; qw: once a week; q2w: 
every 2 weeks; q3w: every 3 weeks. 
 
The I4T-IE-JVBM study was an open-label, single-arm, dose-escalation study 
involving adults with advanced solid tumors. Pharmacokinetic data revealed 
dose-dependent elimination and nonlinear exposure consistent with saturable 
clearance. At all dose levels, mean trough concentrations exceeded 20 µg/mL.  
This was greater than the biologically significant level for target inhibition of 
VEGFR-2. 17,26-28 Serum VEGF-A post-treatment levels were 1.5-3.5 times higher 
than the baseline levels at all dose levels throughout the treatment.  
 
Table 2: Combination studies of fixed-dose ramucirumab and chemotherapy agents in 3 different 
Japanese studies. 48 
Study name 
Study design 
Diagnosis 
Dose range 
     Response 
I4T-IE-JVBW 
Japanese 
Open-label, 
single-arm 
Gastric ACA 
(n=6) 
RAM: 10 mg/kg Days 1 and 15 and 
PAC: 80 mg/m2 - Days 1, 8, and 15 
SD:5; PR:1 
I4T-IE-JVBX 
Japanese 
Open-label, 
single-arm 
Breast CA 
(n=7) 
RAM: 10 mg/kg q3w + DOC: 75 
mg/m2 q3w 
SD:3; PR:4 
I4T-IE-JVBY 
Japanese 
Open-label, 
single-arm 
Colorectal CA 
(n=6) 
RAM: 10 mg/kg q2w + FOLFIRI 
SD:4; PR:1, PD:1 
ACA: adenocarcinoma; CA: carcinoma; DOC: docetaxel; FOLFIRI: folinic acid, 5-FU, irinotecan; n: sample size; 
PAC: paclitaxel; PR: partial response; PD: progressive disease RAM: ramucirumab; SD: stable disease; q2w: every 
2 weeks; q3w: every 3 weeks. 
 
2.3.2 
Phase 2 Studies: 8 mg/kg I.V. q2 weeks as a monotherapy was selected as the 
adult RP2D in certain selected indications based on PK data from the Phase 1 
I4T-IE-JVBM study.17 The results of the Phase 2 studies are summarized in the 
Table 3. 
 
Table 3: Response data from single-arm and double-arm Phase 2 studies48,54-56 
Study name 
Study 
design 
Diagnosis 
Dose range 
ORR/PFS/OS (95% CI) 
I4T-IE-
JVBQ 
Open-label, 
single-arm 
Liver CA  (n=43) 
RAM: 8 mg/kg q2w 
ORR: 9.5% (2.7-22.6%) 
OS: 12 (6.1-19.7) 


                         
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I4-IE-JVBP 
Open-label, 
single-arm 
mRCC. (n=39) 
RAM: 8 mg/kg q2w 
ORR: 5.1% (0.6-17.3%) 
OS: 24.8 (18.9-32.6) 
I4T-IE-JVBJ 
Open-label, 
single-arm 
NSCLC. (n=40) 
RAM (10 mg/kg q3w) + PAC 
+ CARBO 
ORR: 55% 
PFS: 7.85 (5.49-9.86) 
OS: 16.85 (14.82-28.58) 
I4T-IE-
JVBH 
Open-label, 
single-arm 
mCRC. (n=48) 
RAM (8 mg/kg q2w) + OXA 
+ FA + 5-FU 
ORR: 58.3%  
PFS: 11.5 (8.6-13.1) 
OS: 20.4 (18.5-25.1) 
I4T-IE-JVBR Open-label, 
single-arm 
Ovarian/fallopian/ 
primary peritoneal 
 CA  (n=60) 
RAM: 8 mg/kg q2w 
ORR: 5% 
PFS: 3.5 (2.3-5.3) 
OS: 11.1 (8.3-17) 
I4T-IE-
JVBO 
Open-label, 
double-arm 
Melanoma. 
(n=105) 
Arm A: RAM (10 mg/kg 
q3w) + DAC (1000mg/m2) 
q3w 
Arm B:  RAM (10 mg/kg 
q3w) 
Arm A: ORR: 17.3% 
              PFS-2.6 (1.4-5.4)    
              OS-8.7 (7.1-12.9) 
Arm B: ORR: 4% 
              PFS-1.7 (1.4-2.9) 
              OS-11.1 (7.7-14.6) 
I4T-IE-JVBS 
Open-label, 
double-arm 
Prostate CA. 
(n=66) 
Arm A: CIXUT (6 mg/kg 
q3w)+ MITO+ PRED 
Arm B: RAM (6 mg/kg q3w) 
+ MITO + PRED 
Arm A: PFS-4.1 (2.2-5.6)    
               OS-10.8 (6.5-13) 
Arm B: PFS-6.7 (4.5-8.3) 
               OS-13 (9.5-16) 
5-FU: 5-fluorouracil; CA: carcinoma; CARBO: carboplatin; CI: confidence interval; CIXUT: cixutumumab; DAC: 
dacarbazine; FA: folinic acid; mCRC: metastatic colo-rectal carcinoma; mRCC: metastatic renal cell carcinoma; 
MITO: mitoxantrone; n: sample size;  NSCLC: non-small cell lung cancer; ORR: objective response rate; OS: 
median overall survival in months; OXA; oxaliplatin; PAC: paclitaxel; PRED: prednisone; PFS: median 
progression-free survival in months; RAM: ramucirumab; q2w: every 2 weeks; q3w: every 3 weeks. 
 
2.3.3 
Phase 3 Studies: Results from six Phase 3 trials that have been completed and 
summarized in Table 4 below. 
 
Table 4: Median PFS and OS from Phase 3 trials of ramucirumab57-62 
Study name 
Study design 
Diagnosis 
RAM dose 
Median PFS 
(months) 
Median OS    
(months) 
REGARD 
randomized, 
placebo-
controlled, 
blinded 
Advanced 
gastric/GEJ 
CA 
RAM: 8 mg/kg  q2w + BSC 2.1 vs. 1.3 
p<0.0001 
5.2 vs.3.8 
p=0.047 
RAINBOW 
randomized, 
placebo-
controlled, 
blinded 
Gastric/GEJ 
CA 
RAM (8 mg/kg q2w) + 
PAC  
4.40 vs. 2.86  
p<0.0001 
9.63 vs.7.36 
p=0.0169 
REVEL 
randomized, 
placebo-
controlled, 
blinded 
NSCLC 
RAM (10 mg/kg q3w) + 
DOC 
4.5 vs. 3 
p<0.0001 
 10.5 vs.9.1  
p=0.0235          
ROSE 
randomized, 
placebo-
controlled, 
blinded 
Breast CA 
RAM (10 mg/kg q3w) + 
DOC 
9.5 vs. 8.2 
p>0.05 
27.3 vs. 27.2 
p=0.915 
REACH 
randomized, 
placebo-
Liver CA 
RAM: 8 mg/kg q2w + BSC 
NS 
NS 


                         
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controlled, 
blinded 
RAISE 
randomized, 
placebo-
controlled, 
blinded 
Metastatic 
Colorectal 
CA 
RAM (8 mg/kg q2w) + 
FOLFIRI 
5.7 vs. 4.5 
p=0.0005 
13.3 vs. 11.7 
p=0.0219 
BSC: Best Supportive Care; DOC: docetaxel; FOLFIRI: 5-FU, folinic acid and irinotecan; GEJ CA: gastro-
esophageal junction adenocarcinoma; NS: not significant; NSCLC: non-small cell lung cancer; RAM: ramucirumab; 
PAC: paclitaxel; q2w: every 2 weeks; q3w: every 3 weeks.  
 
2.3.4 
Safety: Adverse events (AEs) for 1199 patients who have received ramucirumab 
on 7 Phase 1/1b studies, 16 open-label Phase 2 studies, and 1 Phase 3 study are 
available. Adverse drug reactions (AEs for which a causal relationship to 
ramucirumab was considered at least possible) of special interest include AEs 
which have been associated with other anti-angiogenic agents and monoclonal 
antibodies and include the following categories: infusion-related reactions, 
hypertension, proteinuria, arterial thromboembolic events, bleeding/hemorrhagic 
events, and gastro-intestinal perforation. 
 
In the Phase 3, REGARD study (n=236 ramucirumab arm), the AE profile of 
ramucirumab was similar to the placebo. Majority of patients received full dose 
of ramucirumab (dose intensity= 99.6%) with few dose delays or modifications. 
The most common treatment emergent AE that occurred in the ramucirumab 
group versus the placebo group at a higher rate (any grade) was hypertension 
(16.1% vs 7.8%), diarrhea (14.4% vs.8.7%), and headache (9.3% vs.3.5%). The 
overall incidence of Grade 3-5 treatment emergent AEs were similar between the 
2 groups (56.8% vs.58.3%). The most common Grade ≥ 3 treatment emergent 
AE occurring in the ramucirumab group at a higher rate was hypertension (7.2% 
vs. 2.6% for Grade-3 hypertension). No individual Grade ≥ 3 treatment emergent 
AE was observed in > than 10% of patients. Serious AEs, hospitalization and 
supportive care use were also similar between the 2 groups indicating a good 
therapeutic-index profile for ramucirumab. Discontinuations due to AE were low 
in both groups but higher in the ramucirumab group than the placebo (10.5% 
vs.6%) with no specific AEs resulting in discontinuation. Deaths due to AEs 
were less common in ramucirumab vs. placebo group (9.3% vs.13%). 
 
2.3.5 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
 
Pharmacokinetic Studies: The PK of ramucirumab was first studied in patients 
with solid tumors administered across a range of doses from 2 to 16 mg/kg 
administered weekly via 1-hour I.V. infusions in I4T-IE-JVBM (IMCL CP12-
0401). Apparent nonlinear PK profiles were observed between 2 and 8 mg/kg; 
PK profiles appeared to be linear at doses of 8 mg/kg and above, suggesting 
saturation of the target-mediated (VEGF Receptor 2) clearance pathway.17  
 
Trough concentrations (or minimum concentrations [Cmin]) were collected in two 
Phase 3 studies (REGARD and RAINBOW) in patients with gastric cancer.  
Following the recommended clinical dose regimen of 8 mg/kg every 2 weeks, 
observed Cmin values were similar between REGARD and RAINBOW (Table 1). 
The geometric mean (percentage coefficient of variation [CV%])  observed 
trough values approached 50 µg/mL before the fourth dose, and ranged between 


                         
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60 and 75 µg/mL before the seventh dose.48  
Table 1. 
Summary of Observed Ramucirumab Trough Concentrations for Patients with 
Advanced Gastric Cancer Following Administration of 8 mg/kg of Ramucirumab 
Every 2 Weeks as an IV Infusion over Approximately 1 Hour Alone (REGARD) or 
in Combination with Paclitaxel (RAINBOW) 
 
Trougha Serum Concentrations (µg/mL) 
Dose Number 
4 
7 
 
REGARD 
RAINBOW 
REGARD 
RAINBOW 
nPK 
53 
203 
34 
142 
Geo Mean 
49.5 
45.0 
74.4 
62.8 
Geo CV% 
81 
50 
58 
47 
Abbreviations:  CV% = percentage coefficient of variation; Geo = geometric; IV = intravenous; nPK = number of 
pharmacokinetic observations included in calculation. 
a Trough concentrations were obtained prior to Doses 4 and 7.  They also represent Cmin following Doses 3 and 6. 
 
Pharmacokinetic data from the 8 studies involving 497 patients were also pooled 
together for a population pharmacokinetic (PopPK) analysis. In these studies, 
ramucirumab was administered as a 1-hour I.V. infusion, at either 8 mg/kg once 
every 2 weeks on a 14- or 28-day cycle, or 10 mg/kg every 3 weeks on a 21-day 
cycle. The studies included patients with varying cancer indications:  gastric 
cancer (80.5% of patients), non-small cell lung cancer (NSCLC; 8.2%), breast 
cancer (2.2%), colorectal cancer (CRC; 1.6%), and other tumor types (7.4%). 
The geometric mean of PopPK model-derived estimates of ramucirumab 
clearance (CL), volume of distribution at steady state (Vss) and terminal half-life 
(t1/2) were 0.0140 L/h (29.8%), 5.5 L (14.4%), and 15 days (24.1%), respectively. 
These parameter estimates were consistent with those observed with other human 
monoclonal IgG1 antibodies.63 Results from the PopPK analyses indicate that the 
PK of ramucirumab following 8- and 10-mg/kg dose administrations were dose 
linear (absolute dose range:  169 to 1234 mg) and time independent. In addition, 
covariate analysis indicated that ramucirumab PK was not affected by body 
weight (range, 31.9 to 133.0 kg), sex, age (range, 19 to 86 years), serum albumin 
(range, 15.5 to 64.8 g/L), race (White and Asian), hepatic status (as assessed by 
alanine aminotransferase  [range, 1 to 251 IU/L], aspartate transaminase [range, 
1 to 276 IU/L], alkaline phosphatase [range, 31 to 2300 IU/L], and total bilirubin 
[range, 1.2 to 78.5 µmol/L]), and renal function (as assessed by Cockcroft-Gault 
creatinine clearance [range, 20.2 to 231 mL/min]). 
 
Immunogenicity:  Ramucirumab is a human monoclonal antibody with a 
potential to induce formation of anti-drug antibody (ADA) when administered to 
human. The development of ADA has been studied across 16 studies involving 
1462 evaluable patients (1033 receiving ramucirumab and 429 receiving placebo) 
and the frequency of ADA and neutralizing ADA is low.48 
 
Treatment-emergent ADA positive patients were defined as those patients whose 
post baseline ADA sample was greater than 4-fold higher than baseline value or 
with a titer > than 1:20. Overall the number of patients with treatment emergent 
ADA was low at 1.1% in ramucirumab-treated patients who had at least 1 post 
treatment sample tested (n=884).  In the 321 patients who received either placebo 


                         
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plus best supportive care (BSC) or placebo plus paclitaxel and who had at least 1 
post-treatment sample tested, 16 patients (5.0%) had ADA detected post-
treatment and 2 patients (0.6%) had treatment emergent ADA.  None of these 
321 patients had neutralizing antibodies detected.  Overall, the rates of ADA 
responses and neutralizing antibody were low.  No neutralizing antibodies were 
detected in either the RAINBOW or REGARD Phase 3 studies. 48 
 
Correlative and Biological Studies: 
Pharmacodynamic circulating plasma molecular markers: Ramucirumab, 
(IMC-1121B, LY3009806) is a human receptor-targeted antibody that 
specifically blocks VEGF Receptor 2.  The binding of ramucirumab to VEGF 
Receptor 2 prevents interaction with activating ligands. Pharmacodynamic 
studies using ramucirumab have shown that VEGF-A levels were increased from 
baseline (range: 0 to 10-fold) following ramucirumab administration. Since it 
prevents receptor binding of circulating VEGF, this is consistent with its 
mechanism of action. Other VEGF ligands such as VEGF-D which also bind to 
VEGFR-2 were also elevated. Placental growth factor (PlGF) levels were also 
elevated from baseline (range: 0 to 20 fold), even though PlGF has not been 
shown to bind to VEGFR-2.64,65 The mechanism of the elevation of placental 
growth factor levels is not known. Additionally, using newly-developed assays, 
correlations between pharmacodynamics changes with tumor response and 
survival are currently ongoing for multiple ramucirumab adult Phase 3 trials.  
These analyses may provide insight into ramucirumab activity that could be 
important to investigate in the pediatric population as well.   
 
Circulating pharmacodynamic cellular biomarkers: To date, a consistent 
predictive biomarker for clinical efficacy of anti-VEGF therapy has not been 
identified. This produces challenges for clinicians in the upfront selection of 
which patients might benefit or not from anti-VEGF therapies. In adult patients 
with gastrointestinal stromal tumors treated with sunitinib, a rise in mature 
circulating endothelial cells was associated with clinical benefit66 while results 
from a Phase-I pediatric study of bevacizumab showed circulating endothelial 
cells correlated with prolonged stable disease.36 Circulating endothelial 
progenitor cells (EPCs) have been identified as predictive biomarkers of clinical 
efficacy for anti-angiogenic agents.67 However, there has been a lack of 
consensus in defining EPCs leading to grouping various cell types under the 
umbrella of “EPC” and thus an inability to compare study results. Utilizing a 
novel multi-parametric flow cytometry (MPFC) protocol, our group has 
identified and defined the bona fide EPC,  namely  the  endothelial  colony  
forming  cells  (ECFCs)  that  are  identified  CD31+CD34bright CD45- AC133- 
CD14-LIVE/DEAD- cells, have high proliferative potential, and give rise to 
perfused vessels in vivo. 68-72 In addition, we have also enumerated circulating 
endothelial cells (CECs) that are identified as CD31 bright CD45- CD34dimAC133- 
cells which are mature, apoptotic endothelial cells sloughed off from the vessel 
wall during vascular remodeling and do not form perfused blood vessels in 
vivo. Finally, using MPFC we have identified a unique circulating 
hematopoietic stem and progenitor cell (CHSPC) population in both 
peripheral blood (PB) and umbilical cord blood, which is phenotypically and 
functionally distinct from EPCs but is still actively involved in angiogenesis.68,73 
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pathological states through their interactions with mature endothelial cells and 
ECFCs, and are further classified into 2 distinct cellular subsets based on both 
cell surface antigen expression and function.74 The pro-angiogenic CHSPCs 
(pCHSPCs) express AC133, while the non-angiogenic CHSPCs (nCHSPCs) do 
not, otherwise they are   identical   in    their    phenotypic    definition    
showing  the  expression  of CD31+ CD34bright CD45dim CD14- LIVE/DEAD-. 
The ratio of the pCHSPCs to nCHSPCs is a  way  to  normalize  variability  in  
the  total  number  of  CHSPCs,  with  normal  ratios between 1.2-1.8. An 
increased pCHSPC: nCHSPC ratio (>2.0) is associated with tumor-induced 
angiogenesis.74-76 Further, using an anti-VEGF TKI suntinib in a Phase-II study 
among chemotherapy naïve subjects with metastatic breast cancer, results 
showed a decrease in the pCHSPC: nCHSPC ratio among women who 
responded to treatment.76 Therefore, the pCHSPC: nCHSPC ratio, CECs and the 
ECFCs are the circulating, cellular markers are of particular interest for further 
investigation in additional Phase 1 and 2 studies, in order to evaluate their 
potential role as novel predictive, cellular biomarkers of anti-angiogenic agents, 
which have been elusive so far. 
 
 
2.4 
Pediatric Studies 
 
2.4.1 
Prior Experience in Children  
There is no prior experience with ramucirumab in children. 
 
2.5 
Overview of Proposed Pediatric Study 
Ramucirumab is a highly selective human monoclonal antibody directed against 
VEGFR2. Six Phase 3 pivotal trials of ramucirumab in combination with chemotherapy 
have been completed in adults and 3 additional Phase 3 trials are ongoing.  The 
recommended dose in adults is 8 mg/kg IV administered over 1 hour every 2 weeks for 
patients with gastric cancer. For patients with NSCLC, the recommended dose in adults is 
10 mg/kg IV administered over 1 hour every 3 weeks.  No dose limiting toxicity is 
reported using these doses and schedules in adults. The toxicity profile is consistent with 
class effect, including dose-limiting hypertension at 10 mg/kg IV weekly, and deep 
venous thrombosis at 16 mg/kg IV weekly. Similar to other monoclonal antibodies, 
ramucirumab has a long half-life and is expected to accumulate.  Based on adult PK 
studies, steady state is anticipated to be achieved after the third dose administered q 2 
weeks.  Initial PK studies in adults demonstrated non-dose proportional exposure at dose 
levels 2- 8 mg/kg weekly.  At 8 mg/kg q week and above, systemic clearance decreased 
indicating a saturable receptor mediated clearance mechanism such as binding to 
VEGFR-2. The target trough concentration established in vitro was 18 µg/mL.   
However, in the pivotal Phase 3 trials, REGARD (8 mg/kg I.V. q 2 weeks, as 
monotherapy) and RAINBOW (8 mg/kg IV q 2 weeks in combination with paclitaxel) 
exposure-efficacy analyses indicated that improvements in OS and PFS were associated 
with increasing ramucirumab exposure. In RAINBOW (N=321), patients with 
ramucirumab exposure greater than the median (in the 3rd and 4th quartiles) were 
associated with longer OS and PFS and significantly better treatment effects (smaller HR) 
as compared to patients with ramucirumab exposure lower than the median (in the 1st and 
2nd quartiles). The median OS times for 1st, 2nd, 3rd, and 4th exposure quartiles were 6.5, 
8.6, 11.0, and 12.9 months, respectively, and the hazard ratios were 1.04, 0.84, 0.69, and 
0.53, respectively, in ramucirumab plus paclitaxel arm. Similar exposure-efficacy trend 


                         
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was observed in REGARD despite of smaller samples size (N=72). Further PKPD 
modelling and simulation analysis indicated EC50 value (in terms of minimum 
concentration at steady state, Cmin,ss) was ~ 50 ug/mL, which was also the approximate 
medianCmin,ss value in RAINBOW. It is therefore of interest to identify a dose which will 
produce Cmin,ss  of 50 ug/mL or higher in a majority of patients, and identify a safety 
profile so as to assist in the selection of a potentially efficacious dose for pediatric 
populations entering Phase 2 studies and beyond. 
 
Based on the safety profile in adults and the lack of DLTs at 8 mg/kg IV q 2 week dose 
level, we propose a dose finding study that, in the absence of DLTs, the recommended 
dose of ramucirumab in children and adolescents will be based on achieving a Cmin,ss ≥ 
50 µg/mL after 3 doses of ramucirumab administered every 2 weeks (Cmin will be 
obtained course 1 day 42 ±2 days, ie 2 weeks after dose 3 and just before dose 4).  A 
rolling 6 design will be used.  Starting dose will be 8 mg/kg IV every 2 weeks x 3 doses 
per 42 day course. In this pediatric trial in the absence of dose limiting toxicity that 
defines a maximum tolerated dose, we propose a dose escalation to achieve a Cmin,ss of 
50 µg/mL in children and adolescents with relapsed or refractory solid tumors. One 
observation from the RAINBOW and REGARD trials was a tendency for concentrations 
to be decreased in the lower body weight quartiles in population PK analysis. The 
planned dose escalation in children and adolescents will permit evaluation of a higher 
dose to achieve comparable serum exposures seen in adults [personal communication 
with Eli Lilly]. If the MTD is not exceeded (0 or 1 DLT/6 fully evaluable patients) at 8 
mg/kg dose level, a second dose level will be explored at the escalated dose of 12 mg/kg 
IV q 2 weeks x 3 doses per course. After accrual to Dose Level 2 is completed, PK 
comparisons from dose levels 1 and 2 will be performed. If PK analysis indicates that 
more than one patient treated at 12 mg/kg dose level has a day 42 Cmin significantly less 
than 50 µg/mL, and the MTD has not been exceeded, additional dose levels will be 
considered.  The next dose level will be established based on Cmin from children who 
received 8 mg/kg/dose and 12 mg/kg/dose on this trial, and will not exceed 16 mg/kg per 
dose q 2 weeks x 3 doses (adult MTD: 13 mg/kg weekly). If the MTD in children and 
adolescents is exceeded at 8 mg/kg IV q 2 weeks x 3 doses within the 42 day evaluation 
period for toxicity during course 1, de-escalation to 6 mg/kg will be considered, and the 
recommended dose will be based on the MTD. An expansion cohort will accrue at the 
lowest tolerable dose at which Cmin of ≥ 50 ug/mL has been achieved in at least 5 out of 
6 evaluable patients, to acquire PK data in a representative number of young patients 
(i.e. patients < 12 years old). If at least 10 out of the total 12 evaluable patients have a 
steady state concentration of ramucirumab greater than 50 µg/mL, then the RP2D has 
been defined.  
 
3.0 
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 


                         
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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. Registrars must hold a minimum of an AP 
registration type.   
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
position in the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN 
tab on the CTSU members’ side of the website at https://www.ctsu.org. To assign an IVR or 
NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or investigator receiving 
a transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB 
number used on the site’s IRB approval.   
 
3.1 
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. 
 
3.2 
IRB Approval 
NCI Pediatric CIRB approval of this study must be obtained by a site prior to enrolling 
patients. Sites must submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit 
(CTSU) Regulatory Office and allow 3 business days for processing. The submission 
must include a coversheet (or optional CTSU IRB Transmittal Sheet) and the IRB 
approval document(s). The CTSU IRB Certification Form may be submitted in lieu of the 
signed IRB approval letter.  All CTSU forms can be located on the CTSU web page 
(www.ctsu.org). Any other regulatory documents needed for access to the study 
enrollment screens will be listed for the study on the CTSU Member’s Website under the 
RSS Tab.   
 
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 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 


                         
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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.) 
 
3.3 
Patient Registration 
Prior to enrollment on study, patients must be assigned a COG patient ID number. This 
number is obtained via the COG Registry system once authorization for the release of 
protected health information (PHI) has been obtained. 
 
3.4 
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.  
 
3.5 
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. 
 
3.6 
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) an IRB-approved institutional 
screening protocol or b) 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. 
 
3.7 
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. 
 
3.8 
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 


                         
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from the institutional pathology report prior to submission. 
 
3.9 
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. 
 
3.10 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
4.0 
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. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Age:  Patients must be ≥ 12 months and ≤ 21 years of age at the time of study 
enrollment. 
 
4.1.2 
Diagnosis:  
Part A: Patients with recurrent or refractory non-CNS solid tumors are eligible. 
Patients must have had histologic verification of malignancy at original diagnosis 
or relapse except patients with extra-cranial germ-cell tumors who have 


                         
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elevations of serum tumor markers including alpha-fetoprotein or beta-HCG. 
Patients in Part A cannot have CNS metastases. 
 
Part B: Patients with recurrent or refractory CNS tumors will be eligible and 
must have a histological verification of malignancy at original diagnosis or 
relapse except in patients with intrinsic brain stem tumors, optic pathway 
gliomas, or patients with CNS-germ cell tumors and elevations of CSF or serum 
tumor markers including alpha-fetoprotein or beta-HCG. 
 
4.1.3 
Disease Status: Patients must have either measurable or evaluable disease (see 
Sections 12.2 and 12.3 for definitions).  
 
4.1.4 
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. 
  
4.1.5 
Performance Level:  Karnofsky ≥ 50% for patients > 16 years of age and Lansky 
≥ 50 for patients ≤ 16 years of age (See Appendix I).  Note:  Neurologic deficits 
in patients with CNS tumors must have been relatively stable for at least 7 days 
prior to study enrollment.  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. 
 
4.1.6 
Prior Therapy 
 
4.1.6.1 Patients must have fully recovered from the acute toxic effects of all 
prior anti-cancer therapy. 
 
a. Myelosuppressive chemotherapy:  At least 21 days after the last dose 
of myelosuppressive chemotherapy (42 days if prior nitrosourea).  
b. Hematopoietic growth factors: At least 14 days after the last dose of 
a long-acting growth factor (e.g. Neulasta) 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. 
c. Biologic (anti-neoplastic agent):  At least 7 days after the last dose of 
a biologic agent.  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. 
d. Immunotherapy: At least 42 days after the completion of any type of 
immunotherapy, e.g. tumor vaccines. 
e. Monoclonal antibodies: At least 3 half-lives of the antibody after the 
last dose of a monoclonal antibody. (See table on DVL homepage 
listing monoclonal antibody half-lives.) 
f. XRT:  At least 14 days after local palliative XRT (small port); At 
least 150 days must have elapsed if prior TBI, craniospinal XRT or if 
≥ 50% radiation of pelvis; At least 42 days must have elapsed if 
other substantial BM radiation. 


                         
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g. Stem Cell Infusion without TBI:  No evidence of active graft vs. host 
disease and at least 84 days must have elapsed after transplant or 
stem cell infusion. 
h. Patients must not have received prior exposure to ramucirumab. 
 
4.1.7 
Organ Function Requirements 
 
4.1.7.1 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-escalation part of the study. If dose-limiting 
hematologic toxicity is observed, all subsequent patients enrolled 
must be evaluable for hematologic toxicity. 
 
4.1.7.2 Adequate Renal Function Defined as: 
- 
Urine protein: ≤ 30 mg/dl in urinalysis or ≤ 1+ on dipstick, unless 
quantitative protein is < 1000 mg in a 24 h urine sample. 
- 
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. 
 
4.1.7.3 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT) ≤ 110 U/L.  For the purpose of this study, the ULN for 
SGPT is 45 U/L.  


                         
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- 
Serum albumin ≥ 2 g/dL. 
  
4.1.7.4 Adequate Cardiac Function Defined As: 
- 
Shortening fraction of  ≥ 27% by echocardiogram, or 
- 
Ejection fraction of ≥ 50% by gated radionuclide study. 
 
4.1.7.5 Adequate Blood Pressure Control Defined as: 
A blood pressure (BP) ≤ the 95th percentile for age, height, and gender 
(Appendix VIII) measured as described in Section 6.4, and not receiving 
medication for treatment of hypertension. Please note that 3 serial blood 
pressures should be obtained and averaged to determine baseline BP. 
 
4.1.7.6 Adequate  Coagulation Defined as: 
- 
INR ≤ 1.5  
 
4.1.8 
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.  
 
4.1.9 
Tissue blocks or slides must be sent per Section 8.10. If tissue blocks or slides 
are unavailable, the study chair must be notified prior to enrollment. 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study because there 
is yet no available information regarding human fetal or teratogenic toxicities. 
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 a highly effective method of contraception during protocol therapy and for at 
least 3 months after the last dose of ramucirumab. A highly effective method of 
contraception is defined as one that results in a low failure rate (that is, <1% per 
year) when used consistently and correctly. Barrier methods used alone are not 
highly effective methods of contraception. For female patients, if a barrier 
method is used, a hormonal method must be used with it to ensure that pregnancy 
does not occur. Abstinence is an acceptable method of birth control. Those who 
become pregnant while on treatment with ramucirumab must discontinue 
immediately and consult their treating physician. 
 
4.2.2 
Concomitant Medications 
 
4.2.2.1 Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. 
 
4.2.2.2 Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
 


                         
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4.2.2.3 Anti-cancer Agents:  Patients who are currently receiving other anti-
cancer agents are not eligible. 
 
4.2.2.4 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. 
 
4.2.2.5 Anti-inflammatory agents: Patients who are chronically receiving aspirin, 
ibuprofen or other non-steroidal anti-inflammatory drugs are not eligible. 
 
4.2.2.6 Anti-platelet agents: Patients who are currently receiving anti-platelet 
agents are not eligible. 
 
4.2.2.7 Anti-hypertensives:  
Patients who are receiving anti-hypertensive medications for control of 
blood pressure at the time of enrollment are not eligible for this trial. 
 
4.2.2.8 Anti-coagulation: Patients who are currently receiving therapeutic anti-
coagulation with heparin, low-molecular weight heparin or coumadin are 
not eligible for this trial. 
 
4.2.2.9 Belimumab: Patients who are currently receiving belimumab (a 
monoclonal antibody for systemic lupus erythematosus) are not eligible. 
 
4.2.2.10 Bisphosphonate derivatives: Patients who are currently receiving 
bisphosphonate derivatives are not eligible. 
 
4.2.3 
Surgery: Patients who have had or are planning to have the following invasive 
procedures are not eligible: 
• 
Major surgical procedure, laparoscopic procedure, open biopsy or 
significant traumatic injury within 28 days prior to enrollment.  
• 
Central line placement or subcutaneous port placement is not considered 
major surgery. External central lines must be placed at least 3 days prior 
to enrollment and subcutaneous ports must be placed at least 7 days prior 
to enrollment 
• 
Core biopsy within 7 days prior to enrollment. 
• 
Fine needle aspirate within 7 days prior to enrollment. 
• 
Surgical or other wounds must be adequately healed prior to enrollment 
NOTE: For purposes of this study, bone marrow aspirate and biopsy are not 
considered surgical procedures and therefore are permitted within 14 days 
prior to start of protocol therapy. 
 
4.2.4 
Bleeding and Thrombosis: 
• 
Patients with evidence of active bleeding: intratumoral hemorrhage by 
current imaging, or bleeding diathesis are not eligible.  
• 
Patients with known or prior history in prior 3 months of esophageal 
varices are not eligible. 


                         
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• 
Patients with a history of CNS arterial/ venous thromboembolic events 
including transient ischemic attack (TIA) or cerebrovascular accident 
(CVA) within 6 months prior to study enrollment are not eligible.  
• 
Patients with a history of deep vein thrombosis (including pulmonary 
embolism) within 3 months prior to study enrollment are not eligible.  
• 
Patients with a history of hemoptysis or other signs of pulmonary 
hemorrhage within 3 months prior to study enrollment are not eligible.  
• 
Patients with a history of ≥ Grade 3 bleeding disorders, vasculitis, or had a 
significant (≥ Grade 3) episode from gastrointestinal bleeding, within 6 
months prior to enrollment are not eligible. 
• 
For Part B: Patients with CNS tumors and evidence of new CNS 
hemorrhage of more than punctate size and/or more than three foci of 
punctate hemorrhage on baseline MRI obtained within 14 days prior to 
study enrollment are not eligible. Note: ECHO Gradient MRI sequences 
per institutional guidelines are required for patients with CNS tumors  
 
4.2.5 
Patients with known cardiac disease per the New York Heart Association 
definition such as myocardial infarction, severe or unstable angina, peripheral 
vascular disease, or congestive heart failure or peripheral vascular disease are not 
eligible.  
 
4.2.6 
Patients who have a history of fistula, gastrointestinal ulcer or perforation, or 
intra-abdominal abscess within 3 months of study enrollment are not eligible.  
 
4.2.7 
Patients with a history of hypertensive crisis or hypertensive encephalopathy 
within 6 months of study enrollment are not eligible. 
 
4.2.8 
Patients who have non-healing wound, unhealed or incompletely healed fracture, 
or a compound (open) bone fracture at the time of enrollment are not eligible. 
 
4.2.9 
Immunocompromised patients (other than that related to the primary oncologic 
diagnosis or to the use of corticosteroids) including patients known to be HIV 
positive are not eligible.  
 
4.2.10 Infection:  Patients who have an uncontrolled infection are not eligible. 
 
4.2.11 Patients who have received a prior solid organ transplantation are not eligible. 
 
4.2.12 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. 
 
 
5.0 
TREATMENT PROGRAM 
 
5.1 
Overview of Treatment Plan 
 
Treatment Schedule Table 
Day 
Ramucirumab (i.v. over 60 minutes) 
Disease Evaluation 
1 
X 
 
15 
X 
 


                         
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29 
X 
 
42 
 
X 
 
A cycle of therapy is considered to be 42 days.  A cycle may be repeated for a total of 8 
cycles, up to a total duration of therapy of approximately 12 months. This is an open-
label study. 
 
Effort should be made to begin protocol therapy on Monday through Thursday if possible 
to accommodate correlative sample shipments. 
 
Drug doses should be adjusted based on actual weight measured within 7 days prior to 
the beginning of each cycle.   
 
Update: With the release of Amendment #2A, the dose escalation portion of the 
study is complete. Given this, Part B will open to patients with relapsed or 
refractory CNS tumors.  
 
5.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 42 days if the patient has at least stable disease and has 
again met laboratory parameters as defined in the eligibility section, Section 4.0.  
 
5.3 
Dose Escalation Schema (Completed) 
 
5.3.1 
Inter-Patient Escalation for Part A: 
Part A of the study is an open-label, Phase 1, dose-escalation study. 
Ramucirumab will be administered as an intravenous infusion over 60 minutes 
every other week for 3 infusions over a 6-week period constituting a cycle. The 
anticipated maximum number of evaluable subjects required to complete Part A 
is 24 patients (See Section 11.1). 
 
Patients should receive diphenhydramine (1 mg/kg, maximum dose 50 mg) (or 
alternative antihistamine) within 30 to 60 minutes prior to each infusion with 
ramucirumab. Anaphylactic precautions should be observed during ramucirumab 
administration. If ≥ Grade 2 infusional reaction occurs, the infusion should be 
stopped and supportive care given as per institutional guidelines.  
 
See Section 6.3 for management and dose modification guidelines for infusional 
reactions (IRR). For the first infusion, vital signs should be monitored prior to 
infusion, every 30 (± 5) minutes during the infusion, and every 30 (± 5) minutes 
for a one-hour observation period after the completion of the infusion. If there is 
no evidence of an IRR during the initial 2 infusions of ramucirumab, then no 
observation period is required for subsequent treatment cycles. In the event an 
IRR occurs thereafter, then the one-hour observation period should be 
reinstituted. 
 
The starting dose of ramucirumab will be 8 mg/kg (dose level 1) with dose levels 
for subsequent groups of patients as follows. 
 
Dose Level 
Dose (mg/kg) 


                         
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-1 
6 
1* 
8 
2 
12 
3^ 
≤ 16 
* Starting Dose Level 
^ Escalation to Dose level 3 will only be considered after evaluation of PK and toxicity at 
dose Level 2. If Cmin,ss of ≥ 50 µg/mL has not been achieved in at least 5 out of 6 
evaluable patients from dose level 2, and if the MTD has not yet been reached, then dose 
level 3 will be considered. 
 
Ramucirumab will be provided by Eli Lilly and Company. Do not use 
commercial supply. 
 
There will be no escalations beyond dose level 3 (16 mg/kg). If the MTD has 
been exceeded at the first dose level, then the subsequent cohort of patients will 
be treated at a dose of 6 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. 
 
Defining RP2D: After accrual to dose level 2 is completed, PK comparisons from 
dose levels 1 and 2 will be performed. An expansion cohort will accrue at the 
lowest tolerable dose at which Cmin of ≥ 50 ug/mL has been achieved in at least 5 
out of 6 evaluable patients to acquire PK data in a representative number of 
young patients (i.e. patients < 12 years old). If at least 10 out of the total 12 
evaluable patients have a steady state concentration of ramucirumab greater than 
50 µg/mL, then the RP2D has been defined. If Cmin,ss of ≥ 50 µg/mL has not been 
achieved in at least 5 out of 6 evaluable patients from dose level 2, and if the 
MTD has not yet been reached, then dose level 3 will be considered. 
 
Update: The RP2D was determined to be 12 mg/kg. 
 
5.3.2 
Part B: Once the RP2D has been determined in Part A, Part B will open to enroll 
children with relapsed or refractory CNS tumors who will receive ramucirumab 
at the MTD or RP2D. Part B of the study will require up to 6 evaluable patients 
enrolled at the MTD or RP2D as determined in Part A (See Section 11.1). 
 
5.3.3 
Intra-Patient Escalation 
Intra-patient dose escalation is not allowed.  
 
5.4 
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 
web 
site 
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. 
 
5.5 
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 


                         
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of dose-escalation will be the first cycle of therapy. 
 
Dose limiting hematological and non-hematological toxicities are defined differently.   
 
5.5.1 
Non-hematological dose-limiting toxicity 
5.5.1.1 Any Grade 3 or Grade 4 non-hematological toxicity attributable 
to the investigational drug with the specific exclusion of: 
• 
Grade 3 nausea, vomiting, diarrhea, or constipation < 3 days 
duration 
• 
Grade 3 liver enzyme elevation, including ALT/AST/GGT, that 
returns to Grade ≤ 1 or baseline prior to the time for the next 
treatment cycle. Note:  For the purposes of this study the ULN for 
ALT is defined as 45 U/L. Adverse event grades will be based on 
increases above the upper limit of normal, regardless of the 
subject’s baseline. See Appendix X for toxicity grading table. 
• 
Grade 3 fever < 5 days duration 
• 
Grade 3 infection  
• 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to oral supplementation  
 
5.5.1.2 Dose-limiting hypertension 
• 
Any Grade 4 hypertension 
• 
A blood pressure > 25 mmHg above the 95th percentile for age, 
height, and gender (Appendix VIII) confirmed by repeated 
measurement is dose limiting. 
• 
In patients who begin antihypertensive therapy a blood pressure > 
10 mmHg but ≤ 25 mmHg above the 95th percentile for age, height, 
and gender (Appendix VIII) for > 14 days is dose limiting. 
 
5.5.1.3 Non-hematological toxicity that causes a delay of ≥ 14 days 
between treatment cycles will be considered dose-limiting. 
 
5.5.1.4 Proteinuria: Urine protein/creatinine (P/C) ratio > 1 and < 1.9 
confirmed with a second measurement within 72 hours will be 
considered a DLT (See Section 6.5) 
 
5.5.1.5 Any gastrointestinal perforation event will be considered a DLT 
and require removal from protocol therapy. 
 
5.5.1.6 Grade ≥ 2 wound complication or wound dehiscence will be 
considered a DLT and require removal from protocol therapy. 
 
5.5.1.7 Grade ≥ 3 hepatic failure will be considered a DLT and require 
removal from protocol therapy. 
 
5.5.1.8 Grade ≥ 2 reversible posterior leukoencephalopathy syndrome 
(RPLS) will be considered a DLT and require removal from 
protocol therapy. 
 
5.5.1.9 Grade ≥ 3 congestive heart failure will be considered a DLT and 


                         
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require removal from protocol therapy. 
 
5.5.1.10 Any toxicity that is possibly related to the study medication that 
requires removal from protocol therapy. Note: Allergic reactions 
that necessitate discontinuation of study drug will not be 
considered a dose-limiting toxicity. 
 
5.5.2 
Hematological dose limiting toxicity 
5.5.2.1 In patients evaluable for hematological toxicity (see Section 4.1.7.1), 
hematological dose limiting toxicity is defined as: 
• 
Grade 4 neutropenia for > 7 days 
• 
Platelet count < 20,000/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.  
 
5.5.2.2 Other hematological dose-limiting toxicities:  
• 
Any arterial thromboembolic event (including cerebrovascular 
ischemia, peripheral or visceral arterial ischemia) 
• 
Any ≥ Grade 3 venous thromboembolic event  
• 
Any thrombotic event requiring systemic anti-coagulation 
• 
Any ≥ Grade 3 hemorrhage 
 
5.5.2.3 Note:  Grade 3 or 4 febrile neutropenia will not be considered a dose-
limiting toxicity. 
 
 
 


                         
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6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. 
 
6.1 
Dose Modifications for Hematological Toxicity 
 
6.1.1 
Patients who have dose-limiting thrombocytopenia will have their treatment held. 
Counts should be checked every 3-4 days for thrombocytopenia during this time. 
If the toxicity resolves to meet eligibility criteria parameters within 14 days, the 
patient may resume subsequent infusions at the next lower dose level. Doses 
reduced for toxicity will not be re-escalated, even if there is minimal or no 
toxicity with the reduced dose. 
 
6.1.2 
Patients who have dose-limiting neutropenia will have their treatment held. 
Counts should be checked every other day for neutropenia during this time. If the 
toxicity resolves to meet eligibility criteria parameters within 14 days, the patient 
may resume subsequent infusions at the next lower dose level.  Doses reduced for 
toxicity will not be re-escalated, even if there is minimal or no toxicity with the 
reduced dose. 
 
6.1.3 
Patients who experience dose-limiting thrombocytopenia or neutropenia after two 
dose reductions must be removed from protocol therapy. 
 
6.1.4 
If, within a cycle, a dose-limiting hematological toxicity does not resolve to meet 
eligibility criteria within 14 days as stipulated in Sections 6.1.1 and 6.1.2 above, 
the patient must be removed from protocol therapy. In addition, patients who 
have a dose-limiting hematological toxicity that does not resolve to eligibility 
criteria within 21 days after the planned start of the next treatment cycle must be 
removed from protocol therapy. 
 
6.1.5 
Patients who experience any of the following events must be removed from 
protocol therapy:  
• 
Any arterial thromboembolic event (including cerebrovascular 
ischemia, peripheral or visceral arterial ischemia) 
• 
Any ≥ Grade 3 venous thromboembolic event  
• 
Any thrombotic event requiring systemic anti-coagulation 
• 
Any ≥ Grade 3 hemorrhage 
 
6.2 
Dose Modifications for Non-Hematological Toxicity 
 
6.2.1 
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 infusions at the next 
lower dose level, except as outlined in Sections 6.4 and 6.5.  Doses reduced for 
toxicity will not be re-escalated, even if there is minimal or no toxicity with the 
reduced dose. 
 
 
 


                         
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6.2.2 
If the same non-hematological dose-limiting toxicity recurs after one dose 
reduction, the patient must be removed from protocol therapy. 
 
6.2.3 
Patients who have a dose-limiting non-hematological toxicity that does not 
resolve to baseline or eligibility criteria within 21 days after the planned start of 
the next treatment cycle must be removed from protocol therapy. 
 
6.3 
Dose Modifications for Infusion-Related Reactions 
For patients who have allergic or acute infusion reactions to ramucirumab, therapy 
modifications based on grade should be as follows. 
Grade  
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 ramucirumab administrations, 
slowing infusion rate as above. 
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 ramucirumab will be 
administered at that visit. Administer diphenhydramine 1 
mg/kg with max 50 mg IV (or equivalent), and remain at 
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 
ramucirumab 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 
• Immediately discontinue infusion of ramucirumab.  
• Begin an IV infusion of normal saline, and treat the subject 
as follows. Recommend bronchodilators, epinephrine 0.2 to 


                         
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or without urticaria, 
allergy related 
edema/angioedema, 
hypotension; 
Anaphylaxis 
1 mg of a 1:1,000 solution for subcutaneous administration, 
0.1 to 0.25 mg of a 1:10,000 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. 
• Ramucirumab 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).  
 
6.4 
Dose Modifications for Hypertension 
• Baseline blood pressure (BP) is defined as the blood pressure obtained at the 
examination used for study enrollment. This baseline BP should be obtained 
as follows: 1) Obtain 3 serial blood pressures from the same extremity with 
the patient in the same position at rest with an appropriately sized cuff. 
Measures must be obtained at least 5 minutes apart. Avoid using the lower 
extremity if possible. 2) Average the systolic blood pressure from the 2nd and 
3rd measurements. 3) Average the diastolic blood pressure from the 2nd and 3rd 
measurements. 4) The baseline BP is the average of the systolic over the 
average of the diastolic measurements. 
• Elevation in either the systolic or diastolic blood pressure should be 
considered when following the algorithm below. 
• The upper limit of normal (ULN) is defined as a BP equal to the 95th 
percentile for age, height, and gender. See Appendix VIII. 
• The NCI CTCAE will be utilized to determine the grade of hypertension for 
reporting purposes. 
• Elevated BP measurements should be repeated on the same day to confirm the 
elevation. If confirmed, patients with elevated BP should have BP 
measurements performed at least twice weekly until BP is ≤ ULN. 
• The algorithm below will be used to manage ramucirumab- related 
hypertension. 
• Hypertension should be managed with appropriate anti-hypertensive agent(s) 
as clinically indicated. It is strongly recommended that nephrology or 
cardiology be consulted in the evaluation and management of hypertension. 
 


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Arm 1 of algorithm:
•
If blood pressure (BP) ≤ 95% for age, height, and gender, continue ramucirumab at
the same dose.
Arm 2 of algorithm:
•
If BP ≤ 10 mm Hg above the ULN for age, height, and gender, continue
ramucirumab at the same dose and recheck the BP within 72 hours. 
o
If the BP is ≤ ULN on recheck, continue ramucirumab at the same dose.
o
If the BP remains above the ULN on recheck, then start antihypertensive therapy 
(Section 7.7) and follow Arm 3 of the algorithm from the point that anti-
hypertensive therapy is started.
Arm 3 of algorithm:
•
If BP is 11 to 25 mm Hg above the 95% for age, height, and gender on ≥ 2 of 3 
measurements or > 35 mmHg above baseline on ≥ 2 of 3 measurements, start anti-
hypertensive therapy (see Section 7.7), continue ramucirumab at the same dose, and 
monitor BP at least twice weekly.
o
If the BP returns to ≤ ULN within 14 days, continue ramucirumab at the same
dose and continue anti-hypertensive therapy. 
o
If the BP remains elevated ≤ 25 mm Hg above the 95% or > 35 mm Hg above 
baseline for more than 14 days after the institution of anti-hypertensive therapy, 


                         
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hold ramucirumab, monitor BP at least every 3 days, and follow Arm 4 of the 
algorithm from the point that ramucirumab is held. The antihypertensive therapy 
should be continued until the BP is less than the ULN. 
 
If the BP returns to ≤ ULN within 14 days, restart ramucirumab at a reduced 
dose (Section 6.2). 
 
If the BP remains > ULN for more than 14 days, patient is Off Protocol 
Therapy. 
o  If the BP increases to > 25 mm Hg above the ULN despite anti-hypertensive 
therapy, hold ramucirumab, but continue the anti-hypertensive agent(s). Monitor 
the BP as clinically indicated and follow Arm 4 of the algorithm from the point 
that ramucirumab is held. 
 
If the BP is ≤ ULN within 14 days, ramucirumab may be restarted at a 
reduced dose (Section 6.2). 
 
If the BP is > ULN for > 14 days, the patient is Off Protocol Therapy 
(Section 10.1). 
 
Arm 4 of algorithm: 
• 
If BP is > 25 mm Hg above the 95% for age, height, and gender hold ramucirumab, 
monitor BP and administer anti-hypertensive therapy as clinically indicated. 
o If the BP returns to ≤ ULN within 14 days, ramucirumab may be restarted at a 
reduced dose (Section 6.2). 
o If the BP is > ULN for >14 days, the patient is Off Protocol Therapy (Section 
10.1). 
 
Arm 5 of algorithm: 
• 
If the participant develops Grade 4 hypertension, discontinue ramucirumab, monitor 
BP and administer anti-hypertensive therapy as clinically indicated. The patient is 
Off Protocol Therapy (Section 10.1). 
 
6.5 
Dose Modifications for Proteinuria 
If urinalysis shows ≥ trace protein then obtain Urine Protein to Creatinine (UPC) 
concentrations (See Appendix IX).  
  
Proteinuria: UPC Ratio 
Action 
If < 1 
Continue protocol therapy 
If 1-1.9 
 
Hold next infusion. A second measurement should be 
obtained within 72 hours. A second confirmation of 
urine protein/creatinine (P/C) ratio 1-1.9 will be 
considered a DLT. If resolves to <1 within 14 days, 
resume protocol therapy. Subsequent infusions will be 
given at a lower dose as outlined in Section 6.2. Monitor 
the UPC weekly for 2 consecutive weeks once protocol 
therapy resumes.  UPC ≥ 1 that persists ≥ 14 days will 
require removal from protocol therapy.   
If > 1.9 
Off protocol therapy 
 
 
 
 


                         
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7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
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. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. See Section 7.6 for drugs that should not be used 
concomitantly due to potential interactions with ramucirumab. 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. Patients MUST 
NOT receive prophylactic myeloid growth factor in the first cycle of therapy. The Study 
Chair should be notified before growth factors are initiated in subsequent cycles. 
 
7.5 
Surgery 
Patients should not have elective surgical procedures while on therapy. For patients who 
require emergent or urgent procedures, therapy should be held and may not be restarted 
until 28 days after major procedures and 7 days after minor procedures such as line 
replacement (3 days for external lines [e.g. Hickman or Broviac]), as detailed in Section 
4.2.3. 
 
7.6 
Concomitant Medications 
Anticoagulation: Use of therapeutic anticoagulation with heparin, low-molecular weight 
heparin, or warfarin should be avoided.  
 
Anti-platelet agents: Use of aspirin, ibuprofen or other non-steroidal anti-inflammatory 
drugs or anti-platelet agents for chronic use is not allowed while on study therapy. 
 
Anti-hypertensives: Patients who develop hypertension while on study therapy may be 
treated with anti-hypertensive agents and may remain on therapy as long as hypertension 
is well controlled on medication (See Section 7.7). 
 
The use of belimumab (a monoclonal antibody for systemic lupus erythematosus) and 
bisphosphonate derivatives are prohibited while the patient is on study therapy. 
 
7.7 
Concurrent Anti-Hypertensive Therapy 
The algorithm in Section 6.4 will be used to grade and manage ramucirumab- related 
hypertension. Should initiation of anti-hypertensive therapy be required, single agent 
therapy (commonly including the calcium channel blockers amlodipine or nifedipine, 
which are permissible without discussion with the study chair) should be started and the 
blood pressure should be monitored at least twice weekly until BP is within the 95th 
percentile for age, height, and gender per Section 6.4. 
  
 


                         
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
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 
Subsequent 
Cycles^ 
Off 
Protocol 
Therapy  
(30 days 
after last 
dose) 
History 
X 
Weekly 
 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
X 
Pregnancy Test1 
X 
 
X 
 
Height, weight 
X 
 
X 
 
Performance Status 
X 
 
 
X 
Blood Pressure2 
X 
Weekly 
Every other week 
X 
CBC, differential, platelets 
X 
Twice Weekly  
(every 3 to 4 days)3 
Weekly4 
X 
Urinalysis5 
X 
 Every 2 weeks 
X 
X 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
X 
Albumin 
X 
 
X 
X 
INR 
X 
 
X 
X 
Tumor Disease Evaluation6 
X 
End of Cycle 1 
End of Cycle 2, 
then every other 
cycle 
 
Plain radiograph tibial growth plate7 
X 
 
Prior to cycles 2, 5 
and every 6 
months 
X 
ECHO or gated radionuclide study 
X 
 
 
X 
Pharmacokinetic (PK) Studies8 
X 
X 
 
X 
Immunogenicity Studies9 
X 
X 
 
X 
Circulating Plasma Molecular Marker 
Studies10 
X 
X 
 
X 
Pharmacogenomic Studies11 
 
X 
 
 
Peripheral Blood Flow-Cytometry (PBFC) 
Studies (Part A Only)12 
X 
 
 
 
Tumor Tissue Studies13 
X 
 
 
 
 
 
 
 
 
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 


                         
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1 
Women of childbearing potential require a negative pregnancy test prior to starting treatment and 
before starting each subsequent cycle; sexually active patients must agree to use a highly effective 
method of contraception during protocol therapy and for at least 3 months after the last dose of 
ramucirumab. Abstinence is an acceptable method of birth control. 
2 
Blood pressure will be measured with an appropriate sized cuff at rest. Blood pressure measurement 
will be repeated within the same day if the blood pressure (BP) is elevated (> the 95th percentile for 
age, height, and gender). Please note that 3 serial blood pressures should be obtained and averaged to 
determine baseline BP (See Section 6.4). If both BP measurements are >95th percentile for age, 
height, and gender, follow the guidelines in Section 6.4. Patients with elevated BP at any time should 
have BP measurements performed at least twice weekly until BP is within the 95th percentile for age, 
height, and gender (See Appendix VIII). 
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 
See Appendix IX for UPC rationale and calculation and Section 6.5 for dose modifications if UPC > 1. 
If patient is being followed for prior proteinuria and UPC is obtained at the scheduled time points, 
urinalysis is not also required. If patient has proteinuria (urine protein/creatinine (P/C) ratio >1), a 
second measurement should be obtained within 72 hours. 
6 
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. 
For patients with CNS disease (Part B), ECHO gradient MRI sequences per institutional standards are 
required to evaluate for hemorrhage (See Appendix X).  
7  
Plain radiographs of at least one tibial growth plate should be obtained in all patients prior to first dose 
of protocol therapy. In patients with open growth plates, follow-up plain radiographs of the same 
growth plate(s) should be obtained according to Section 8.2.1. 
8 
See Section 8.4 and Appendix III for timing and details of PK studies. 
9 
See Section 8.5 and Appendix IV for timing and details of Immunogenicity studies. 
10 
See Section 8.6 and Appendix V-A for timing and details of the pharmacodynamic Circulating Plasma 
Molecular Marker studies. 
11 
See Section 8.7 and Appendix V-B for details of Pharmacogenomic studies. 
12 
See Section 8.8 and Appendix VI for details of Peripheral Blood Flow-Cytometry (PBFC) cellular 
marker studies. 
13 
See Section 8.10 and Appendix VII for details of Tumor Tissue studies. 
 
8.2 
Monitoring for Specific Toxicities 
 
8.2.1 
Growth Plate Toxicity 
Patients will have a plain AP radiograph of a single proximal tibial growth plate 
obtained prior to the first dose of protocol therapy.  
a. If patients are found to have a closed tibial growth plate, no further 
radiographs will be required.  
b. If patients are found to have an open tibial growth plate, then repeat plain AP 
radiographs of the same tibial growth plate will be obtained prior to cycles 2, 
5 and every 6 months. 
• 
Patients with evidence of growth plate thickening or other changes 
should have a knee MRI performed to further assess the degree of 
physeal pathology and undergo more frequent x-ray follow up at least 
every 3 cycles or as clinically indicated. MRI should be performed 
without contrast. 
• 
Patients with knee MRI changes should be managed in an individualized 
manner. Decisions regarding continuation of ramucirumab should be 


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ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
41 
Version Date: 01/31/19 
 
reaction, at the time of its resolution, and approximately 30 days after resolution 
of the event. 
 
8.4.3 
Sample Collection and Handling Instructions (Appendix III) 
Blood samples (2 ml) will be collected in 2 mL red top serum tubes at a site 
distant from the infusion for pharmacokinetic evaluation. 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. 
 
8.4.4 
Sample Processing 
1. Immediately after collection, gently invert each blood sample > 5 times and 
allow blood to clot for 30-45 minutes at room temperature (20-25°C, 60 min. 
max). 
2. Centrifuge samples at room temperature for 15-20 minutes at ~1500-2000 x 
g. 
3. Transfer serum into appropriately labeled transfer tube.  
4. Store the serum samples immediately at -20°C until shipment on dry ice to 
Covance. 
 
8.4.5 
Sample Labeling 
Each tube must be labeled with the patient’s I.D. and accession number and the 
study I.D. (ADVL1416). 
 
8.4.6 
Sample Shipping Instructions 
Refer to lab manual for detailed instructions regarding shipment of these 
specimens.  
 
8.4.7 
Sample Storage   
Bioanalytical samples collected to measure ramucirumab concentration will be 
retained for a maximum of 1 year following study publication. 
 
 
8.5 
Immunogenicity Studies (Required) 
 
8.5.1 
Description of Studies and Assay: 
Immunogenicity analysis to determine antibody production against ramucirumab 
will be conducted by Eli Lilly and Company using validated ELISA assay in 
serum. 
 
 
8.5.2 
Sampling Schedule  
Blood samples (2.5 ml of whole blood) will be obtained prior to drug 
administration and at the time points outlined in Appendix IV. In the event an 
infusion-related reaction is experienced, an additional blood sample for PK and 
Immunogenicity will be collected as close to the onset of the infusion-related 
reaction, at the time of its resolution, and approximately 30 days after resolution 
of the event. 
 
8.5.3 
Sample Collection and Handling Instructions (Appendix IV) 
Blood samples will be collected in 2.5 mL gold top serum tube at a site distant 


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
42 
Version Date: 01/31/19 
 
from the infusion for pharmacokinetic evaluation. 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. 
 
8.5.4 
Sample Processing 
1. Immediately after collection, thoroughly mix the blood with the clotting 
activation agent by inverting the tube not less than five times. 
2. Allow blood to clot for 30 minutes (tube standing upright). 
3. Centrifuge samples for 15-20 minutes at ~1500-2000 x g until clot and serum 
are well separated by a well formed polymer barrier. 
4. Use pipette provided to transfer equally the serum into three appropriately 
labeled transfer tubes 
5. Freeze serum samples at -20°C or colder until shipment on dry ice to 
Covance. 
 
8.5.5 
Sample Labeling 
Each tube must be labeled with the patient’s I.D. and accession number and the 
study I.D. (ADVL1416).   
 
8.5.6 
Sample Shipping Instructions 
Refer to lab manual for detailed instructions regarding shipment of these 
specimens.  
 
8.5.7 
Sample Storage   
Samples may be stored for a maximum of 15 years after study completion to 
enable further analysis of immune responses to ramucirumab and allow the 
sponsor to respond to regulatory requests related to ramucirumab. 
 
8.6 
Circulating Plasma Molecular Marker Studies  
 
8.6.1 
Description of Studies: Plasma samples will be collected as part of the ongoing 
efforts to understand the relationship between cancer, genetics/biology, and 
response to therapy, this study may analyze biomarkers relevant to pathways 
associated with cancer-related conditions, the mechanism of action of 
ramucirumab, and/or angiogenesis, and may also be used for related research 
methods or validation of diagnostic tools or assay(s). Potential 
pharmacodynamics and/or circulating markers may include, but are not limited 
to, placental growth factor, vascular endothelial growth factor A (VEGF-A), 
VEGF-C, VEGF-D, soluble vascular endothelial growth factor receptors 1, 2 and 
3 (sVEGFR-1,VEGFR-2, and sVEGFR-3). 
 
 
8.6.2 
Sampling Schedule 
Blood samples will be obtained prior to drug administration and at the time 
points outlined in Appendix V-A. 
 
8.6.3 
Sample Collection and Handling Instructions (Appendix V-A) 
Blood samples (4 ml) will be collected in 4 mL lavender top EDTA tubes at a site 
distant from the infusion. Record the exact time that the sample is drawn along 
with the exact time that the drug is administered. 


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
43 
Version Date: 01/31/19 
 
 
8.6.4 
Sample Processing 
1. Immediately after collection, thoroughly mix the blood by gently inverting 
tube at least 8 to 10 times. 
2. Centrifuge samples at ~1500-2000 x g until clot for 15 minutes until cells 
and plasma are well separated. 
3. Use pipette provided to transfer plasma equally into three appropriately 
labeled transfer tubes 
4. Freeze serum samples at -20°C until shipment on dry ice to Covance. 
 
8.6.5 
Sample Labeling 
Each tube must be labeled with the patient’s I.D. and accession number and the 
study I.D. (ADVL1416).   
 
8.6.6 
Sample Shipping Instructions 
Refer to lab manual for detailed instructions regarding shipment of these 
specimens.  
 
8.6.7 
Sample Storage   
The samples will be coded with the patient number and stored for up to a 
maximum 15 years after the study completion at a facility selected by the 
sponsor. 
 
8.7 
Pharmacogenomic Studies  
 
8.7.1 
Description of Studies: A blood sample will be collected for pharmacogenetic 
analysis.  These samples are not being collected to create a biobank for 
unspecified disease or population genetic research either now or in the future.  
Samples may be periodically assessed and used to investigate variable response 
to ramucirumab and to investigate genetic variants thought to play a role in 
cancer.  Assessment of variable response may include evaluation of adverse 
events or differences in efficacy.  
 
8.7.2 
Sampling Schedule 
A single blood sample (0.5 mL) will be collected in 0.5 mL lavender top 
microtainer and spotted on a FTA card. 
  
8.7.3 
Sample Collection and Handling Instructions: (Appendix V-B)  
Record the exact time that the sample is drawn along with the exact time that the 
drug is administered. 
 
Blood will be spotted onto a DBS or FTA card:  
• 
Always use sterile technique when handling the FTA card.   
• 
Collect 0.5 ml whole blood in a tuberculin syringe and immediately transfer 
to the K2EDTA lavender top tube. Gently mix blood by inverting 10-15 
times.  
• 
Using enclosed pipette and FTA card, transfer 1 drop of K2EDTA whole 
blood into each of the four circles on the FTA card, taking precaution not to 
contaminate the FTA card. 
• 
Attach the bar code label containing patient identifier information in the 
designated area of the FTA card. 


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
44 
Version Date: 01/31/19 
 
• 
Allow the blood spots to air dry for at least one hour at room temperature. 
• 
After the sample has dried, carefully fold the flap over the specimen. 
• 
Place the FTA card into the pre-labeled, foil-lined pouch provided in the kit, 
and seal the pouch. 
• 
Store ambient and ship to Covance with next ambient shipment. 
 
8.7.4 
Sample Labeling 
Each tube must be labeled with the patient’s I.D. and accession number and the 
study I.D. (ADVL1416).   
 
8.7.5 
Sample Shipping Instructions 
Refer to lab manual for detailed instructions regarding shipment of these 
specimens.  
 
8.7.6 
Sample Storage   
Samples will be retained for a maximum of 15 years after study completion. This 
retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until 
later in drug development or when the drug is commercially available.  
Genotyping data generated will be used only for the specific research scope 
described here, will not be used for any other purpose and will be otherwise 
destroyed.  
 
8.8 
Peripheral Blood Flow-Cytometry (PBFC) Studies (Part A Only) 
 
8.8.1 
Description of Studies:  
The Peripheral Blood Flow –Cytometry (PBFC) cellular marker assay must be 
performed within 24 hours after PB collection. The Angio BioCore located at 
Indiana University will perform the PBFC studies.  
 
8.8.2 
Sampling Schedule (See Appendix VI) 
Samples will be collected at baseline on Day 1 of Cycle 1 prior to the 1st infusion 
and on Day 43, 2 weeks following the 3rd infusion (Cycle 2, Day 1). 
 
8.8.3 
Sample Collection and Handling Instructions 
Blood samples (8 ml) will be collected in 2 six-ml K2EDTA tubes for 
flow cytometry quantification of progenitor cells. Record the exact 
time that the sample is drawn.  
 
8.8.4 
Sample Processing                          
1. Invert at least 5 times gently to avoid hemolyzing the sample. 
2. Transfer blood from the K2EDTA tubes into the CPT tube by pouring the 
blood gently into the CPT tube. 
3. Replace the cap on the CPT and be sure that the cap is secure. CPTs should 
remain upright at room temperature at all times. Discard the K2EDTA tube. 
4. Centrifuge the CPT at 1500-1800 x g for 30 minutes at room temperature. 
Centrifugation should occur within 2 hours of drawing blood into the 
lavender top K2EDTA tube. A CPT tube filled with water will be used as a 
balance tube. The same centrifuge should be used for all specimens if 
possible. 
 


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ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
47 
Version Date: 01/31/19 
 
9.1.1 
Description 
Ramucirumab is an anti-VEGF Receptor 2 recombinant human monoclonal 
antibody of the IgG1 subclass. It is composed of 4 polypeptide chains, 2 identical 
heavy (γ) chains consisting of 446 amino acids each, and 2 identical light (κ) 
chains consisting of 214 amino acids each. The antibody contains 1 conserved N-
linked glycosylation site at each heavy chain, in the Fc region. All excipients 
used for the manufacture of ramucirumab are of pharmacopeial grade. No 
animal-derived components are used in the manufacture of ramucirumab 
excipients. 
 
9.1.2 
Supplied by: Eli Lilly and Company. Do not use commercial supply. 
 
9.1.3 
Formulation 
Ramucirumab is supplied in single-use, 50-mL nominal volume, United States 
Pharmacopeia (USP) Type I glass vials. Each vial contains 500 mg of 
ramucirumab at a concentration of 10 mg/mL in a sterile, preservative-free 
solution. Each vial is stoppered with a chlorobutyl elastomer stopper laminated 
with FluroTec® (West Pharmaceutical Services, Inc., Exton, PA), and secured 
with an aluminum 2-piece flip-top seal. The buffer contains 10mM histidine, 
75mM sodium chloride, 133mM glycine, and 0.01% polysorbate 80. 
Ramucirumab is a clear to slightly opalescent and colorless to slightly yellow 
liquid without visible particles. The pH is 6.0. The osmolality is 285 mmol/kg. 
 
9.1.4 
Storage 
Store intact vials of ramucirumab refrigerated at 2-8 °C (36-46°F). Protect from 
light. DO NOT FREEZE OR SHAKE. The formulation contains no 
preservatives. 
 
Prepared dosing solution should be used immediately in order to minimize the 
risk of microbial contamination. If not used immediately, the prepared 
ramucirumab dosing solution should be stored under refrigeration at 2°C to 8°C 
(36°F to 46°F), for a duration not to exceed 24 hours. If the prepared solution is 
stored at room temperature (below 25°C [77°F]), it must be used within 4 hours. 
Store protected from light. Brief exposure to ambient light is acceptable while 
preparation and administration is taking place. DO NOT FREEZE AND/OR 
SHAKE PREPARED RAMUCIRUMAB FOR INFUSION. 
 
9.1.5 
Solution Preparation  
Ramucirumab is compatible with common infusion containers. The use of a low 
protein binding 0.22 micron in–line filter is required. Aseptic technique is to be 
used when preparing and handling ramucirumab for infusion. Drug doses should 
be adjusted based on actual weight measured within 7 days prior to the beginning 
of each cycle. Based on the calculated volume of ramucirumab, add (or remove 
from pre-filled [with 0.9% normal saline] I.V infusion container) a sufficient 
quantity of sterile normal saline (0.9% weight/volume) to the container to a 
concentration > 0.4 mg/mL by making the total volume 100 mL for patients 
weighing 8-25 kg, and total volume 250 mL for patients weighing > 25 kg. For 
patients < 8 kg total volume should be at least 50 mL and concentration should 
be > 0.4 mg/mL. Do not use dextrose containing solutions. The container should 
be gently inverted to ensure adequate mixing.   
 


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
48 
Version Date: 01/31/19 
 
9.1.6 
Stability 
Prepared solutions of ramucirumab are stable for up to 24 hours refrigerated (2 – 
8° C). If the prepared solution is stored at room temperature (below 25°C 
[77°F]), it must be used within 4 hours. 
 
9.1.7 
Administration 
See Treatment and Dose Modification sections of the protocol. 
Patients should receive premedication with diphenhydramine or alternative 
antihistamine within 30 to 60 minutes prior to each infusion with ramucirumab 
(see Section 5.3.1). The infusion should be delivered via infusion pump over 60 
minutes. The infusion rate should not exceed 25 mg/minute. Infusions of duration 
longer than 60 minutes are permitted in specific circumstances (that is, for larger 
patients in order to maintain an infusion rate that does not exceed 25 mg/minute, 
or in the setting of prior ramucirumab infusion-related reaction); the infusion 
duration must always be accurately recorded. The infusion set must be flushed 
post infusion with sterile sodium chloride 0.9% equal to or greater than infusion 
set holdup volume to ensure delivery of the calculated dose. 
 
9.1.8 
Ramucirumab Toxicities 
The toxicities in the table below are based on version 15.0 of the Investigator’s 
Brochure and US prescribing information data from single agent trials. The 
following events have been observed in patients receiving single agent 
ramucirumab in clinical trials or are potential toxicities for anti-angiogenic 
agents. 
 
Incidence 
Toxicities 
Common 
(>20% of patients) 
Gastrointestinal: Abdominal pain 
Occasional 
(4-20% of patients) 
Cardiovascular: Hypertension 
Blood and Lymphatic System Disorders: Neutropenia 
Gastrointestinal: Diarrhea 
Metabolism & Nutrition Disorders: Hypokalemia, Hyponatremia 
Nervous System Disorders: Headache 
Respiratory, Thoracic, & Mediastinal Disorders: Epistaxis 
Skin and Subcutaneous Tissue Disorders: Rash 
Rare 
(≤ 3% of patients) 
Blood and Lymphatic System Disorders: Severe bleeding 
Cardiovascular: Arterial thromboembolic events 
Gastrointestinal: Intestinal obstruction, Gastrointestinal perforation,  
General Disorders and Administration Site Conditions: Infusion-
related reactions, Impaired wound healing* 
Hepatic disorders: Worsening Liver failure** 
Renal and urinary disorders: Proteinuria 
Pregnancy 
& 
Lactation 
Pregnancy 
Discontinue use in pregnant women. Animal studies have not been 
specifically conducted to evaluate the effect of ramucirumab on female 
reproduction and fetal development, and there are no studies in 
pregnant women. Based on ramucirumab’s mechanism of action, it is 
likely to inhibit angiogenesis and may potentially result in adverse 
effects during pregnancy and postnatal development. Patients (male 
and female) of childbearing potential must agree to use highly effective 


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
49 
Version Date: 01/31/19 
 
birth control methods during and for 3 months after participation in this 
study. 
 
 
Lactation 
There is no information on the presence of ramucirumab in human 
milk, the effects on the breast-fed infant, or the effects on milk 
production. Human IgG is present in human milk, but published data 
suggest that breast milk antibodies do not enter the neonatal and infant 
circulation in substantial amounts. Because of the potential risk for 
serious adverse reactions in nursing infants from ramucirumab, advise 
women that breastfeeding is not recommended during treatment with 
ramucirumab. 
 
* Potential toxicity for anti-angiogenic class of agents 
**Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or 
hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received 
single-agent ramucirumab. 
  
9.2 
Agent Accountability 
Accountability for the study drug at the trial site is the responsibility of the investigator.  
The investigator will ensure that the study drug is used only in accordance with this 
protocol. Where allowed, the investigator may choose to assign some of the drug 
accountability responsibilities to a pharmacist or other appropriate individual. Drug 
accountability records indicating the drug’s delivery date to the site, inventory at the site, 
use by each patient, and amount returned to Eli Lilly or disposed, if approved, will be 
maintained by the clinical site. Before destroying any unused inventory, site should 
contact the Operations Center to confirm that it should not instead be returned to Eli 
Lilly. These records will adequately document that the patients were provided the doses 
as specified in the protocol and should reconcile all ramucirumab received from Eli Lilly. 
Accountability records will include dates, quantities, batch/serial numbers, expiration 
dates (if applicable), and patient numbers.  
 
All unused or expired ramucirumab will be returned to Eli Lilly or if authorized, disposed 
of at the study site and documented. All material containing ramucirumab will be treated 
and disposed of as hazardous waste in accordance with governing regulations. 
 
9.3 
Obtaining the Agent 
Ramucirumab will be supplied by Eli Lilly. Ramucirumab can be obtained by following 
the instructions on the agent request form provided on the ADVL1416 protocol page of 
the COG website (https://members.childrensoncologygroup.org/). 
 
The drug supply must be stored in a locked limited access area. Ramucirumab 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. 
 
 


                         
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10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
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 8 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 ramucirumab (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. 
 
10.2 
Off Study Criteria 
 
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) 
Patient did not receive protocol treatment after study enrollment 
 
 
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
The study will be completed in 2 parts. Part A will be a dose-escalation phase including 
patients with non-CNS solid tumors, and Part B will include a safety and imaging 
evaluation in patients with CNS tumors. 
 


                         
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A minimum of 2 evaluable patients will be entered at each dose level for determination of 
MTD. 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 hematologic 
evaluability may be enrolled to acquire PK data in a representative number of young 
patients (e.g six patients < 12 years old and six patients ≥12 years old).  Review of the 
enrollment rate into previous COG new agent studies indicates that 1-2 patients per 
month are available.  The anticipated maximum number of evaluable subjects required to 
complete Part A is 24 patients. Assuming a 20% inevaluable rate, 29 patients may be 
enrolled and the study would be expected to be completed within 15-29 months. A 
maximum of 51 patients may be required in the unlikely event that each of the three dose 
levels are expanded to 12 because two DLTs of different types are observed at each of the 
three dose levels, 6 additional patients are needed for PK analysis, and a 20% inevaluable 
rate. The maximum of 51 would be completed within 26-51 months. 
 
Part B of the study will require up to 6 evaluable patients enrolled at the MTD or RP2D 
as determined in Part A. Allowing for 20% inevaluability, 8 patients may be enrolled, and 
this would be expected to be completed within 4-8 months. If Part B is expanded to 12 
because of two different classes of DLTs, then up to 15 patients could be enrolled. The 
maximum of 15 patients is expected to be completed within 8-15 months. 
 
11.2 
Definitions 
 
11.2.1 Evaluable For Adverse Effects 
Any patient who receives at least one dose of the study drug(s) and who 
experiences a dose-limiting toxicity is considered evaluable for Adverse Events. 
In addition, during Cycle 1, patients must have the appropriate toxicity 
monitoring studies performed to be considered evaluable for dose limiting 
toxicity. Patients who do not have DLT and do not receive at least 85% of the 
prescribed dose within the first cycle for reasons other than toxicities (e.g. 
progressive disease) will not be considered evaluable for toxicity and will be 
replaced. 
 
11.2.2 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.  
 
• 
In the event that two DLTs observed out of 6 evaluable patients are different 
classes of Adverse Effects (e.g. hepatotoxicity and myelosuppression), 
expansion of the cohort to 12 patients will be considered if all of the 
following conditions are met:  
 
•  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 can proceed. 
 


                         
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• 
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 expansion) experience DLT 
then the MTD will be exceeded.  
 
11.2.3 Recommended Phase 2 Dose (RP2D):  
After accrual to dose level 2 is completed, PK comparisons from dose levels 1 
and 2 will be performed. An expansion cohort will accrue at the lowest tolerable 
dose at which Cmin of ≥ 50 ug/mL has been achieved in at least 5 out of 6 
evaluable patients to acquire PK data in a representative number of young 
patients (i.e. patients < 12 years old). If at least 10 out of the total 12 evaluable 
patients have a steady state concentration of ramucirumab greater than 50 µg/mL, 
then the RP2D has been defined. If Cmin,ss of ≥ 50 µg/mL has not been achieved in 
at least 5 out of 6 evaluable patients from dose level 2, and if the MTD has not 
yet been reached, then dose level 3 will be considered. 
 
11.3 
Dose Escalation and Determination of MTD 
 
The rolling six phase 1 trial design will be used for the conduct of this study. 82 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 
 
2 
2 
0 
0 
De-escalate* 


                         
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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). If there are no further dose escalations based on toxicity assessment, 
then the Recommended Phase 2 Dose (RP2D) will be confirmed as per Section 11.2.3. 
 
In addition to determination of the MTD or RP2D, a descriptive summary of all toxicities 
will be reported. 
 
 
 
11.4 
Inclusion of Children, Women and Minorities 
 
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. 
 
 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
 
A descriptive analysis of pharmacokinetic (PK) parameters of ramucirumab will be 
performed to define systemic exposure, drug clearance, and other pharmacokinetic 
parameters. The PK parameters will be summarized with simple summary statistics. 


                         
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While the primary aim of this study is to evaluate the toxicity of ramucirumab, 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 in nature. 
 
11.6 
Statistical methods 
 
11.6.1 Analysis Sets  
Safety Analysis Set (SAS) will consist of subjects who receive any amount of 
study drug.  
 
11.6.2 Dose Evaluable Set (DES) will consist of: 1) subjects who receive any amount 
of study drug and then experience DLT during Cycle 1; and 2) subjects who 
receive at least 85% of the prescribed dose in Cycle 1 and have an adverse event 
assessment in the first cycle. DES will be used for evaluation of each dose level 
for dose-escalation. 
 
11.6.3 Pharmacokinetic Analysis Set (PAS) will include subjects who have sufficient 
PK data to derive at least one PK parameter.  
 
11.6.4 Efficacy Analyses: 
Preliminary efficacy analyses will also be performed by dose cohort for the 
Safety Analysis Set. Data cut-off for primary study analysis will occur when all 
enrolled subjects have completed 6 cycles of treatment or discontinued study 
drug administration. After the final analysis, additional analyses may be 
performed as appropriate.  
 
11.6.5 Pharmacokinetic Analyses  
Serum concentrations of Ramucirumab will be tabulated and summarized by 
dose level and time. Ramucirumab PK parameters will be derived from serum 
concentrations by non-compartmental analyses using actual times. Minimally, the 
following PK parameters will be calculated: Cmax, tmax, and AUC (t½, CL, and 
Vdss will be calculated only if the data permit). Additional analysis utilizing the 
population pharmacokinetic approach may also be conducted if deemed 
appropriate. 
 
11.6.6 Immunogenicity Analyses  
Immunogenicity incidence will be tabulated, and correlation of immunogenicity 
to ramucirumab drug level, activity, and safety will be assessed as appropriate. 
 
 
11.6.7 Statistical Analyses  
Baseline demographics and baseline disease characteristics will be summarized 
for all enrolled patients who had at least one dose of study therapy. 
  
Listing of patients including those treated at the MTD will be generated. 
 
Treatment-emergent CTCAEs will be summarized by each dose level and for 


                         
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overall population by each CTCAE grade separately. 
 
Best overall response, duration of response, and duration of stable disease will 
also be summarized descriptively by each dose level. 
 
Listing of deaths on study or 30 day post-discontinuation will be provided. 
Listing of SAEs will also be produced. Listing of AEs leading to treatment 
discontinuation will be provided. 
 
CTCAEs possibly study drug related or regardless of causality will be presented 
separately.  
 
 


                         
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12.0 
EVALUATION CRITERIA 
 
12.1 
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 web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
12.1.1 Adverse Event (AE or Adverse Experience): Any untoward medical 
occurrence associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product 
(attribution of Unrelated [“unrelated”, “unlikely”] or Related [“possible”, 
“probable”, or “definite”]). (International Conference on Harmonisation [ICH] 
E2A, E6). 
 
12.1.2 All AEs for which a CTCAE term exists must be reported routinely as 
outlined in the protocol (see Section 13.5). All Serious AEs (as defined in Table 
A in Section 13.1) must be reported expeditiously. For detailed AE reporting 
guidelines refer to the “NCI Guidelines for Investigators: Adverse Event 
Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs”:    
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm. 
 
12.1.3 Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs, including 
all CTCAE v 4.0 grades (for both increasing and decreasing severity) and SAEs; 
regular laboratory evaluation for hematology, blood chemistry, and urine values; 
periodic measurement of vital signs; and the performance of physical 
examinations. 
 
12.2 
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 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. 
 
12.2.1 Definitions 
 
12.2.1.1 Evaluable for objective response: Patients who exhibit objective 
disease progression prior to the end of cycle 1 will be considered 
evaluable for response. For all other patients, only those patients who 
have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response.  


                         
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12.2.1.2 Evaluable Non-Target Disease Response: Patients who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for 
non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
12.2.2 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. 
 
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 


                         
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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.  
 
12.2.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers.  
 
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.  
 
 


                         
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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 
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. 
 
 
 
 


                         
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12.2.4 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 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. 
 


                         
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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.     
 
12.2.5 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 12.7 from a sequence of overall response assessments. 
 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
12.3.1 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.  
 
12.3.2 Complete Response 
Disappearance of all evaluable disease. 
 
12.3.3 Partial response 
Partial responses cannot be determined in patients with evaluable disease 
 
12.3.4 Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), 
or Progressive Disease. 
 
12.3.5 Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, clinical, or 
radiographic progression. 
 
12.3.6 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 12.7 from a sequence of overall response assessments. 
 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
12.4.1 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. 


                         
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12.4.2 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 
 
12.4.3 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 8.3.2 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).  
 
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 


                         
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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. 
 
12.4.4 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 5 in Section 12.7. 
 
12.5 
 Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
12.5.1 Bone Marrow Involvement  
Bone marrow obtained within 14 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. 
 
12.5.2 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes 


                         
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of analysis of treatment effect.  Best response is determined from the sequence of 
the overall response assessments as described in Section 12.7. 
 
12.6 
Response Criteria for Patients with CNS Tumors 
 
12.6.1 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
12.6.2 Evaluable Disease  
Evaluable disease is defined as 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, 
CSF cytology, or other reliable measures. 
 
12.6.3 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is 
considered a “target” for measurement/follow up to assess for tumor 
progression/response. If multiple measurable lesions are present, up to 5 should 
be selected as “target” lesions. Target lesions should be selected on the basis of 
size and suitability for accurate repeated measurements. All other lesions will be 
followed as non-target lesions. The lower size limit of the target lesion(s) should 
be at least twice the thickness of the slices showing the tumor to decrease the 
partial volume effect (e.g., 8 mm lesion for a 4 mm slice). 
 
Any change in size of non-target lesions should be noted, though does not need to 
be measured. 
 
12.6.4 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and 
its longest perpendicular diameter. Development of new disease or progression in 
any established lesions is considered progressive disease, regardless of response 
in other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions: 
 
• 
Complete Response (CR): Disappearance of all target lesions. 
 
• 
Partial response (PR): ≥50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements. 
 
• 
Stable Disease (SD): Neither sufficient decrease in the sum of the products 
of the two perpendicular diameters of all target lesions to qualify for PR, nor 
sufficient increase in a single target lesion to qualify for PD. 
 
• 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 


                         
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12.6.5 Response Criteria for Non-Target Lesions: 
 
• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
• 
Progressive Disease (PD): The appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 
 
12.6.6 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
12.6.7 Overall Response Assessment 
The overall response assessment takes into account response in both target and 
non-target lesions, the appearance of new lesions and normalization of markers 
(where applicable), according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns.   
 
 
Target Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 
Response 
CR 
CR 
Normal 
No 
CR 
CR 
IR/SD 
Normal 
No 
PR 
CR  
CR, IR/SD 
Abnormal 
No 
PR 
PR 
CR, IR/SD 
Any 
No 
PR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
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 12.7 from a sequence of overall response assessments. 
 
 
12.7 
Best Response 
 
12.7.1 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria. 
 
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Non-Target 
New 
Overall 
Best Overall Response 


                         
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Lesions 
Lesions 
Lesions 
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 
 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  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 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 
 
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 


                         
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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 
 
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 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 
 
 
 
12.7.2 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). This will be described by descriptive measures of 
duration of response as opposed to standard time to event analysis. 
 
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. This will be described by descriptive measures of 
duration of stable disease as opposed to standard time to event analysis. 
 
 
 
 


                         
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13.0 
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 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. 
 
All CTCAE v 5.0 codable AEs are considered reportable for this study. For detailed AE 
reporting guidelines refer to the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs”:    
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm. 
 
13.1 
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 web 
site 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;  
 
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 as Related (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 (Unrelated, Unlikely); Related (Possible, Probable, and 
Definite). 
 
 


                         
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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). 
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-Hour, 7 Calendar Days 
 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
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 “24-Hour; 7 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 7 calendar days of the initial 24-
hour report. 
 
Important note: In the narrative of the CTEP-AERS Report, please provide an explanation of the 
investigator’s opinion regarding the determination of seriousness and indicate whether the reported 
event(s) is related or unrelated to any protocol procedures aside from the investigational agent (e.g 
required observations in Table 8.1). 
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 24-hour notification followed by complete report within 7 calendar days for: 
• Grade 1 and 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 that precipitates hospitalization (or prolongation of existing hospitalization) 
must be reported regardless of attribution and designation as expected or unexpected. 


                         
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• 
Any adverse event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects or exposure to study drug through breastfeeding must be reported via 
CTEP-AERS if the event occurs following treatment with the study drug. 
 
• 
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: 
 
• Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions”. Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed as Related (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. 
Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD/LYMPHATICS DISORDERS 
Anemia 
 
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. 
 
13.2 
When to Report an Event in an Expedited Manner  
 
• 
Some adverse events require notification within 24 hours (refer to Table A) via the 
web at http://ctep.cancer.gov (email the ADVL1416 COG Study Assigned 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 


                         
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Expedited Reporting System), accessed via the CTEP home page https://eapps-
ctep.nci.nih.gov/ctepaers. 
 
13.3 
Expedited Reporting Methods  
 
13.3.1 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-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. 
 
Email supporting documentation to the ADVL1416 COG Study Assigned 
Research Coordinator.  ALWAYS include the ticket number on all emailed 
documents. 
 
13.3.2 Reporting to Eli Lilly 
The ADVL1416 COG Study Assigned Research Coordinator will automatically 
forward SAE reports via email to Eli Lilly within 24 hours of receipt from the 
site. 
 
13.4 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG data 
submission forms and do not alter the guidelines for CTEP-AERS reporting. 
 
13.4.1 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. 
 
13.4.2 If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported. 
 
13.4.3 The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects.  
 
13.4.4 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."   
 
13.4.5 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.  
 
13.5 
Other Recipients of Adverse Event Reports 
 
13.5.1 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 


                         
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should be reported at the end of each cycle using the forms provided in the CRF 
packet (See Section 14.1). 
 
13.5.2 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). The CTEP-AERS reports will be filed with Eli Lilly 
Global Patient Safety (GPS) by the Operations Center. Eli Lilly will retain 
responsibility for global reporting and distribution of all such reports to the health 
authorities, ethics committees and investigators. 
 
13.5.3 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. 
 
13.6 
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 
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.  
All secondary malignancies that occur following treatment must 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. 
 
13.7 
Reporting Pregnancy, Pregnancy Loss, 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 
ADVL1416 COG Study Assigned Research Coordinator along with any additional 
medical information 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. 
 
13.7.1 Pregnancy 


                         
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• 
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. 
 
13.7.2 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 
since CTEP-AERS recognizes any Grade 5 event as a patient death. 
 
13.7.3 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 necessary follow-ups. This form is available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyRepo
rtForm.pdf.  
 
 
 


                         
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14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
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. 
 
14.2 
Access to Rave for Data Submission/ Data Reporting 
Data collection for this study will be done through the Medidata Rave clinical data 
management system.  Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS).  To access Rave via iMedidata, the site user must have an active CTEP-
IAM account (check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and the 
appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on either the COG or 
COGC roster at the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata.  To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page.  Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed.  Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will also receive a separate invitation 
from iMedidata to activate their account.  Account activation instructions are located on 
the CTSU website, Rave tab under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance).  Additional information on iMedidata/Rave 
is available on the CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ 
or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com, or by email to the COG Study Assigned Data Manager. 
 
14.3 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports 
are due January 31, April 30, July 31 and October 31.  This is not a responsibility of 
institutions participating in this trial. 


                         
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14.4 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.4.1 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 chair 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. 
 
14.4.2 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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quantitation of proteinuria. Clin Chim Acta 350(1-2):35-9, 2004  
 
 


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APPENDIX II: CORRELATIVE STUDIES GUIDE  
   
Correlative Study 
Appx. 
Tube Type 
Blood 
Volume per 
Sample 
Total 
Volume 
Cycle 1 
Total Volume  
 
Pharmacokinetics 
III 
Refer to manual 
2 mL 
24 mL 
34 mL 
Immunogenicity 
IV 
Refer to manual 
2.5 mL 
7.5 mL 
15 mL 
Circulating Plasma 
Molecular Marker 
Studies  
V-A 
Refer to manual 
4 mL 
4 mL 
12 mL 
Pharmacogenomics 
V-B 
Refer to manual 
0.5 mL 
0.5 mL 
0.5 mL 
Peripheral Blood 
Flow-Cytometry 
Studies (Part A 
Only) 
VI 
K2EDTA tube 
8 mL 
8 mL 
16 mL 
Total Volume for 
All Studies 
 
44 mL 
77.5 mL 
Tumor Tissue 
VII 
 
 
 
 


                         
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APPENDIX III: PHARMACOKINETIC STUDY FORM 
 
COG Pt ID # _______________ ACC # _______________ 
Please do not write patient names on this form or on samples. 
 
Weight: _______kg 
Dose Level: _______mg/kg 
  Total Dose: _______mg 
 
 
Blood samples (2 mL) will be collected for pharmacokinetic studies at the time points listed in the table below. 
Record the exact date and time each sample is drawn and the time of the ramucirumab administration. If this form 
will be used as a source document, the site personnel who collected the samples or research staff responsible for the 
research specimen must initial in the table below, next to the respective sample. 
Blood 
Sample 
No. 
Time Point 
Scheduled Sample Collection Time 
Scheduled  
Ramucirumab 
Time Point 
Actual Date 
Sample Collected 
or Dose Given 
Actual Time 
Sample 
Collected or 
Dose Given 
(24-hr clock) 
Staff 
Initials 
1 
Cycle 1, Day 1 
Prior to Infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
 
Cycle 1, Day 1 
___/___/___ 
|__|__| : |__|__| 
 
2 
Cycle 1, Day 1 
End of Infusion (EOI) on Cycle 1, Day 1 
 
___/___/___ 
|__|__| : |__|__| 
 
3 
Cycle 1, Day 1 
1 hour after EOI on Cycle 1, Day 1 
 
___/___/___ 
|__|__| : |__|__| 
 
4 
Cycle 1, Day 3 ± 1 
48 (± 24) hours after Cycle 1, Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
 
5 
Cycle 1, Day 8 ± 1 
7 (± 1) days after Cycle 1, Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
 
6 
Cycle 1, Day 15 
Prior to Infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
 
Cycle 1, Day 15 
___/___/___ 
|__|__| : |__|__| 
 
7 
Cycle 1, Day 15 
1 hour after EOI on Day 15 
 
___/___/___ 
|__|__| : |__|__| 
 
8 
Cycle 1, Day 29 
Prior to Infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
 
Cycle 1, Day 29 
___/___/___ 
|__|__| : |__|__| 
 
9 
Cycle 1, Day 29 
End of Infusion (EOI) on Day 29 
 
___/___/___ 
|__|__| : |__|__| 
 
10 
Cycle 1, Day 29 
1 hour after EOI on Day 29 
 
___/___/___ 
|__|__| : |__|__| 
 
11 
Cycle 1, Day 31 ± 
1 
48 (± 24) hours after Day 29 dose 
 
___/___/___ 
|__|__| : |__|__| 
 
12 
Cycle 1, Day 36 ± 
1 
7 (± 1) days after Day 29 dose 
 
___/___/___ 
|__|__| : |__|__| 
 
13* 
Cycle 2, Day 1* 
14 (± 1) days after Day 29 dose 
(Prior to dose on Cycle 2, Day 1) 
 
___/___/___ 
|__|__| : |__|__| 
 
 
Cycle 2, Day 1 
___/___/___ 
|__|__| : |__|__| 
 
14 
Cycle 2, Day 1 
1 hour after EOI on Cycle 2, Day 1 
 
___/___/___ 
|__|__| : |__|__| 
 
15 
Cycle 3, Day 1 
Prior to Infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
16 
Cycle 5, Day 1 
Prior to Infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
FOLLOW-UP:   Date of last dose of Ramucirumab:     ___/___/___ Cycle #______ 
 
Sample 
No. 
Scheduled Sample Collection Time 
Date Sample 
Collected  
Time Sample 
Collected (24-
hr clock) 
 
17 
~ 30 days after last dose of ramucirumab 
___/___/___ 
|__|__| : |__|__| 
 
 
* Patients who are removed from therapy during Cycle 1 after receiving the dose should have this sample collected on 
Day 42 ± 1 of Cycle 1. 
 
In the event an infusion-related reaction is experienced, an additional blood sample for each PK and Immunogenicity 
will be collected if possible as close to the onset of the infusion-related reaction, at the time of its resolution, and 
approximately 30 days after resolution of the event. 
Sample 
No. 
Time Point 
Scheduled Sample 
Collection Time 
Date of IRR 
Onset/Resolution 
Date Sample 
Collected  
Time Sample 
Collected or Dose 
Given (24-hr clock) 
Staff Initials 
IRR-1 
Onset of IRR 
unscheduled 
___/___/___ 
___/___/___ 
  |__|__| : |__|__| 
 
IRR-2 
Resolution of IRR 
unscheduled 
___/___/___ 
___/___/___ 
  |__|__| : |__|__| 
 
IRR-3 
~30  Days Post-Resolution 
unscheduled 
 
___/___/___ 
  |__|__| : |__|__| 
 
 
Sample Collection and Processing: Refer to manual for sample processing and shipping details. 


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
84 
Version Date: 01/31/19 
 
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. See manual for detailed guidelines for packaging 
and shipping PK samples to Covance.   
 


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
85 
Version Date: 01/31/19 
 
 
APPENDIX IV: IMMUNOGENICITY FORM:  ANTI- RAMUCIRUMAB ANTIBODY STUDIES 
 
COG Pt ID # _______________ 
 
ACC # _______________ 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__| 
 
 
 
Weight: _______kg 
Dose Level: _______ mg/kg 
   
Total Dose: _______mg 
 
Sample Collection: Blood samples (2.5 ml) will be obtained at the time points listed in the table below. Record the 
exact date and time each sample is drawn and the time of the ramucirumab administration. If this form will be used 
as a source document, the site personnel who collected the samples or research staff responsible for the research 
specimen must initial in the table below, next to the respective sample. 
 
Blood 
Sample 
No. 
Time Point 
Scheduled 
Sample 
Collection Time 
Scheduled  
Ramucirumab 
Time Point 
Date Sample 
Collected or 
Dose Given 
Time Sample Collected or 
Dose Given (24-hr clock) 
Staff 
Initials 
1 
Cycle 1, Day 1 
Prior to infusion 
 
___/___/___ 
  |__|__| : |__|__| 
 
 
Cycle 1, Day 1 
___/___/___ 
Start time |__|__| : |__|__| 
 
2 
Cycle 1, Day 15 
Prior to infusion 
 
___/___/___ 
  |__|__| : |__|__| 
 
 
Cycle 1, Day 15 
___/___/___ 
Start time |__|__| : |__|__| 
 
3 
Cycle 1, Day 29 
Prior to infusion 
 
___/___/___ 
  |__|__| : |__|__| 
 
 
Cycle 1, Day 29 
___/___/___ 
Start time |__|__| : |__|__| 
 
4 
Cycle 3, Day 1 
Prior to infusion 
 
___/___/___ 
  |__|__| : |__|__| 
 
 
Cycle 3, Day 1 
___/___/___ 
Start time |__|__| : |__|__| 
 
5 
Cycle 5, Day 1 
Prior to infusion 
 
___/___/___ 
  |__|__| : |__|__| 
 
 
Cycle 5, Day 1 
___/___/___ 
Start time |__|__| : |__|__| 
 
FOLLOW-UP:   Date of last dose of Ramucirumab:     ___/___/___ Cycle #______ 
 
Blood 
Sample 
No. 
Scheduled Sample Collection Time 
Date Sample 
Collected  
Time Sample 
Collected (24-hr 
clock) 
 
6 
~ 30 days after last dose of ramucirumab 
___/___/___ 
   |__|__| : |__|__| 
 
 
In the event an infusion-related reaction is experienced, an additional blood sample for PK and Immunogenicity will 
be collected as close to the onset of the infusion-related reaction, at the time of its resolution, and approximately 30 
days after resolution of the event. 
Blood 
Sample 
No. 
Time Point 
Scheduled Sample 
Collection Time 
Date of IRR 
Onset/Resolution 
Date Sample 
Collected  
Time Sample 
Collected or Dose 
Given (24-hr clock) 
Staff Initials 
IRR-1 
Onset of IRR 
unscheduled 
___/___/___ 
___/___/___ 
  |__|__| : |__|__| 
 
IRR-2 
Resolution of IRR 
unscheduled 
___/___/___ 
___/___/___ 
  |__|__| : |__|__| 
 
IRR-3 
~30  Days Post-Resolution 
unscheduled 
 
___/___/___ 
  |__|__| : |__|__| 
 
 
Sample Processing Procedures: Refer to manual for sample processing and shipping details.  
 
One copy of this Immunogenicity Study Form should be uploaded into RAVE. See manual for detailed 
guidelines for packaging and shipping Immunogenicity samples to Covance.   
 
 
 


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
86 
Version Date: 01/31/19 
 
APPENDIX V-A: CIRCULATING PLASMA MOLECULAR MARKER STUDIES FORM 
 
COG Pt ID # _______________ 
 
ACC # _______________ 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__| 
 
 
 
Weight: _______kg 
Dose Level: _______ mg/kg 
   
Total Dose: _______mg 
 
 
Blood samples (4 mL) will be obtained at the time points listed in the table below. Record the exact date 
and time each sample is drawn and the time of the ramucirumab administration. If this form will be used 
as a source document, the site personnel who collected the samples or research staff responsible for the 
research specimen must initial in the table below, next to the respective sample. 
 
Sample Collection:  
Blood 
Sample 
No. 
Time Point 
Scheduled Sample 
Collection Time 
Scheduled  
Ramucirumab 
Time Point 
Date Sample 
Collected or 
Dose Given 
Time Sample Collected 
or Dose Given (24-hr 
clock) 
Staff 
Initials 
1 
Cycle 1, Day 1 
Prior to infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
 
Cycle 1, Day 1 
___/___/___ 
Start time |__|__| : |__|__| 
 
2* 
Cycle 2, Day 1  Prior to infusion 
 
___/___/___ 
|__|__| : |__|__| 
 
 
Cycle 1, Day 1 
___/___/___ 
Start time |__|__| : |__|__| 
 
FOLLOW-UP:   Date of last dose of Ramucirumab:     ___/___/___ Cycle #______ 
 
Blood 
Sample 
No. 
Scheduled Sample Collection Time 
Date Sample 
Collected 
Time Sample Collected 
(24-hr clock) 
 
3 
~ 30 days after last dose of ramucirumab 
___/___/___ 
|__|__| : |__|__| 
 
* Patients who are removed from therapy during Cycle 1 after receiving the dose should have this sample collected 
on Day 42 of Cycle 1. 
  
Sample Processing Procedures: Refer to manual for sample processing and shipping details.  
 
 
One copy of this Circulating Plasma Molecular Marker Studies Form should be uploaded into RAVE. See 
manual for detailed guidelines for packaging and shipping Circulating Molecular Biomarker samples to 
Covance.   
 
 
Notification of sample shipping: 
Notification of sample shipment is necessary.  
 
 
 


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
87 
Version Date: 01/31/19 
 
APPENDIX V-B: PHARMACOGENOMICS STUDY FORM 
 
COG Pt ID # _______________ 
 
ACC # _______________ 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__| 
 
 
 
Weight: _______kg 
Dose Level: _______ mg/kg 
   
Total Dose: _______mg 
 
 
A single blood sample (0.5 mL) will be obtained in consenting patients. Effort should be made to collect 
the sample prior to infusion on Cycle 1 Day 1. See Section 8.7 for sample collection and processing 
details. If this form will be used as a source document, the site personnel who collected the samples or 
research staff responsible for the research specimen must initial in the table below, next to the respective 
sample. 
 
Sample Collection:  
Blood 
Sample 
No. 
Time Point 
Scheduled Sample 
Collection Time 
Date Sample 
Collected or 
Dose Given 
Time Sample Collected or 
Dose Given (24-hr clock) 
Staff Initials 
1 
Cycle 1, Day 1 
Prior to infusion* 
___/___/___ 
              |__|__| : |__|__| 
 
 
*If sample is not collected at Cycle 1 Day 1, please collect at a later visit using the Retest Kit provided by Covance. 
 
 
 
One copy of this Pharmacogenomics Form should be uploaded into RAVE. See manual for detailed 
guidelines for packaging and shipping Pharmacogenomics samples to Covance.   
 
Notification of sample shipping: 
Notification of sample shipment is necessary.  
 
 
 


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ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
89 
Version Date: 01/31/19 
 
APPENDIX VII: TISSUE STUDIES FORM  
 
COG Pt ID # _______________ 
ACC # _______________     Date:__________ 
(Please do not write patient names on this form or on samples) 
 
Sample Labeling: 
Samples should be labeled with the following information: 
Protocol number:    ADVL1416 
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 
  
Archived paraffin-embedded tissue must be available for any previous resections for that patient 
(approximately 10 unstained slides or tumor block). The blocks or slides of tumor material should be sent 
at room temperature via courier. During the warmer months (June – August), it is advisable to ship the 
block(s) with a frozen gel ice-pack in order to prevent the melting of paraffin-embedded tissue blocks 
during transit. Ensure cold pack is not in direct contact with specimen. 
  
All blocks or slides must be labeled with the patient’s study registration number (COG Patient ID #), the 
study I.D. (ADVL1416), and the sample collection date. Data should be recorded on this Tissue Studies 
Form, which must accompany the sample(s).  
 
One copy of this Tissue Studies Form should be uploaded into RAVE. See lab manual for detailed 
guidelines for packaging and shipping Pharmacogenomics samples to Covance.   
 
One copy of this form should be uploaded into RAVE. If this form will be used as a source document, the site 
personnel responsible for samples must sign and date this form below: 
 
Signature: _______________________________               Date:__________________________________ 
(site personnel responsible for samples) 
 
 
 


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
90 
Version Date: 01/31/19 
 
APPENDIX VIII: BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT PERCENTILE 
 
 
Blood pressure (BP) levels for BOYS  
 
 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm Hg 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) 
Percentile 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
95th 
98 
99 
101 
103 
104 
106 
106 
54 
54 
55 
56 
57 
58 
58 
2 
95th 
101 
102 
104 
106 
108 
109 
110 
59 
59 
60 
61 
62 
63 
63 
3 
95th 
104 
105 
107 
109 
110 
112 
113 
63 
63 
64 
65 
66 
67 
67 
4 
95th 
106 
107 
109 
111 
112 
114 
115 
66 
67 
68 
69 
70 
71 
71 
5 
95th 
108 
109 
110 
112 
114 
115 
116 
69 
70 
71 
72 
73 
74 
74 
6 
95th 
109 
110 
112 
114 
115 
117 
117 
72 
72 
73 
74 
75 
76 
76 
7 
95th 
110 
111 
113 
115 
117 
118 
119 
74 
74 
75 
76 
77 
78 
78 
8 
95th 
111 
112 
114 
116 
118 
119 
120 
75 
76 
77 
78 
79 
79 
80 
9 
95th 
113 
114 
116 
118 
119 
121 
121 
76 
77 
78 
79 
80 
81 
81 
10 
95th 
115 
116 
117 
119 
121 
122 
123 
77 
78 
79 
80 
81 
81 
82 
11 
95th 
117 
118 
119 
121 
123 
124 
125 
78 
78 
79 
80 
81 
82 
82 
12 
95th 
119 
120 
122 
123 
125 
127 
127 
78 
79 
80 
81 
82 
82 
83 
13 
95th 
121 
122 
124 
126 
128 
129 
130 
79 
79 
80 
81 
82 
83 
83 
14 
95th 
124 
125 
127 
128 
130 
132 
132 
80 
80 
81 
82 
83 
84 
84 
15 
95th 
126 
127 
129 
131 
133 
134 
135 
81 
81 
82 
83 
84 
85 
85 
16 
95th 
129 
130 
132 
134 
135 
137 
137 
82 
83 
83 
84 
85 
86 
87 
≥17 
95th 
131 
132 
134 
136 
138 
139 
140 
84 
85 
86 
87 
87 
88 
89 
Instructions for using this BP Chart: 
1. 
Measure the patient’s blood pressure using an appropriate size cuff. 
2. 
Select appropriate chart for a female or male patient. 
3. 
Using the “age” row and “height” column determine if the BP is within the ULN. 
4. 
See Section 5.5.1 for definition of dose limiting hypertension, Section 6.4 for management and grading of hypertension, and Section 7.7 for medical 
treatment of ramucirumab related hypertension.  
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents” PEDIATRICS 
Vol. 114 No. 2 August 2004, pp. 555-576. 
 


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
91 
Version Date: 01/31/19 
 
 
Blood pressure (BP) levels for GIRLS  
 
 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm Hg 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) 
Percentile 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
95th 
100 
101 
102 
104 
105 
106 
107 
56 
57 
57 
58 
59 
59 
60 
2 
95th 
102 
103 
104 
105 
107 
108 
109 
61 
62 
62 
63 
64 
65 
65 
3 
95th 
104 
104 
105 
107 
108 
109 
110 
65 
66 
66 
67 
68 
68 
69 
4 
95th 
105 
106 
107 
108 
110 
111 
112 
68 
68 
69 
70 
71 
71 
72 
5 
95th 
107 
107 
108 
110 
111 
112 
113 
70 
71 
71 
72 
73 
73 
74 
6 
95th 
108 
109 
110 
111 
113 
114 
115 
72 
72 
73 
74 
74 
75 
76 
7 
95th 
110 
111 
112 
113 
115 
116 
116 
73 
74 
74 
75 
76 
76 
77 
8 
95th 
112 
112 
114 
115 
116 
118 
118 
75 
75 
75 
76 
77 
78 
78 
9 
95th 
114 
114 
115 
117 
118 
119 
120 
76 
76 
76 
77 
78 
79 
79 
10 
95th 
116 
116 
117 
119 
120 
121 
122 
77 
77 
77 
78 
79 
80 
80 
11 
95th 
118 
118 
119 
121 
122 
123 
124 
78 
78 
78 
79 
80 
81 
81 
12 
95th 
119 
120 
121 
123 
124 
125 
126 
79 
79 
79 
80 
81 
82 
82 
13 
95th 
121 
122 
123 
124 
126 
127 
128 
80 
80 
80 
81 
82 
83 
83 
14 
95th 
123 
123 
125 
126 
127 
129 
129 
81 
81 
81 
82 
83 
84 
84 
15 
95th 
124 
125 
126 
127 
129 
130 
131 
82 
82 
82 
83 
84 
85 
85 
16 
95th 
125 
126 
127 
128 
130 
131 
132 
82 
82 
83 
84 
85 
85 
86 
≥17 
95th 
125 
126 
127 
129 
130 
131 
132 
82 
83 
83 
84 
85 
85 
86 
Instructions for using this BP Chart: 
1. 
Measure the patient’s blood pressure using an appropriate size cuff. 
2. 
Select appropriate chart for a female or male patient. 
3. 
Using the “age” row and “height” column determine if the BP is within the ULN. 
4. 
See Section 5.5.1 for definition of dose limiting hypertension, Section 6.4 for management and grading of hypertension, and Section 7.7 for medical 
treatment of ramucirumab related hypertension.  
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents” PEDIATRICS 
Vol. 114 No. 2 August 2004, pp. 555-576.


                         
ADVL1416 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
92 
Version Date: 01/31/19 
 
APPENDIX IX:  URINE PROTEIN TO CREATININE (UPC) RATIO 
 
 
Clinical Meaning of UPC 
There is a good correlation between the ratio of urine protein to creatinine concentrations (UPC) in a 
random urine sample and the amount of protein excreted in a 24-hour urine collection period.83 Thus, the 
UPC allows for an estimation of the 24-hour urine protein excretion from a random sample.  The 
creatinine excretion is fairly constant throughout the day regardless of changes in urine flow rate: 
• 
Men excrete 20 mg to 25 mg of creatinine/kg of body weight/day 
• 
Women excrete 15 mg to 20 mg of creatinine/kg of body weight/day 
• 
Normal protein excretion is <100 mg to 150 mg per 24 hours. 
• 
The UPC ratio is roughly equal to the 24 hour urine protein excretion in g/day 
 
 
Calculating UPC Ratio 
UPC ratio = (Urine protein [mg/dL]) / (urine creatinine [mg/dL]) = numerically equivalent to grams (g) 
protein excreted in urine over 24 hours.  
 
Example:  If a subject has a urine protein of 90 mg/dL and urine creatinine of 30 mg/dL,   
then UPC ratio =  
90 (mg/dL)  = 3 
30 (mg/dL) 
Result UPC is 3 correlating to roughly 3g of protein excretion in a 24-hour period. 
 
 
Units for UPC ratio 
UPC is a calculated ratio. The guidelines in the protocol are based on having urine protein and urine 
creatinine measured in the same units (e.g., mg/dL). The SI units for urine protein and urine creatinine are 
not the same, so these must be converted to mg/dL before calculating the ratio.  For reference, the 
conversion factors for commonly used units for protein and creatinine are provided below. 
 
Starting units 
Conversion to mg/dL 
Protein (g/L) 
Multiply by 100 
Creatinine (µmol/L) 
Divide by 88.4 
Creatinine (mmol/L) 
Multiply by 11.3 
 
 
 


                         
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APPENDIX X: 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 XI: CTEP AND CTSU REGISTRATION PROCEDURES  
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored trials to register and to renew their registration annually.  To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration 
type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site 
staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete 
their annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined in the 
table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI 
Biosketch 
(education, 
training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list 
all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow 
the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the RCR Help 
Desk by email at < RCRHelpDesk@nih.gov >. 
 
 
 


                         
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CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol 
and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can 
be approved to enroll patients.  Assignment of site registration status in the CTSU Regulatory Support 
System (RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory 
criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
ites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not required 
to submit IRB approval documentation to the CTSU Regulatory Office. For sites using the CIRB, IRB 
approval information is received from the CIRB and applied to the RSS in an automated process. 
Signatory Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the CIRB via 
IRBManager to indicate their intent to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office.  In order for the SSW approval to be processed, the 
Signatory Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
 
Requirements For ADVL1416 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-signed 
CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
For applicable studies with a radiation and/or imaging (RTI) component, the enrolling site must be 
aligned to a RTI provider.  To manage provider associations access the Provider Association tab on 
the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove 
associated providers.  Sites must be linked to at least one IROC credentialed provider to participate on 
trials with an RT component. Enrolling sites are responsible for ensuring that the appropriate 
agreements are in place with their RTI provider, and that appropriate IRB approvals are in place.   
 


                         
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Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and 
tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab Regulatory 
Submission  
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. 

SAP_001.pdf: 
Statistical Analysis Plan: I4T-MC-JVDA
A Phase 1 Study of Ramucirumab, a Humanized, Monoclonal Antibody Against the Vascular 
Endothelial Growth Factor-2 (VEGFR-2) Receptor in Children with Recurrent or Refractory 
Solid Tumors, including CNS Tumors
NCT02564198
Approval Date: 21-Jan-2019


I4T-MC-JVDA Statistical Analysis Plan Version 1
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1.
Statistical Analysis Plan:  
I4T-MC-JVDA:  A Phase 1 Study of Ramucirumab, a 
Humanized, Monoclonal Antibody Against the Vascular 
Endothelial Growth Factor-2 (VEGFR-2) Receptor in 
Children with Recurrent or Refractory Solid Tumors, 
including CNS Tumors
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Ramucirumab (LY3009806)
Phase 1 Study of Ramucirumab in Children with Recurrent or Refractory Solid Tumors, 
including CNS Tumors.  
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I4T-MC-JVDA
Phase 1
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 21-Jan-2019 GMT


I4T-MC-JVDA Statistical Analysis Plan Version 1
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I4T-MC-JVDA:  A Phase 1 Study of 
Ramucirumab, a Humanized, Monoclonal Antibody Against the 
Vascular Endothelial Growth Factor-2 (VEGFR-2) Receptor in 
Children with Recurrent or Refractory Solid Tumors, including CNS 
Tumors ...............................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................4
4.
Study Objectives.................................................................................................................5
4.1.
Primary Objective ..........................................................................................................5
4.2.
Secondary Objectives.....................................................................................................5
4.3.
Exploratory Objectives...................................................................................................5
5.
Study Design.......................................................................................................................6
5.1.
Summary of Study Design..............................................................................................6
5.2.
Determination of Sample Size ........................................................................................6
5.3.
Method of Assignment to Dose Level.............................................................................7
6.
A Priori Statistical Methods ................................................................................................8
6.1.
Handling of Dropouts or Missing Data...........................................................................8
6.2.
Patient Disposition .........................................................................................................9
6.3.
Patient Characteristics ..................................................................................................10
6.4.
Concomitant Therapy...................................................................................................10
6.5.
Efficacy Analyses ........................................................................................................10
6.5.1.
Efficacy Analysis Variables .................................................................................10
6.5.2.
Description of Efficacy Analyses .........................................................................11
6.6.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................12
6.7.
Safety Analyses............................................................................................................12
6.7.1.
Extent of Exposure...............................................................................................12
6.7.2.
Adverse Events ....................................................................................................13
6.7.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................14
6.7.4.
Clinical Laboratory Evaluation.............................................................................14
6.7.5.
Vital Signs and Other Physical Findings...............................................................14
6.8.
Annual Report Analyses...............................................................................................14
6.9.
Clinical Trial Registry Analyses...................................................................................15
7.
References ........................................................................................................................16


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Table of Contents
Table
Page
Table JVDA.1.
Dose Level Decision Rules in Rolling 6 Design...............................................7


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to final analysis of the study.   


I4T-MC-JVDA Statistical Analysis Plan Version 1
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4.
Study Objectives
4.1.
Primary Objective
The primary objectives of the study are as follows:

to estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose 
(RP2D) of ramucirumab administered as an intravenous (IV) infusion over 60 minutes, 
every 2 weeks, to children with recurrent or refractory solid tumors

to determine the tolerability of the MTD and/or RP2D of ramucirumab in children with 
recurrent or refractory central nervous system (CNS) tumors

to define and describe the toxicities of ramucirumab administered on this schedule

to characterize the pharmacokinetics (PK) and immunogenicity of ramucirumab in 
children with recurrent or refractory solid tumors including CNS tumors
4.2.
Secondary Objectives
The secondary objective of the study is as follows:

to preliminarily define the antitumor activity of ramucirumab within the confines of a 
Phase 1 study
4.3.
Exploratory Objectives
The exploratory objectives of the study are as follows:

to explore the pharmacodynamics (PD) effects of ramucirumab in this pediatric 
population

to explore potential predictive biomarkers relevant to pediatric cancers, cancer-related 
conditions, ramucirumab and angiogenesis


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LY3009806 
5. Study Design 
5.1. Summary of Study Design 
The study will be completed in 2 parts.  Part A will be a safety and dose-finding phase of the 
study for patients with non-CNS solid tumors, and will include dose-escalation and dose-
expansion components. Part B will include a safety evaluation specifically for patients with CNS 
tumors.  
For the dose-escalation phase, a rolling 6 design will be used.  Starting dose will be 8 mg/kg IV 
every 2 weeks (Q2W) with 3 doses per 42 day cycle (Dose Level 1).  The decision rules of dose 
level assignment based on dose-limiting toxicity (DLT) are introduced in the section below.  If 
the MTD is not exceeded (0 or 1 DLT/6 fully evaluable patients) at 8 mg/kg dose level, a second 
dose level will be explored at the escalated dose of 12 mg/kg IV Q2W with 3 doses per cycle 
(Dose Level 2).  After accrual to Dose Level 2 is completed, PK comparisons from dose levels 1 
and 2 will be performed. The goal is to expand at the dose level at which at least 5 out of 6 
patients achieve a day 42 ܥ௠௜௡ >= 50 ߤ݃/݉ܮ. If PK analysis indicates that more than 1 patient 
treated at 12 mg/kg dose level has a day 42 ܥ௠௜௡ significantly less than 50 ߤ݃/݉ܮ, and the MTD 
has not been exceeded, additional dose levels will be considered.  If the MTD in children and 
adolescents is exceeded at 8 mg/kg IV Q2W, de-escalation to 6 mg/kg will be considered, and 
the recommended dose will be based on the MTD.   
An expansion cohort will accrue at the lowest tolerable dose at which ܥ௠௜௡ of ൒50 ߤ݃/݉ܮ has 
been achieved in at least 5 out of 6 evaluable patients, to acquire PK data in a representative 
number of young patients (ie, patients <12 years old).  If at least 10 out of the total of 12 
evaluable patients have a steady state concentration of ramucirumab greater than 50 ߤ݃/݉ܮ, 
then the RP2D has been defined.  
5.2. Determination of Sample Size 
The primary objective for the dose-escalation phase and the dose-expansion cohort in Part A is to 
evaluate safety and tolerability in patients with non-CNS solid tumors for the purpose of 
determining a RP2D; the primary objective in Part B is to evaluate safety in patients with CNS 
tumors at dose selected as the RP2D in Part A.  The sample size of each part of the study is 
selected to allow adequate assessment of safety at the recommended dose for ramucirumab.  
Part A: 
A minimum of 2 evaluable patients will be entered at each dose level for determination of MTD.  
Once the MTD or RP2D has been defined, up to 6 additional patients with recurrent or refractory 
solid tumors without restrictions on hematologic evaluability may be enrolled to acquire PK data 
in a representative number of young patients.  The anticipated maximum number of evaluable 
subjects required to complete Part A is 24 patients.  Assuming a 20% inevaluable rate, 
29 patients may be enrolled.  
Part B: 


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Once the RP2D has been determined in Part A, Part B will open to enroll children with relapsed 
or refractory CNS tumors who will receive ramucirumab at the MTD or RP2D. Part B of the 
study will require up to 6 evaluable patients enrolled at the MTD/RP2D as determined in Part A.
Allowing for 20% inevaluability, 8 patients may be enrolled. 
5.3.
Method of Assignment to Dose Level
In the rolling 6 study design, 2 to 6 patients can be concurrently enrolled onto a dose level, based 
on the number of patients currently enrolled in the cohort, the number of DLTs observed, and the 
number of patients at risk for developing a DLT. Accrual is suspended when a cohort of 6 has 
enrolled or when the study endpoints have been met.
Table JVDA.1 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. For example, when 3 patients are enrolled onto a dose cohort, if toxicity data is 
available for all 3 when the fourth patient entered and there are no DLTs, the dose is escalated 
and the fourth patient is enrolled to the subsequent dose level. If data is not yet available for 1 or 
more of the first 3 patients and no DLT has been observed, or if one DLT has been observed, the 
new patient is entered at the same dose level. Lastly, if 2 or more DLTs have been observed, the 
dose level is de-escalated. If the dose for the fourth patient is escalated, another patient will be 
enrolled in the subsequent dose level and restart the decision rules for the new dose level.
Table JVDA.1.
Dose Level Decision Rules in Rolling 6 Design
# 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
2
2
0
0
De-escalatea
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
Escalateb
3
≥ 2
0 or 1
0 or 1
De-escalatea
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
Escalateb
4
≥ 2
0, 1 or 2
0, 1 or 2
De-escalatea
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
Escalateb
5
≥ 2
0, 1, 2 or 3
0, 1, 2 or 3
De-escalatea
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
Escalateb
6
≥ 2
0, 1, 2, 3 or 4
0, 1, 2, 3 or 4
De-escalatea
Abbreviations:  DLT = dose-limiting toxicity; MTD = maximum tolerated soe; Pts = patients.
a
If six patients already entered at next lower dose level, the MTD has been defined.
b
If final dose level has been reached, the recommended dose has been reached.


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6.
A Priori Statistical Methods
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee. The study PK scientist will be responsible for designing, conducting, and interpreting 
the PK analysis and delivering PK parameters. The interpretation of final study results will be 
the responsibility of the clinical research physician (CRP) and the study statistician. 
Exploratory statistical analysis procedures not specified in the present document will be executed 
as deemed appropriate by the statistician and study team. 
The following general terms will be used globally in the SAP:

Unless otherwise specified, summary statistics stand for the number of patients with an 
observation (n), mean, standard deviation, median, minimum, and maximum for 
continuous variables; and population size (N), the number of events, the number of 
subjects with events (n) and the proportion of subjects with events (p=n/N) for 
categorical variables.

Safety population will consist of subjects who receive any amount of study drug. The 
safety population will be used for all analyses of dosing, exposure and safety.

DLT-evaluable population will consist of:  1) subjects who receive at lease 1 dose of 
the study drug and then experience DLT during Cycle 1; and 2) subjects who receive at 
least 85% of the prescribed dose in Cycle 1 and have an adverse event (AE) assessment 
in the first cycle.  Dose-limitig toxicity-evaluation population will be used for evaluation 
of each dose level for dose-escalation.

Pharmacokinetic population will include subjects who have sufficient PK data to derive 
at least one PK parameter.

Efficacy population will include all patients who receive any quantity of study treatment 
at the dose recommended.
6.1.
Handling of Dropouts or Missing Data
Rules for handling dropouts or missing data are listed by type of analysis alphabetically. Unless
otherwise specified, observed data will be used and missing data will not be imputed or carried
forward.
General rules for imputing dates related to AEs or concomitant therapy:

Onset date of an AE or start date of a concomitant therapy:
o
If only the day is missing, the date will be set to:

First day of the month that the event occurred, if the onset yyyy-mm is 
after the yyyy-mm of first study treatment.

The day of the first study treatment, if the onset yyyy-mm is the same 
as yyyy-mm of first study treatment.


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o
If both the day and month are missing, the complete date will be set to:

January 1 of the year of onset, if the onset year is after the year of the 
first study treatment.

The date of the first dose, if the onset year is the same as the year of 
the first study treatment.

Resolution date of an AE or end date of a concomitant therapy:

If only the day is missing, the date will be set to the last day of the month of the 
occurrence, or to the date of death of the patient died in the same month.

If both the day and month are missing, the date will be set to December 31 of the year 
of occurrence, or to the date of death of the patient died in the same year.
If a date is completely missing, then the AE will be considered treatment emergent. In case of 
additional therapies, the therapy will be considered concomitant.
General rule for imputing other dates: If a date variable is needed for an analysis, use the
following general rule to impute incomplete date:

If the day of a date is missing, but not the month or year, then assign Day 1 of the month 
to the day.

If the the month of a date is missing, but not the day or the year, then assign January to 
the month.
After imputation, the imputed date should be logically consistent with other relevant date
variable(s). 
Safety analysis: The following rule for missing data processing will apply for safety analysis:

Missing classifications concerning study medication relationship will be considered as 
related to study medication.

If the AE onset date is missing or partial, the date will be compared as far as possible 
with the date of first dose of study medication when determining whether or not the AE is 
present at baseline. In this case, the AE will be assumed to be treatment emergent, unless 
there is clear evidence (through comparison of partial dates) to suggest that the AE 
started prior to the first dose of study medication.
Time-to-event analysis: All censored data will be accounted for using appropriate statistical 
methods.
6.2.
Patient Disposition
All patient discontinuation data will be listed, including the extent of the patient participation in 
the study. If known, a reason for their discontinuation from treatment and from study will be 
listed and summarized. All patients entered in the study will be included in the summary and 
listing.


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All significant protocol violations will be listed by pre-determined categories (eg, 
inclusion/exclusion criteria, errors/missing data in the informed consent/assent process, 
noncompliance with protocol procedures, errors and missing data in drug dosage/intervention, 
errors in recording DLTs, use of excluded treatments, patients continuing after meeting 
withdrawal criteria, or other violations as recorded on electronic case report form (eCRF) or 
monitoring reports).
6.3.
Patient Characteristics
The following patient demographic and other baseline characteristics will be summarized:

patient demographics: age (years) and age group (<12 vs. ≥12), gender, race, ethnicity, 
weight (kg), height (cm), body surface area (BSA) (m2) and Performance Level 
(Karnofsky ≥50% for patients > 16 years of age and Lansky ≥50% for patients ≤ 16 
years of age, see protocol for details)

baseline disease characteristics: initial pathological diagnosis type and subtype, disease
stage at initial diagnosis only, current disease stage and duration of disease (months) at 
study entry

prior cancer therapies
Patient listings of demographic data and baseline characteristics will be provided. Patient 
listings of prior cancer therapies (surgery, radiotherapy, and systemic therapy) will be provided.
6.4.
Concomitant Therapy
The following concomitant medications will be summarized and listed for the safety population:

Anticoagulation: Use of therapeutic anticoagulation with heparin, low-molecular weight 
heparin, or Coumadin should be avoided.

Anti-platelet agents: Use of aspirin, ibuprofen or other non-steroidal anti-inflammatory 
drugs or anti-platelet agents for chronic use is not allowed while on study therapy.

Anti-hypertensives: Patients who develop hypertension while on study therapy may be 
treated with anti-hypertensive agents and may remain on therapy as long as hypertension 
is well controlled on medication.
The use of belimumab (a monoclonal antibody for systemic lupus erythematosus) and 
bisphosphonate derivatives are prohibited while the patient is on study therapy.
6.5.
Efficacy Analyses
6.5.1. Efficacy Analysis Variables
Definition of efficacy analysis variables are listed below:


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
Objective response rate (ORR) is defined as the proportion of treated patients achieving 
a best overall response of partial response (PR) or complete response (CR) per Response 
Evaluation Criteria in Solid Tumors Version 1.1(RECIST v.1.1). Patients who do not
have any postbaseline tumor response assessments for any reason are considered 
nonresponders and are included in the denominator when calculating the response rate.

Disease control rate (DCR) is defined as the proportion of treated patients achieving a 
best overall response of CR, PR, or stable disease (SD) per RECIST v.1.1. Patients who 
do not have any postbaseline tumor response assessments for any reason are considered 
non-responders and are included in the denominator when calculating the response rate.

Duration of response (DOR) is defined from the date of first documented CR or PR
(responder) to the date of objective progression or the date of death due to any cause,
whichever is earlier. If a responder is not known to have died or have objective
progression, then the patient will be censored at the date of last evaluable tumor
assessment.

Progression-free survival (PFS) is defined as the time from the date of randomization
until the date of radiographic documentation of progression (as defined by RECIST v. 
1.1) based on investigator assessment or the date of death due to any cause, whichever is 
earlier. The censoring is taken in the following order:
o
If a patient does not have a baseline disease assessment, then the PFS time will be 
censored at the randomization date, regardless of whether or not objective
progressive disease (PD) or death has been observed for the patient.
o
If a patient is not known to have died or have investigator-assessed PD as of the 
data-inclusion cut-off date for the analysis, the PFS time will be censored at the 
date of last postbaseline adequate radiological tumor assessment, or at the date of 
randomization if the patient does not have any postbaseline adequate radiological 
assessment.

Overall survival (OS) is defined as time from the date of randomization to the date of 
death from any cause. For each patient who is not known to have died as of the data
inclusion cut-off date for a particular analysis, OS will be censored for that analysis at the 
date of last contact prior to the data-inclusion cut-off date (contacts considered in the 
determination of last contact date include AE date, lesion assessment date, visit date, and 
last known alive date).
6.5.2. Description of Efficacy Analyses
Best overall response is the best response recorded from the start of treatment until disease 
progression, in the order of CR, PR, and SD. Best overall response will be summarized for all 
patients evaluable for efficacy whose disease is assessable by RECIST 1.1.
If appropriate, the following analyses will be performed.

Objective response rate will be estimated and reported for each dose level.

Disease control rate will be summarized and provided for each dose level.


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
Progression-free survival will be estimated using a Kaplan-Meier method (Kaplan and 
Meier 1958) by median and 95% confidence interval (CI). Additional exploratory 
analyses using proportional hazards models to control for other factors may be 
performed.

Overall survival will be summarized using the Kaplan-Meier method.
6.6.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods
All PK/PD analysis and creation of table, figures, and listings will be the responsibility of Lilly 
Global PK/PD and Pharmacometrics group based on applicable Global PK/PD and 
Pharmacometrics Standard Operating Procedures and software approved by Global PK/PD and 
Pharmacometrics group’s management.
6.7.
Safety Analyses
All patients who receive at least 1 dose of study therapy will be summarized for safety and 
toxicity. Dose-limiting toxicity will be listed for Phase 1a only by ramucirumab dose schedules. 
Please refer to the protocol for the definition of DLT.
The descriptions and grading scales found in the revised National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting. Unless otherwise specified, when summarized by Preferred Term (PT), AEs will be 
presented in decreasing frequency of PT accross dose levels; when summarized by System 
Organ Class (SOC) and PT, AEs will be presented in decreasing frequency of PT within SOC 
across dose levels.
6.7.1. Extent of Exposure
The following exposure-related variables will be reported:

Cumulative dose (mg/kg) is calculated as sum of all calculated dose levels, where 
calculated dose level (mg/kg) = (actual total dose [mg]) / (closest body weight [kg] prior 
to the treatment).

Duration of treatment (week) is calculated as (date of last dose in last cycle – date of 
first dose + 14)/7.

Dose intensity (mg/kg/week) is calculated as cumulative dose / duration of treatment.

Relative dose intensity (%) is calculated as dose intensity / planned dose intensity * 
100.
The following analyses on the defined rexposure-related variables will be performed using 
summary statistics (number of patients, mean, and standard deviation) by dose group:

Exposure: duration of treatment, number of cycles received, number of patients 
who received ≥1 cycle, ≥2 cycles, …, ≥8 cycles; and cumulative dose.

Dose adjustment: number of patients with dose adjustments: dose reduction, dose 
omission and dose delay; reason for dose adjustments.


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
Dose intensity: weekly dose intensity, relative dose intensity.
6.7.2. Adverse Events
Adverse events are defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product, without regard to the possibility of a causal relationship.
Treatment-emergent adverse events (TEAE) is defined as any untoward medical occurrence
that either occurs or worsens at any time after treatment baseline and that does not necessarily 
have to have a causal relationship with this treatment.
Serious adverse events (SAE) are defined as any of the AEs that results in one of the following 
outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect considered significant by the investigator 

considered significant by the investigator for any other reason based upon appropriate 
medical judgement
A summary overview of all AEs will be provided per study arm. The overview will tabulate 
number of subjects with:

at least 1 TEAE

at least 1 CTCAE grade ≥3 TEAE

at least 1 serious AE

discontinuation from study treatment due to AE

discontinuation from study treatment due to SAE

death due to AE on study treatment

death due to AE within 30 days of last infusion or discontinuation from study treatment
The summary will be provided regardless of study drug causality, and repeated for events 
deemed by investigator to be possibly related to study medication. 
The following summaries of TEAEs by treatment dose levels will be provided (*repeated for 
events deemed by the investigator to be possibly related to study medication)

by PT *

by maximum CTCAE grade and by SOC and PT
Consolidated AE may be summarized for TEAE and study treatment-related TEAE. A patient 
listing of all AEs will be provided. 


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6.7.3. Deaths, Other Serious Adverse Events, and Other Notable
Adverse Events
Reasons for deaths will be summarized separately for 1) all deaths, 2) deaths on therapy, 
3) deaths within 30 days of treatment discontinuation, and 4) deaths after 30 days of treatment 
discontinuation. 
Serious AEs will be summarized by PT, and repeated for serious adverse events deemed by the 
investigator to be possibly related to study medication, with consolidated summary performed if 
needed. A listing of SAEs will be produced. 
In addition, the following analyses will be performed:

adverse events leading to death by PT

adverse events leading to study treatment discontinuation by PT

adverse events leading to study treatment dose modification by PT

adverse events of special interest (AESI) by PT, and repeated for AESIs deemed by the 
investigator to be possibly related to study medication

listings of AESI, AEs leading to death, AEs leading to discontinuation, and AEs leading 
to dose modifications
6.7.4. Clinical Laboratory Evaluation
The severity of laboratory results will be classified according to CTCAE version 4.0. The shifts 
in CTCAE toxicity grading from baseline to worst grade postbaseline (first dose up to 30 days 
after study treatment discontinuation) will be produced. 
A patient listing of all laboratory will be provided with a flag for values outside of the laboratory 
normal range as well as investigator site, patient identifier, age, gender, race, weight, and visit.
6.7.5. Vital Signs and Other Physical Findings
All vital signs including temperature, blood pressure, heart rate, and respiratory rate will be listed 
for all enrolled patients.
6.8.
Annual Report Analyses
The following reports are needed for a Development Update Safety Report (DSUR):

estimated cumulative subject exposure

cumulative exposure to investigational drug, by demographic characteristics for ongoing 
unblinded clinical trials and completed clinical trials

exposure information for ongoing clinical trials and clinical trials that completed during 
the reporting period

listing of subjects who died during the DSUR reporting period

discontinuations due to AEs during the DSUR reporting period


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6.9.
Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
Summary of adverse events, provided as a dataset which will be converted to an XML file. Both 
Serious Adverse Events and ‘Other’ Adverse Events are summarized by treatment group and by
Medical Dictionary for Regulatory Activities (MedDRA) PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each Serious AE and ‘Other’ AE, for each term and treatment group, the following are 
provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may be excluded if a 5% threshold 
is chosen.

adverse event reporting is consistent with other document disclosures for example, the 
clinical study report (CSR), manuscripts, and so forth. 


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7.
References
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc.
1958;53(282):457-481.


Leo Document ID = 631f4499-ec86-4c10-a534-5b5a1cf7e2ff
Approver: 
Approval Date & Time: 21-Jan-2019 15:47:30 GMT
Signature meaning: Approved
PPD