Conditions: Childhood Solid Neoplasm Recurrent Malignant Solid Neoplasm Recurrent Primary Central Nervous System Neoplasm Refractory Malignant Solid Neoplasm Refractory Primary Central Nervous System Neoplasm
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of prexasertib in treating pediatric patients with solid tumors that have come back after a period of time during which the tumor could not be detected or does not respond to treatment. Checkpoint kinase 1 inhibitor LY2606368 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of prexasertib (LY2606368) administered as an intravenous (IV) infusion over 60 minutes, every 14 days of a 28-day cycle to children with recurrent or refractory solid tumors.

II. To define and describe the toxicities of LY2606368 administered on this schedule.

III. To characterize the pharmacokinetics of LY2606368 in children with recurrent or refractory cancer.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of LY2606368 within the confines of a phase 1 study.

II. To examine checkpoint kinase (CHK)1/2 expression status in archival tumor tissue from solid tumor pediatric patients using immunohistochemistry.

III. To evaluate tumor tissue for deletion and/or mutation of tumor protein 53 (TP53) as a potential biomarker of Chk1 inhibition.

IV. To evaluate autophosphorylation of Chk1 and H2A histone family, member x (H2AX) in peripheral blood mononuclear cells as a potential pharmacodynamic marker of LY2606368 activity.

OUTLINE: This is a dose-escalation study.

Patients receive prexasertib IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.

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

Arms:
arm 1: Patients receive prexasertib IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Pharmacokinetic (PK) study intervention 3: Prexasertib
Intervention descriptions: intervention 1: Correlative studies intervention 2: Correlative studies intervention 3: Given IV

Protocol document:
Prot_SAP_000.pdf: 
                                            
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1 
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Activated: 
February 27, 2017 
Version Date: 
01/31/19 
Closed: 
May 9, 2019 
Amendment #: 
3 
 
 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
ADVL1515 
 
A PHASE 1 STUDY OF LY2606368 (prexasertib mesylate monohydrate) (
), A 
CHK1/2 INHIBITOR, IN PEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY 
SOLID TUMORS, INCLUDING CNS TUMORS 
 
Lead Organization: COG Pediatric Early Phase Clinical Trials Network (PEP-CTN)  
 
 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED 
OR USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN 
THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY 
ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT 
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL 
HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
 
 
  
 
 
For COG PEP-CTN Operations Contacts see: http://members.childrensoncologygroup.org 
 
 


 
                              
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TABLE OF CONTENTS 
SECTION 
 
PAGE 
 
STUDY COMMITTEE 
5 
STUDY COMMITTEE, CONT. 
6 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
1.1 
Primary Aims 
9 
1.2 
Secondary Aims 
9 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development 
9 
2.2 
Preclinical Studies 
10 
2.3 
Adult Studies 
13 
2.4 
Pediatric Studies 
14 
2.5 
Overview of Proposed Pediatric Study 
14 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
15 
3.1 
Current Study Status 
15 
3.2 
IRB Approval 
15 
3.3 
Patient Registration 
16 
3.4 
Reservation and Contact Requirements 
16 
3.5 
Informed Consent/Assent 
16 
3.6 
Screening Procedures 
16 
3.7 
Eligibility Checklist 
16 
3.8 
Institutional Pathology Report 
17 
3.9 
Study Enrollment 
17 
3.10 
Dose Assignment 
17 
4.0 
PATIENT ELIGIBILITY 
17 
4.1 
Inclusion Criteria 
18 
4.2 
Exclusion Criteria 
21 
5.0 
TREATMENT PROGRAM 
22 
5.1 
Overview of Treatment Plan 
22 
5.2 
Criteria for Starting Subsequent Cycles 
22 
5.3 
Dose Escalation Schema 
22 
5.4 
Grading of Adverse Events 
23 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
23 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
24 
6.1 
Dose Modifications for Day 15 Dosing due to Toxicity on Day 15 
24 
6.2 
Dose Modifications for Hematological Toxicity 
25 
6.3 
Dose Modifications for Non-Hematological Toxicity 
26 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
26 
7.1 
Concurrent Anticancer Therapy 
26 
7.2 
Investigational Agents 
26 
7.3 
Supportive Care 
26 
7.4 
Growth Factors 
26 
7.5 
Concomitant Medications 
27 


 
                              
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
27 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
27 
8.2 
Radiology Studies 
28 
8.3 
Pharmacology 
28 
8.4 
Tissue Studies (required) 
30 
8.5 
Correlative Biology Studies (optional) 
30 
9.0 
AGENT INFORMATION 
32 
9.1 
LY2606368 (prexasertib mesylate monohydrate) 
32 
9.2 
Agent Accountability 
35 
9.3 
Obtaining the Agent 
36 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
36 
10.1 
Criteria for Removal from Protocol Therapy 
36 
10.2 
Off Study Criteria 
37 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
37 
11.1 
Sample Size and Study Duration 
37 
11.2 
Definitions 
37 
11.3 
Dose Escalation and Determination of MTD 
38 
11.4 
Inclusion of Children, Women and Minorities 
39 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
40 
12.0 
EVALUATION CRITERIA 
41 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
41 
12.2 
Response Criteria for Patients with Solid Tumors 
41 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
46 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
47 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
49 
12.6 
Response Criteria for Patients with CNS Tumors 
49 
12.7 
Best Response 
51 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
52 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
52 
13.2 
When to Report an Event in an Expedited Manner 
56 
13.3 
Expedited Reporting Methods 
56 
13.4 
Definition of Onset and Resolution of Adverse Events 
57 
13.5 
Other Recipients of Adverse Event Reports 
57 
13.6 
Reporting Secondary AML/MDS 
57 
13.7 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
58 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
59 
14.1 
Categories of Research Records 
59 
14.2 
CDUS 
59 
14.3 
Data and Safety Monitoring Plan 
60 
REFERENCES 
61 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
63 
APPENDIX II: CORRELATIVE STUDIES GUIDE 
64 
APPENDIX III: PREGNANCY INFORMATION FORM 
65 
APPENDIX IV: MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
66 


 
                              
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APPENDIX V:  PHARMACOKINETIC STUDY FORM 
67 
APPENDIX VI:  TISSUE STUDY FORM (REQUIRED TISSUE) 
68 
APPENDIX VII:  PHARMACODYNAMIC STUDY FORM 
69 
APPENDIX VIII:  ISOLATION OF PBMCS AND PLASMA FOR CORRELATIVE STUDIES 
70 
APPENDIX IX: TOXICITY-SPECIFIC GRADING 
72 
 
 
 


 
                              
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For PEP-CTN Operations and Data/Statistics 
Contacts see: 
 
http:members.childrensoncologygroup.org 
 
 
 
AGENT NSC# AND IND#’s 
 
 
 
Agent Supplied by Eli Lilly & Co.: 
LY2606368 (NSC# 789570, 
) 
 
 
IND Sponsor: COG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEE SECTIONS 8.3.6, 8.4.2 AND 8.5.6 FOR SPECIMEN SHIPPING ADDRESSES 
 


 
                              
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This trial is covered by a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects. The Certificate protects against the involuntary release of 
information about subjects collected during the course of our covered studies.  The researchers involved in 
the studies cannot be forced to disclose the identity or any information collected in the study in any legal 
proceedings at the federal, state, or local level, regardless of whether they are criminal, administrative, or 
legislative proceedings.  However, the subject or the researcher may choose to voluntarily disclose the 
protected information under certain circumstances. For example, if the subject or his/her guardian requests 
the release of information in writing, the Certificate does not protect against that voluntary disclosure. 
Furthermore, federal agencies may review our records under limited circumstances, such as a DHHS 
request for information for an audit or program evaluation or an FDA request under the Food, Drug and 
Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
ABSTRACT 
In response to DNA damage or replication stress, cells initiate a DNA damage response (DDR) that 
activates cell cycle checkpoints to halt progress through the cell cycle to allow for DNA repair. DNA 
damage can arise from normal metabolic processes within the cell (e.g. replication stress) as well as from 
external sources such as environmental insults (e.g. UV radiation) and DNA-damaging agents.  
Checkpoint kinase proteins 1 (CHK1) and 2 (CHK2) are conserved serine/threonine kinases that are key 
effectors of multiple checkpoint responses in eukaryotic cells exposed to genotoxic stress. CHK1 has also 
been determined to directly affect repair of DNA, confirming its role in maintaining genomic integrity. 
Inhibition of CHK1 abrogates the DDR checkpoint, allowing cells that have sustained DNA damage to 
prematurely enter mitosis and undergo mitotic catastrophe due to incompletely replicated chromosomes. 
LY2606368 is a novel, second generation selective, dual inhibitor of CHK1/2. In vitro studies focused in 
cell lines derived from human pediatric tumors (ALL, Ewing’s sarcoma, medulloblastoma, neuroblastoma, 
osteosarcoma, retinoblastoma and rhabdomyosarcoma) indicate that LY2606368 is a potent inhibitor of cell 
proliferation. Additionally, the antitumor activity of LY2606368 has been evaluated in 14 pediatric tumor 
xenograft models. LY2606368 was well tolerated and an objective response was noted in 6 of 14 (43%) 
solid tumor xenografts including neuroblastoma, rhabdomyosarcoma (n=3), Ewing sarcoma, and 
desmoplastic small round cell tumor (DSRCT). An adult phase I trial in women with breast or ovarian 
cancer and patients with advanced solid tumors showed that LY2606368 is generally well-tolerated with 
common side effects of neutropenia, thrombocytopenia, fatigue, nausea, headache, diarrhea, and anorexia. 
We will conduct a phase 1 trial of LY2606368 in children with relapsed/refractory solid tumors, including 
CNS, using the rolling six design. The primary aims of this trial will be to establish the maximum tolerated 
dose of LY2606368 and to characterize the toxicities and pharmacokinetics of LY2606368 in children with 
these tumors. Our secondary aims will be to preliminarily define the anti-tumor efficacy of LY2606368 
within the confines of a phase I trial and to examine CHK1/2 expression status in archival tumor tissue. 
Additional exploratory aims will seek to define new pharmacodynamic markers of LY2606368 activity by 
evaluating tumor tissue for deletion and/or mutation of TP53 and peripheral blood mononuclear cells for 
autophosphorylation of Chk1 and H2AX. 
 
 
 


 
                              
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
Treatment Schedule Table 
Cycles- 28 day duration 
Agent 
 
 
 
 
 
Day 1                Day 15                Day 28 
LY2606368 intravenous infusion 
over 60 minutes 
 
Treatment will be discontinued if there is evidence of progressive disease or drug-related dose-limiting 
toxicity that requires removal from therapy. Patients with stable disease or greater response may continue 
receiving protocol therapy provided that the patient meets the criteria for starting subsequent cycles (Section 
5.2) and does not meet any of the criteria for removal from protocol therapy or off study criteria (Section 
10.0). 
 
 
 
 
 
 
Infusion 
Infusion 
Evaluation 


 
                              
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1.0 
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 of LY2606368 administered as an IV infusion over 60 minutes, every 14 days 
of a 28-day cycle to children with recurrent or refractory solid tumors. 
 
1.1.2 
To define and describe the toxicities of LY2606368 administered on this schedule. 
 
 
1.1.3 
To characterize the pharmacokinetics of LY2606368 in children with recurrent or 
refractory cancer. 
 
1.2 
Secondary Aims 
 
1.2.1 
To preliminarily define the antitumor activity of LY2606368 within the confines of 
a Phase 1 study. 
 
1.2.2 
To examine CHK1/2 expression status in archival tumor tissue from solid tumor 
pediatric patients using immunohistochemistry. 
 
1.2.3 
To evaluate tumor tissue for deletion and/or mutation of TP53 as a potential 
biomarker of Chk1 inhibition. 
1.2.4 
To evaluate autophosphorylation of Chk1 and H2AX in peripheral blood 
mononuclear cells as a potential pharmacodynamic marker of LY2606368 activity.  
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
Genetic material within a cell is exposed to endogenous as well as exogenous sources of 
stress. Continuous monitoring and maintenance of genetic structure is essential for cell 
survival and proliferation. In response to DNA damage or replication stress, cells initiate a 
DNA damage response (DDR) that activates cell cycle checkpoints to halt progress through 
the cell cycle to allow for DNA repair.1 DNA damage can arise from normal metabolic 
processes within the cell (e.g. replication stress) as well as from external sources such as 
environmental insults (e.g. UV radiation) and DNA-damaging agents.2 There are primary 
checkpoints that mediate cell cycle progression – G1/S, S and G2/M that induce cell cycle 
arrest and allow for DNA damage repair prior to replication or mitosis.3-5 
 
Checkpoint kinase proteins 1 (CHK1) and 2 (CHK2) are conserved serine/threonine 
kinases and are key effectors of multiple checkpoint responses in eukaryotic cells exposed 
to genotoxic stress. CHK1 is activated by DNA damaging agents like chemotherapy and 
plays a key role in the intra-S and G2/M DNA damage checkpoints that slow DNA 
replication and limit mitotic entry, respectively.6,7 CHK1 is also critical to enforcing the 
S/M checkpoint when DNA synthesis is blocked and replication is incomplete.8,9 
 
CHK1 has also been determined to directly affect repair of DNA, confirming its role in 
maintaining genomic integrity. Inhibition of CHK1 abrogates the DDR checkpoint, 
allowing cells that have sustained DNA damage to prematurely enter mitosis and undergo 
mitotic catastrophe due to incompletely replicated chromosome.3,10 While the mechanism 


 
                              
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of cell death is not well elucidated, it appears that CHK1 inhibitors may be most effective 
in cells that have a level of DNA damage and/or replication stress.2,11 In most cases, the 
level of DNA damage within a tumor cell was the most consistent indicator of drug 
sensitivity to CHK1 inhibitor. These data suggest that CHK inhibitors would be beneficial 
therapeutic agents in MYC-driven cancers. Preclinical evidence suggests that targeting 
intracellular regulation of the cell cycle may be useful in treating tumors such as melanoma 
that respond poorly to traditional chemotherapeutic agents.12 Inhibitors of CHK can act in 
a synthetically lethal manner in cancers with replication stress as a result of these cancers 
being reliant on CHK proteins for an effective DDR and cell survival. 
 
In normal cell cycle progression, CHK1 prevents the activation of late-stage origins until 
near the end of S phase and stabilizes active replication forks. Inhibition of CHK1 results 
in an increased number of active replication origins, which results in stalled replication 
forks and DNA strand breakage.6,13,14 Cells deficient in CHK1 have increased spontaneous 
chromosome missegregation. These cells lose the ability to recruit spindle checkpoint 
proteins to kinetochores and fail to activate the spindle checkpoint in response to 
misaligned chromosomes.5 This finding suggests that CHK1 is essential for stable 
attachment of mitotic spindles to metaphase chromosomes. Thus, it is postulated that 
CHK1 inhibition alone can generate DNA damage and induce mitotic catastrophe. 
 
 
2.2 
Preclinical Studies 
 
2.2.1 
Antitumor Activity 
LY2606368 is a novel, second generation ATP-competitive, selective, dual 
inhibitor of CHK1/2 that has shown activity in xenograft models of ovarian and 
prostate cancer as a single agent, as well as in combination with cisplatin or 
paclitaxel.15,16 CHK1 inhibition has been reported potentiate the activity of DNA-
damaging agents such as cisplatin by exacerbating the cellular DNA damage and 
reducing the cell’s capacity to repair the damage.17,18 When used as a single agent, 
LY2606368 causes double-stranded DNA breakage while also removing the 
protection of the DNA damage checkpoints. Inhibition of CHK1 results in an 
increase in CDC25A activation of CDK2. The cellular consequences are stalled 
replication forks, an increase in DNA strand breaks, and replication 
catastrophe.6,13,19 Treatment of cells with LY2606368 results in the rapid 
appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in cells 
in the S-phase of the cell cycle.19 In this regard, CHK1 functions as a negative 
regulator of replication origin activation; specifically, keeping replication origins 
silent until late S phase. When CHK1 protein is depleted, more replication origins 
are activated in early S phase than the replication apparatus can tolerate, resulting 
in slowed and arrested DNA replication forks and DNA double-strand breakage. 
Treatment with LY2606368 causes a cellular phenotype identical to that reported 
in ribonucleic acid (RNA) interference (RNAi) knockdown experiments such that 
HeLa cells treated with LY2606368 show a clear defect in chromatin condensation 
and failure of the mitotic spindle to attach to chromosomes.20 These data suggest 
that as a single agent in vitro, LY2606368 behaves mechanistically as a DNA- 
damaging agent, a checkpoint inhibitor, and as an inhibitor of DNA replication and 
mitosis. 
 
Additional in vitro studies focused in cell lines derived from human pediatric 
tumors (ALL, Ewing’s sarcoma, medulloblastoma, neuroblastoma, osteosarcoma, 


 
                              
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retinoblastoma and rhabdomyosarcoma) indicate that LY2606368 is a potent 
inhibitor of cell proliferation. In particular, all of the 19 pediatric cell lines tested 
were highly sensitive to LY2606368 such that the IC50 values for growth inhibition 
were 1 nM or lower.21 Notably, LY2606368 was more potent than most other 
agents evaluated which included vincristine, cisplatin, doxorubicin and 
gemcitabine. There were only 3 situations wherein LY2606368 did not show 
greater potency that the other single agents and, in these cases LY2606368 showed 
equivalent, but not lower potency to one of the other 4 agents tested. 
 
The antitumor activity of LY2606368 has been evaluated in 14 pediatric tumor 
xenograft models.22 LY2606368 was well tolerated and all models were considered 
evaluable; an objective response was noted in 6 of 14 (43%) solid tumor 
xenografts. The models showing regression include neuroblastoma and 
rhabdomyosarcoma (n=3), Ewing sarcoma and desmoplastic small round cell 
tumor (DSRCT). Xenograft models showing either disease stabilization or no 
antitumor effect include osteosarcoma (n=4), retinoblastoma, rhabdomyosarcoma 
and Ewing sarcoma. Neuroblastoma cells are more sensitive to depletion or 
inhibition of CHK1 as compared to normal controls, and sensitivity correlates with 
expression of the oncogene N-MYC and elevated levels of phospho-CHK1.23 
 
The preclinical rationale for a study in pediatrics is compelling given the robust 
antitumor activity of LY2606368 in murine xenograft models of several pediatric 
tumors. 
 
 
 
 
 
 
Figure 1:  LY2606368 monotherapy in a cell 
line-derived 
alveolar 
rhabdomyosarcoma 
xenograft model.  Athymic nude mice bearing an 
alveolar rhabdomyosarcoma SJCRH-30 xenograft  
were treated with vehicle (2835015), doxorubicin 
or 
 
LY2606368 
methanesulfonate 
hydrate 
(“2940930”) beginning on day 24 after average 
tumor size reached ~ 200 mm3.  LY2606368 at a 
dose of 10 mg/kg was given during each weekly 
cycle by subcutaneous injection (SC) twice-daily 
(BID, at 12-hour intervals) for 3 consecutive days 
followed by 4 days without dosing for a total of 4 
weeks (BIDx3, rest4) x 4.  The red bar just below 
the X-axis illustrates the dosing period. Tumor 
volume measurements were taken during the 
course of the study and are plotted versus days 
following tumor cell implantation. 
 
(Courtesy of Louis Stancato, Richard Beckman, 
Eli Lilly and Company) 


 
                              
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2.2.2 
Animal Toxicology 
Preclinical studies in rats and dogs demonstrated treatment-related findings 
associated with LY2606368 were generally similar to those of a cytotoxic 
chemotherapeutic agent, with dose-limiting effects primarily related to bone 
marrow suppression and GI injury. These effects were dose-dependent. The 
hematologic effects have also been shown to be schedule-dependent. In rats, 
treatment-related neutropenia was schedule-dependent, with more severe effects 
associated with 3 consecutive days per week followed by 14 day recovery period, 
compared with a single dose the first week. Important effects on cardiovascular 
function consisting of increased heart rate and decreased blood pressure were 
attributed to LY2606368 in dogs. On the basis of these collective studies in 
animals, the dose- limiting toxicity in humans was expected to be 1 or more of the 
following: myelosuppression, gastrointestinal (GI) toxicity, tachycardia, and 
hypotension. Patients receiving LY2606368 were closely monitored for these 
potential effects.21 
 
 
2.2.3 
Preclinical Pharmacokinetic Studies 
 
2.2.3.1 Single dose studies in dogs. 
The PK of LY2606368 and LY2606368-derived radioactivity were 
evaluated in rats and dogs following an IV administration of 
[14C]LY2606368. Concentrations of LY2606368 declined rapidly in a 
monoexponential fashion following a single 1-hour IV infusion of 
[14C]LY2606368 in both rats and dogs. At Cmax, LY2606368 accounted for 
approximately 37% and 69% of the plasma radioactivity in rats and dogs, 
respectively. However, the exposure (area under the plasma concentration-
time curve [AUC] from time 0 to infinite time [AUC(0-∝)]) of 
LY2606368 accounted for approximately 16% and 2% of the radioactivity 
exposure in plasma in rats and dogs, respectively, indicating the presence 
Figure 2:  LY2606368 monotherapy in a 
patient-derived Ewing’s sarcoma xenograft 
model.  Athymic nude mice bearing an Ewing’s 
sarcoma PDX model CTG-1094  were treated with 
vehicle, 
doxorubicin 
or 
 
LY2606368 
methanesulfonate hydrate (“2940930”) beginning 
on day 24 after average tumor size reached ~ 200 
mm3.  LY2606368 at a dose of 10 mg/kg was 
given during each weekly cycle by subcutaneous 
injection (SC) twice-daily (BID, at 12-hour 
intervals) for 3 consecutive days followed by 4 
days without dosing for a total of 4 weeks (BIDx3, 
rest4) x 4.  The red bar just below the X-axis 
illustrates the dosing period. Tumor volume 
measurements were taken during the course of 
the study and are plotted versus days following 
tumor cell implantation. 
 
(Courtesy of Louis Stancato, Richard Beckman, 
Eli Lilly and Company) 


 
                              
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of circulating metabolites. Total radioactivity in plasma was followed by 
a biexponential decline with a steep alpha phase observed during the first 
8 hours post start of infusion, and a relatively longer terminal elimination 
half-life (t1/2) for the residual low levels of radioactivity. Metabolites 
appear to contribute to the longer t1/2 of radioactivity when compared with 
that of LY2606368. 
 
2.2.3.2 Repeated-dose studies in dogs. 
 
LY2606368 was administered as a 1-hour IV infusion to male and female 
dogs in doses ranging from 1 to 10 mg/kg/day and as a 2-hour IV infusion 
to male and female dogs at a dose of 40 mg/kg/day on 3 consecutive days 
per week for 3 weeks (dosed on Days 1, 2, 3, 8, 9, 10, 15, 16, and 17). 
Systemic exposures to LY2606368 were similar for male and female 
animals. No accumulation of LY2606368 in plasma was observed 
following multiple dosing. The increase in Cmax and AUC(0-24) was roughly 
dose proportional on Days 1 and 17. 
 
2.3 
Adult Studies 
 
2.3.1 
Phase 1 Studies 
LY2606368 is a novel, second generation, ATP-competitive selective inhibitor of 
Chk1/2 dual inhibitor that is in early phase clinical trials in women with breast 
cancer or ovarian cancer (ClinicalTrials.gov NCT02203513) and in patients with 
advanced solid tumors. As of 4 April 2016, 210 patients have been exposed to 
LY2606368 with PK data available from 194 patients from 3 ongoing clinical trials 
(Study JTJA, Study JTJF and Study JTJK). Study JTJA is the first-in-human Phase 
1 evaluation of LY2606368.21 In addition, the National Cancer Institute is 
sponsoring a Phase 2 study in patients with breast, ovarian or prostate cancer 
(NCT0220351). 
 
Neutropenia and febrile neutropenia are the most frequent toxicities in these 
studies and have been observed at all doses and schedules of LY2606368. 
Neutrophils counts reached their nadir on day 8 of a cycle and resulted in transient 
grade 4 neutropenia that was less than 5 days. (IB) Grade 4 neutropenia was 
observed in 66% of the adult patients treated at 105 mg/m2 every 2 weeks, and a 
total of 11% of patients experienced febrile neutropenia that was felt by 
investigators to be related to LY2606368 therapy. None of the febrile neutropenia 
events required discontinuation of the study and none were associated with an 
outcome of death.  Other hematologic toxicities included anemia (Grade 4: 0%) 
and thrombocytopenia (Grade 4: 6%). 
 
The most common non-hematologic treatment related adverse events (AEs) and 
occurring in >5% of patients treated at 105 mg/m2 every 14 days were fatigue 
(25%), nausea (12%), headache (11%), diarrhea (9%) and anorexia (8%).  The 
majority of these events were Grade 1 in severity.  
 
In non-clinical studies, LY2606368 elicited effects on the cardiovascular system 
of dogs consisting of moderate-to-severe increases in heart rate and minimal 
decreases in blood pressure. Electrocardiogram (ECG) abnormalities were also 
observed in dogs and prolongation of the QRS duration and QT intervals were 


 
                              
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observed at doses above the nonclinical MTD (>80 mg/m2). A total of 7 patients 
(6.9%) had a QT change of >30 msec from baseline. No statistically significant 
changes from baseline were observed. 
 
 
2.3.2 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
LY2606368 infused over 1 hour had a half-life (t1/2) of 10.5 hours in adults with 
advanced cancer. The major route of metabolism was by CYP450 and 75% of the 
metabolite was excreted in the feces and 11% in urine.21 The LY2606368 exposure 
increased in a dose-dependent manner across the dose range of 10 to 130 mg/m2 
on Day 1 of Cycle 1 across both schedules of administration. The mean t1/2 (range: 
8.30 to 18.3 hours) varied across days and cycles of treatment after administration 
of the recommended Phase II dose (RP2D) of 105 mg/m2. Moderate- to-large 
degree of inter-patient PK variability in LY2606368 systemic clearance has also 
been observed. However, the linear relationship between LY2606368 PK 
parameters and body surface area (BSA) from Study JTJA indicates that 
administration of LY2606368 based on BSA is an appropriate dosing paradigm. 
This is the approach we propose to use in pediatric patients. 
 
While in vitro data suggested that drug-drug interactions may be possible when 
LY62606368 is co-administered with cytochrome P450 (CYP)1A2 and CYP2D6 
substrates, minimal potential for drug-drug interactions with either substrates was 
predicted. 
 
While overexpression of Chk1 in adult non-small cell lung cancer tumor tissue has 
been correlated with poor prognosis24, phosphorylation of pChk1(S296) has been 
proposed as a potential predictive biomarker of CHk1 inhibitor sensitivity in breast 
cancer.25 We are proposing to evaluate the immunohistochemical localization of 
Chk1 as an exploratory aim to determine if this may be feasible in a Phase I 
pediatric study. 
 
2.4 
Pediatric Studies 
 
2.4.1 
Prior Experience in Children  
There have been no pediatric studies of LY2606368. 
 
 
2.4.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
 
There have been no pediatric studies of LY2606368. 
 
 
2.5 
Overview of Proposed Pediatric Study 
We propose a phase 1 study of LY2606368 in pediatric patients with recurrent/refractory 
solid tumors using a rolling 6 design.26 Based upon the published preclinical data on the 
importance of cell cycle checkpoint perturbation in tumor types carrying a variety of 
molecular lesions, we propose this phase 1 study to establish the maximum tolerated dose 
(MTD) and recommended phase 2 dose (RP2D) of LY2606368. The starting dose selection 
is based on data from the adult study and RP2D of 105 mg/m2 once daily on Days 1 and 
15, every 28 days. The initial dose level in pediatric patients will be 80 mg/m2, which is 
approximately 80% of the adult RP2D, with one dose de-escalation for toxicity and 3 dose 
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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.). This is the same account (user id and password) used for 
credentialing in the CTSU members’ web site (refer to Appendix X for CTEP and CTSU 
registration procedures). 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. 
 
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 or local IRB approval of this study must be obtained by a 
site prior to enrolling patients. Sites must submit CIRB/IRB approvals to the NCI’s Cancer 
Trials Support Unit (CTSU) Regulatory Office and allow 3 business days for processing. 
The CTSU IRB Certification Form may be submitted in lieu of the signed IRB approval 
letter. All CTSU forms can be located on the CTSU web page (www.ctsu.org). Any other 
regulatory documents needed for access to the study enrollment screens will be listed for 
the study on the CTSU Member’s Website under the Regulatory Tab. 
 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 
are not required to submit separate IRB approval documentation to the CTSU Regulatory 
Office for initial, continuing or amendment review. This information will be provided to 
the CTSU Regulatory Office from the CIRB at the time the site’s Signatory Institution 
accepts the CIRB approval. The Signatory site may be contacted by the CTSU Regulatory 
Office or asked to complete information verifying the participating institutions on the 
study. 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
 


 
                              
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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 1100 
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 in the OPEN 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) the COG screening protocol, b) an IRB-
approved institutional screening protocol or c) the study-specific protocol.  Documentation 
of the informed consent for screening will be maintained in the patient’s research chart. 
Studies or procedures that were performed for clinical indications (not exclusively to 
determine eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
3.7 
Eligibility Checklist 


 
                              
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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 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 re-check is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging 
studies must be obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging 
if necessary). For patients whose disease is evaluated with a bone marrow examination, the bone 
marrow aspirates and biopsies are required within 14 days prior to the start of chemotherapy. 
 
 
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 


 
                              
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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 ≥ than 12 months and ≤ 21 years of age at the time of study 
enrollment. 
 
4.1.2 
Diagnosis: Patients with recurrent or refractory solid tumors, including CNS tumors, 
are eligible. Patients must have had histologic verification of malignancy at original 
diagnosis or relapse except in patients with intrinsic brain stem tumors, optic 
pathway gliomas, or in patients with pineal 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 and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the defined eligibility criteria are met, e.g. blood count criteria, 
the patient is considered to have recovered adequately. 
 
a. Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive. See DVL homepage for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 
of this interval must be discussed with the Study Chair and the study-
assigned Research Coordinator prior to enrollment. 
• 
≥ 21 days after the last dose of cytotoxic or myelosuppressive 
chemotherapy (42 days if prior nitrosourea).  
 
 
b. Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥ 7 days must have 
elapsed from last dose of agent. See DVL homepage for commercial 
and Phase 1 investigational agent classifications. For agents not listed, 


 
                              
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the duration of this interval must be discussed with the study chair and 
the study-assigned Research Coordinator prior to enrollment.  
 
c. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1. 
 
d. Corticosteroids: See Section 4.2.2.1. If used to modify immune 
adverse events related to prior therapy, ≥ 14 days must have elapsed 
since last dose of corticosteroid. 
 
e. Hematopoietic growth factors: ≥ 14 days must have elapsed since the 
last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days 
for short-acting growth factor. For agents that have known adverse 
events occurring beyond 7 days after administration, this period must 
be extended beyond the time during which adverse events are known 
to occur. The duration of this interval must be discussed with the Study 
Chair and the study-assigned Research Coordinator. 
 
f. Interleukins, Interferons and Cytokines (other than Hematopoietic 
Growth Factors): ≥ 21 days must have elapsed since the completion of 
interleukins, interferon or cytokines (other than Hematopoietic 
Growth Factors). 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥ 84 
days must have elapsed after infusion, and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion:  ≥ 42 days 
must have elapsed after completion. 
 
h. Cellular Therapy: ≥ 42 days must have elapsed since the completion 
of any type of cellular therapy (e.g. modified T cells, NK cells, 
dendritic cells, etc.). 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days must 
have elapsed after local XRT; ≥ 150 days after TBI, craniospinal XRT 
or if radiation to ≥ 50% of the pelvis; ≥ 42 days if other substantial 
BM radiation. 
 
j. 
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 
131I-
MIBG): ≥ 42 days must have elapsed since systemically administered 
radiopharmaceutical therapy. 
 
k. Patients must not have received prior exposure to LY2606368. 
 
 
 
4.1.7 
Organ Function Requirements 
 


 
                              
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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 ≥ 75,000/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 PRBC 
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: 
- 
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 regardless of baseline. 
- 
SGPT (ALT) ≤ 135 U/L (3x ULN).  For the purpose of this study, the 
ULN for SGPT is 45 U/L regardless of baseline.  
- 
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 
- 
QTc ≤ 480 msec 
 


 
                              
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Note:  Patients should avoid concomitant medication known or suspected 
to prolong QTc interval or cause Torsades De Pointes. If possible, 
alternative agents should be considered. 
Patients who are receiving drugs that prolong the QTc are eligible if the 
drug is necessary and no alternatives are available. See Appendix IV for 
drugs that may prolong the QTc. 
 
4.1.7.5 Adequate Neurologic Function Defined as: 
- 
Patients with seizure disorder may be enrolled if on anticonvulsants 
and well controlled. 
- 
Nervous system disorders (CTCAE v5) resulting from prior therapy 
must be ≤ Grade 2 with the exception of decreased tendon reflex 
(DTR). Any grade of decreased tendon reflex is eligible. 
- 
For patients with CNS tumors, any baseline neurologic deficit, 
including seizures, must be stable for at least one week prior to 
initiating study treatment. 
 
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 8.4 if available. If tissue blocks or 
slides are unavailable, the study chair must be notified prior to study 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 an effective contraceptive method both during and for 3 months after 
participation in this study. Abstinence is an acceptable method of contraception. 
 
4.2.2 
Concomitant Medications 
 
4.2.2.1 Corticosteroids: Patients receiving corticosteroids must have been on a 
stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment. If used to modify immune adverse events related to prior 
therapy, ≥ 14 days must have elapsed since last dose of corticosteroid (See 
Section 4.1.6.1.d). 
 
4.2.2.2 Investigational Drugs: Patients who are currently receiving another 
investigational drug are not eligible. 
 
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 
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disease post bone marrow transplant are not eligible for this trial. 
 
4.2.2.5 Strong CYP1A2 Inhibitors: Patients must not have received strong 
CYP1A2 inhibitors (ciprofloxacin, fluvoxamine, zafirlukast) for at least 7 
days prior to enrollment and must not receive them for the duration of the 
study. 
 
4.2.2.6 Infection:  Patients who have an uncontrolled infection are not eligible. 
 
4.2.2.7 Patients who have received a prior solid organ transplantation are not 
eligible. 
 
4.2.2.8 Patients with a history of allergic reactions attributed to compounds of 
similar chemical or biologic composition to LY2606368 or to its 
formulation are not eligible. 
 
4.2.2.9 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 
 
Day 1 
Day 15 
Day 28 
LY2606368 IV 
LY2606368 IV 
End of Cycle/Evaluation 
 
 
LY2606368 will be administered intravenously over 60 minutes on Days 1 and 15 of a 28 
day cycle. A cycle may be repeated for a total of 13 cycles, up to a total duration of therapy 
of approximately 12 months. 
 
Drug doses should be adjusted based on the BSA calculated from height and weight 
measured within 7 days prior to the beginning of each cycle. 
 
Criteria for delaying or omitting the Day 15 dose of LY2606368 are specified in Section 
6.1. 
 
Patients should be monitored for signs and symptoms of infusion reactions during 
LY2606368 administration and for 30 minutes after the flush completion. See Section 6.3.4 
for management guidelines for infusion reactions. 
 
 
5.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease and has 
again met laboratory parameters as defined in the eligibility section, Section 4.0.  
 
5.3 
Dose Escalation Schema 
 
5.3.1 
Inter-Patient Escalation 


 
                              
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The starting dose of LY2606368 will be 80 mg/m2 (dose level 1) with dose levels 
for subsequent groups of patients as follows. 
 
Dose Level 
LY2606368 (mg/m2) 
0 
60 
1* 
80 
2 
100 
3 
125 
4 
150 
* Starting Dose Level 
 
There will be no escalations beyond dose level 4 (150 mg/m2), as previous pediatric 
Phase 1 studies have rarely defined a MTD greater than 160% of the adult MTD. 
 
If the MTD has been exceeded at the first dose level, then the subsequent cohort 
of patients will be treated at a dose of 60 mg/m2 (dose level 0). If dose level 0 is 
not well tolerated, further de-escalation will not occur. The study will be closed to 
accrual. 
 
5.3.2 
Intra-Patient Escalation 
There will not be intra-patient dose escalation.  
 
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 website (http://ctep.cancer.gov). 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 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 greater non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
• Grade 3 nausea and vomiting < 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 and the ULN for AST is defined as 50 
U/L. Adverse event grades will be based on increases above the 
upper limit of normal, regardless of the subject’s baseline. See 
Appendix IX for values that represent thresholds between CTCAE 
grades. 
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• Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to supplementation. 
 
5.5.1.2 Non-hematological toxicity that causes a delay of ≥ 14 days between 
treatment cycles. 
 
5.5.1.3 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: 
• 
Day 15:  
o Grade 4 neutropenia or Grade 3 thrombocytopenia (platelets 
< 50,000/mm3) that does not resolve to ANC ≥ 500/mm3 and 
platelets ≥ 50,000/mm3 (transfusion independent) by Day 18 will 
be considered dose-limiting (See Section 6.1). 
• 
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 Note:  Grade 3 or 4 febrile neutropenia will not be considered a dose-
limiting toxicity. 
 
 
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 Day 15 Dosing due to Toxicity on Day 15 
 
6.1.1 
Hematologic Toxicity 
 
6.1.1.1 Patients who have Grade 4 neutropenia or Grade 3 thrombocytopenia 
(platelets < 50,000/mm3) on Day 15 will have their dose withheld. If the 
toxicity resolves to ANC ≥ 500/mm3 and platelets ≥ 50,000/mm3 
(transfusion independent) by Day 18, the dose may be given. If the toxicity 
does not resolve to ANC ≥ 500/mm3 and platelets ≥ 50,000/mm3 by Day 
18, the dose will be omitted and this will be considered a DLT. Patients 
should receive subsequent cycles of drug per Section 6.2. Patients who 
require that their Day 15 dose be omitted for Grade 4 neutropenia or Grade 
3 platelets (< 50,000/mm3) after two dose reductions must be removed 
from protocol therapy. 
 
6.1.1.2 Patients who meet hematological DLT criteria as defined in Section 
5.5.2.1 on Day 15 will have their Day 15 dose omitted. Patients should 
receive subsequent cycles of drug per Section 6.2 after their toxicity 
resolves, no sooner than the planned start of the subsequent cycle. Patients 


 
                              
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who require that their Day 15 dose be omitted for hematologic DLT as 
defined in Section 5.5.2.1 after two dose reductions must be removed from 
protocol therapy. 
 
6.1.2 
Non-Hematologic Toxicity 
 
 
 
 
6.1.2.1 Patients who have Grade 3 or Grade 4 non-hematological toxicity 
attributable to the study drug prior to the Day 15 dose (with the exception 
of the DLT exclusions in Section 5.5.1.1) will be considered to have had 
a DLT. If the toxicity resolves to meet eligibility or ≤ Grade 2 (if not part 
of eligibility criteria) by Day 15, the dose may be given but at the next 
lower dose level. 
 
6.1.2.2 Patients who have Grade 3 or Grade 4 non-hematological toxicity 
attributable to the study drug on Day 15 prior to dosing (with the exception 
of the DLT exclusions in Section 5.5.1.1) will have their dose withheld 
and this will be considered a DLT. If the toxicity resolves to meet 
eligibility or ≤ Grade 2 (if not part of eligibility criteria) by Day 18, the 
dose may be given but at the next lower dose level. If the toxicity does not 
resolve by Day 18, the dose will be omitted. Patients should receive 
subsequent cycles of drug but with dose modifications according to 
Section 6.3. 
 
 
6.2 
Dose Modifications for Hematological Toxicity 
 
6.2.1 
Patients who have dose-limiting thrombocytopenia should receive subsequent cycles 
at the next lower dose level. 
 
6.2.2 
Patients who have dose-limiting neutropenia with no other dose-limiting toxicity 
should receive the same dose in the next cycle with myeloid growth factor support. 
[Note: Patients MUST NOT receive prophylactic myeloid growth factor in the first 
cycle of therapy (See Section 7.4).] If dose-limiting neutropenia recurs after myeloid 
growth factor is added, then the patient should be given the next lower dose level for 
subsequent cycles. If dose-limiting neutropenia recurs in a patient that has received 
a dose level reduction but has not received myeloid growth factor, then myeloid 
growth factor should be administered. Patients who experience dose-limiting 
neutropenia after the addition of myeloid growth factor and one dose reduction must 
be removed from protocol therapy. 
 
6.2.3 
Patients who meet hematological DLT criteria as defined in Section 5.5.2.1 on Day 
15 and have their Day 15 dose omitted will begin the subsequent cycle at the planned 
start of that cycle, if their toxicity has resolved. 
 
6.2.4 
Patients who experience dose-limiting thrombocytopenia after two dose reductions 
or dose-limiting neutropenia after addition of myeloid growth factor and one dose 
reduction must be removed from protocol therapy. 
 
6.2.5 
Patients who have a dose-limiting hematological toxicity that does not resolve to 
eligibility parameters within 21 days after the planned start of the next treatment 
cycle must be removed from protocol therapy. 


 
                              
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6.2.6 
No dose reduction beyond dose level 0 is allowed. 
 
6.3 
Dose Modifications for Non-Hematological Toxicity 
 
6.3.1 
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 doses at the next lower dose 
level.  
 
6.3.2 
If the same non-hematological dose-limiting toxicity recurs after one dose reduction, 
the patient must be removed from protocol therapy. 
 
6.3.3 
Patients who have a dose-limiting non-hematological toxicity that does not resolve 
to baseline or eligibility within 21 days after the planned start of the next treatment 
cycle must be removed from protocol therapy. 
 
6.3.4 
No dose reduction beyond dose level 0 is allowed. 
 
6.3.5 
Infusion Reactions:  Patients experiencing an infusion reaction should be treated as 
per institutional guidelines. For subsequent infusions, premedication with 
diphenhydramine 0.5-1 mg/kg (max 50 mg) and/or other premedications may be 
considered at investigators discretion. The infusion rate may also be decreased by 
50%. Patients should be monitored for signs and symptoms of infusion reactions with 
subsequent infusions. 
 
 
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 4.2.2.5 for drugs that should not be 
used concomitantly due to potential interactions with LY2606368. Drugs that prolong the QTc 
may be used only if the drug is necessary and no alternatives are available. See Appendix IV 
for drugs that may prolong the QTc. 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered in accordance with Section 6.2.2 or for culture proven bacteremia or invasive 
fungal infection. G-CSF may be used only after completion of cycle 1 and may be given 
24 hours after the administration of the dose on day 1 and day 15. G-CSF administration 
must be stopped 7 days prior to initiation of the subsequent cycle. 
The Study Chair should be notified before growth factors are initiated. 


 
                              
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7.5 
Concomitant Medications 
 
7.5.1 
Drugs that prolong the QTc may be used only if the drug is necessary and no 
alternatives are available. See Appendix IV for drugs that may prolong the QTc. 
 
7.5.2 
Sensitive CYP1A2 substrates (alosetron, caffeine, duloxetine, melatonin, 
ramelteon, tasimelteon, theophylline, tizanidine) may be used, but should be 
recorded as concomitant medications. 
 
 
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 
Prior to Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
Neurologic Exam 
X 
 
X 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
 
CBC, differential, platelets 
X 
Twice Weekly 
(every 3 to 4 days)3 
Weekly4 
Pharmacokinetics1 
X 
X 
 
Electrolytes including Ca2+, PO43-, Mg2+ 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Albumin 
X 
 
X 
Tumor Disease Evaluation 
X 
End of Cycle 1 
Every other cycle x 2 
then q 3 cycles 5 
Bone Marrow Evaluation6 
X 
X 
Every other cycle x 2 
then q 3 cycles6 
Pregnancy Test2 
X 
 
 
ECHO or gated radionuclide study 
X 
 
 
EKG9 
X 
X 
X9 
Tumor Tissue Submission7 
X 
 
 
Correlative Biology Studies (optional)8 
X 
X 
 


 
                              
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^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle, unless otherwise 
specified within the table. 
1 
See Section 8.3 for timing and details of pharmacokinetic (PK) studies. 
2 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually 
active patients must use an acceptable method of birth control during the study and for 3 months after 
participation in this study. Abstinence is an acceptable method of birth control. 
3 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery 
to Grade 3 or until meeting the criteria for dose-limiting toxicity. 
4 
If patients develop Grade 4 neutropenia then CBCs should be checked every 3 to 4 days until recovery 
to Grade 3 
5 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation 
of either a PR or CR. Subsequent scans may restart 2 cycles after the confirmatory scan. Please note that 
for solid tumor patients, if the institutional investigator determines that the patient has progressed based 
on clinical or laboratory evidence, he/she may opt not to confirm this finding radiographically. 
6 
If a solid tumor patient is suspected to have or has a history of bone marrow involvement then a pre-
study bone marrow biopsy and/or aspirate is required. This should then be repeated with each tumor 
disease evaluation. 
7 
See Section 8.4 for details regarding tumor tissue submission for the required and optional studies. If 
tissue blocks or slides are unavailable, the study chair must be notified prior to study enrollment. 
8 
See Section 8.5 for timing and details regarding correlative biology studies. 
9 
EKGs to be performed at baseline, and then immediately prior to and one hour after each infusion of 
LY2606368 is complete for the first 2 cycles. For subsequent cycles, EKGs are to be obtained as 
clinically indicated. 
 
8.2 
Radiology Studies 
 
Patients who respond (CR, PR) to therapy or have long term stable disease (SD) 
(≥ 6 cycles) on protocol therapy will be centrally reviewed. COG Operations 
Center will notify the Imaging Center of any patient requiring central review. The 
Imaging Center will then request that the treating institution forward the requested 
images for central review. The central image evaluation results will be entered into 
RAVE for review by the COG Operations Center and for data analysis.  
 
The images are to be forwarded electronically to the Imaging Research Center at 
Children’s Hospital Los Angeles via the ImageInBox. 
 
COG institutions that are not connected via the ImageInBox can send the images 
on CD ROM or USB flash drive. Submitted imaging studies should be clearly 
marked with the COG patient ID, study number (STUDY #ADVL1515) and date 
and shipped to Syed Aamer at the address below: 
 
Syed Aamer, MBBS, CRP 
Administrator, Imaging Research Center 
Children’s Hospital Los Angeles  
4650 Sunset Boulevard, MS # 81 
Los Angeles, CA 90027 
Phone: (323) 361-3898 
Fax: 
(323) 361-3054 
E-mail: saamer@chla.usc.edu 
 
 
8.3 
Pharmacology 
 


 
                              
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8.3.1 
Description of Studies and Assay 
Pharmacokinetics (PK) will be performed to determine the PK of LY2606368 in 
children. Plasma will be collected and LY2606368 concentrations will be 
determined by a validated LC/MS/MS method. Samples will be analyzed by 
Covance Laboratories. 
 
8.3.2 
Sampling Schedule (See Appendix V) 
Blood samples will be obtained at the following time points:  
Day 1: pre-dose, and at 1 (end of infusion), 1.5, 2, 4, and 8 hours after beginning 
the infusion. 
Day 2: 24 hrs. (± 2 hrs.) after beginning the infusion.  
Day 5 (± 1): 96 hrs. (± 24 hrs.) after beginning the infusion.  
Day 8: During CBC evaluation  
Day 15: pre-dose and end of infusion (1 hour after beginning the infusion). 
 
8.3.3 
Sample Collection and Handling Instructions 
Blood samples (2 -3 ml) will be collected in K2EDTA or K3EDTA 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 
start and stop time of the infusion. 
 
8.3.4 
Sample Processing 
1. Invert the tube gently at least 8 to 10 times to ensure mixing of the K2EDTA or 
K3EDTA and blood.  
2. Immediately after collection place K2EDTA or K3EDTA tube on ice or at 4°C 
for no longer than 30 minutes.  
3. Centrifuge tube within 30 minutes of collection at 2000 g for 10 minutes at 4°C 
until red cells and plasma are well separated.  
4. Transfer the plasma to cryovials. Do not transfer the buffy coat or any of the red 
cell pellet into the plasma sample as this will render the sample unusable for 
analysis.  
5. Immediately after transfer of the plasma to cryovials, freeze the plasma samples 
on dry ice, snapfreeze in liquid nitrogen, or place directly into a -70°C freezer. 
6. Store in -70°C freezer until shipment. 
 
8.3.5 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn. Data should be recorded on the 
Pharmacokinetic Study Form, which must accompany the sample(s). 
 
8.3.6 
Sample Shipping Instructions 
Samples should be stored at -70°C until shipping, batched per patient and shipped 
frozen on dry ice in opaque containers at the end of Cycle 1. Shipments should only 
be sent out on Monday through Thursday via Fedex priority overnight to the 
following address: 
 
Covance Bioanalytical Laboratory Services Inc. 
3301 Kinsman Boulevard 
Madison, WI 53704-2523 
Attn: Sample Management – Bioanalytical (Rm131D 1S) 


 
                              
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Call the Covance Bioanalytical Services Sample Management department on the day 
prior to shipment (1-888-541-7377 Ext 2540, Ext 2187, or Ext 2327), as notification 
of the intended shipment, or e-mail madison.SA@covance.com with shipment 
information (tracking numbers and number of boxes to be sent). 
 
Please note the Covance study #8366627 for this study. 
 
For further guidance, please see the sample shipping guidelines provided by Covance 
attached to the memo dated July 4th 2017.  
 
8.4 
Tissue Studies (required) 
Archival tumor tissue should be submitted for all patients. If a patient does not have tissue 
available, the study chair must be notified prior to enrollment. 
 
8.4.1 
Description of Studies 
 
8.4.1.1 CHK 1/2 Expression 
Tissue will be collected either from diagnosis or relapse to evaluate 
CHK1/2 expression in pediatric solid tumors prior to treatment with 
LY2606368. Tumor tissue will be analyzed by immunohistochemistry. 
 
8.4.1.2 TP53 Deletion/Mutation 
Tissue will be collected either from diagnosis or relapse to evaluate for a 
deletion and/or mutation of TP53 by immunohistochemistry and/or 
sequencing. 
 
8.4.2 
Sample Collection, Handling, and Shipment 
Paraffin-embedded tissue blocks or slides will be shipped to Dr. Cynthia Wetmore 
at Phoenix Children’s Hospital. Detailed instructions regarding collection, 
handling, and shipping of tissue samples are located in Appendix VI. 
 
8.4.3 
Sample Labeling 
Each sample must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was taken. Data should be recorded on the 
Tissue Study Form, which must accompany the sample(s). 
 
8.5 
Correlative Biology Studies (optional) 
 
8.5.1 
Description of Studies 
Peripheral blood mononuclear cells (PBMCs) will be evaluated in consenting 
patients for autophosphorylation of Chk1 and H2AX using immunohistochemistry 
and/or phospho-flow cytometry. 
 
8.5.2 
Sampling Schedule (See Appendix VII) 
Blood samples (5 ml) will be collected at baseline prior to infusion and at 24 hours 
after start of infusion (at time of PK sample collection). 
 
8.5.3 
Sample Collection and Handling Instructions 


 
                              
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Blood samples (5 ml) will be collected in CPT tubes at a site distant from the 
infusion for pharmacodynamic evaluation. Record the exact time that the sample 
is drawn along with the exact time that the drug was administered. 
 
8.5.4 
Sample Processing 
Instructions for isolating PBMCs can be found in Appendix VIII. PBMCs should 
be kept on ice or refrigerated and processed within 1 hour of collection. Samples 
should be frozen standing upright in a rack or box to ensure that samples do not 
freeze to the sides and cap of the tube. Whenever possible, sites should use standard 
cryovials (i.e. volumes ≤ 2.0 mL) that can fit in a standard 81-place freezer box. 
 
8.5.5 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D., the date and time the sample was drawn, and the type of sample (either PMBC 
or plasma). Data should be recorded on the Correlative Study Form, which must 
accompany the sample(s).  
 
8.5.6 
Sample Shipping Instructions 
Samples should only be sent between Monday and Wednesday to ensure that 
sample shipments arrive at the lab during the work week. Please send an email 
confirmation prior to shipment to CCTDC@emory.edu while copying the study 
specific research coordinator. This email should include the patient ID, tracking 
number, and the name of the shipping site. 
 
Frozen samples may be batched and shipped together on dry ice to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
                              
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9.0 
AGENT INFORMATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.5 
 
 
 
 
 
 
 
 
 
 
 


 
                              
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9.1.6 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
                              
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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.2 
 
 
 
 
 
 
 
 
 


 
                              
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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 13.0). 
c) 
Refusal of protocol therapy by patient/parent/guardian 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Completion of 13 cycles of therapy. 
f) 
Physician determines it is not in the patient’s best interest. 
g) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of LY2606368 (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.  
 


 
                              
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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  
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
A minimum of 4 patients will be enrolled in this study. The expected maximum number of 
evaluable patients required to estimate the MTD/RP2D is 24. Once the MTD or 
recommended Phase 2 dose has been defined, up to 6 additional patients with recurrent or 
refractory solid tumors without restrictions on heme evaluability may be enrolled to acquire 
PK data in a representative number of young patients (i.e. patients < 12 years old). 
Therefore, a maximum of 36 patients are expected to be enrolled which allows for 6 
patients at each of 4 dose levels, 6 additional patients enrolled at the MTD/RP2D for PK 
analysis, and a 20% inevaluable rate. Review of the enrollment rate into previous COG 
new agent studies indicates that 1-2 patients per month are available, which will permit 
completion of the study within 18-36 months. An absolute maximum of 65 patients is 
anticipated in the unlikely scenario that each of 4 dose levels is expanded to 12 patients 
due to different classes of AEs, 6 additional patients are enrolled at the MTD for PK 
analysis, and a 20% inevaluable rate. The absolute maximum would require about 33-65 
months for completion. 
 
 
11.2 
Definitions 
 
11.2.1 Evaluable For Adverse Events 
Any patient who receives at least one dose of the study drug(s) and/or who 
experiences a dose-limiting toxicity is considered evaluable for Adverse Events. 
In addition, for the dose-escalation portion during Cycle 1, patients must receive 
at least 85% of the prescribed dose per protocol guidelines and must have the 
appropriate toxicity monitoring studies performed to be considered evaluable for 
dose limiting toxicity. Patients who do not have DLT and are not considered 
evaluable for toxicity 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.  
 


 
                              
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• 
In the unlikely event that two DLTs observed out of 6 evaluable patients are 
different 
classes 
of 
Adverse 
Effects 
(e.g. 
hepatotoxicity 
and 
myelosuppression), AND all of the following conditions are met, expansion 
of the cohort to 12 patients will be considered:  
 
•  One of the DLTs does not appear to be dose-related 
•  The Adverse Effects are readily reversible 
•  The study chair, DVL statistician, DVL committee chair or vice chair, and 
IND sponsor all agree that expansion of the cohort is acceptable 
 
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting 
toxicities, the dose escalation can proceed. 
 
• 
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.  
 
 
11.3 
Dose Escalation and Determination of MTD 
 
The rolling six phase 1 trial design will be used for the conduct of this study.26 Two to six 
patients can be concurrently enrolled onto a dose level, dependent upon (1) the number of 
patients enrolled at the current dose level, (2) the number of patients who have experienced 
DLT at the current dose level, and (3) the number of patients entered but with tolerability 
data pending at the current dose level. Accrual is suspended when a cohort of six has 
enrolled or when the study endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in the 
cohort, the number of DLTs observed, and the number of participants at risk for developing 
a DLT (i.e., participants enrolled but who are not yet assessable for toxicity). For example, 
when three participants are enrolled onto a dose cohort, if toxicity data is available for all 
three when the fourth participant entered and there are no DLTs, the dose is escalated and 
the fourth participant is enrolled to the subsequent dose level. If data is not yet available 
for one or more of the first three participants and no DLT has been observed, or if one DLT 
has been observed, the new participant is entered at the same dose level. Lastly, if two or 
more DLTs have been observed, the dose level is de-escalated. This process is repeated for 
participants five and six. In place of suspending accrual after every three participants, 
accrual is only suspended when a cohort of six is filled. When participants are inevaluable 
for toxicity, they are replaced with the next available participant if escalation or de-
escalation rules have not been fulfilled at the time the next available participant is enrolled 
onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the current dose 
level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the study 
is suspended to accrual: 
 
 
# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 


 
                              
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2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
3 
0 
3 
0 
Escalate** 
 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
 
4 
0 
4 
0 
Escalate** 
 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
 
5 
0 
5 
0 
Escalate** 
 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
* If six patients already entered at next lower dose level, the MTD has been defined. 
**If final dose level has been reached, the recommended dose has been reached. 
 
If two or more of a cohort of up to six patients experience DLT at a given dose level, then 
the MTD has been exceeded and dose escalation will be stopped (see Section 11.2.2 for 
exception to rule). 
 
In addition to determination of the MTD, a descriptive summary of all toxicities will be 
reported. 
 
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. 
 
 


 
                              
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The gender and minority distribution of the study population is projected to be1: 
 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American 
Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
2 
2 
0 
0 
4 
Native 
Hawaiian or 
Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or 
African 
American 
4 
7 
0 
0 
11 
White 
16 
26 
4 
3 
49 
More Than 
One Race 
1 
0 
0 
0 
1 
Total 
23 
35 
4 
3 
65 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
 
A descriptive analysis of pharmacokinetic (PK) parameters of LY2606368 will be 
performed to define systemic exposure, drug clearance, and other pharmacokinetic 
parameters. The PK parameters will be summarized with simple summary statistics, 
including means, medians, ranges, and standard deviations (if numbers and distribution 
permit).   
 
While the primary aim of this study is to evaluate the toxicity of LY2606368, patients will 
have disease evaluations performed as indicated in Section 8.1. Disease response will be 
assessed according to RECIST criteria for patients with solid tumors, and will be reported 
descriptively. 
 
All these analyses will be descriptive and exploratory and hypotheses generating in nature. 
 
 
 
                                                 
1These distributions are based on historical Phase 1 enrollments. 


 
                              
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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 website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
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 on the next consecutive cycle 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).27 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.  
 
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 
must show definitive evidence of progression to be considered 
measurable. 
 
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 


 
                              
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by CT scan (CT scan slice thickness no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
12.2.2.3 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter < 10 mm or pathological lymph nodes 
with ≥ 10 to < 15 mm short axis), are considered non-measurable 
disease. 
 
Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
12.2.2.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion that can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
 
12.2.2.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
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. 


 
                              
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Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
12.2.3.1 Clinical lesions: Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
12.2.3.2 Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  
However, CT is preferable.  
 
12.2.3.3 Conventional CT and MRI: This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body 
scans). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  
 
12.2.3.4 PET-CT: At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
12.2.3.5 Tumor markers: Tumor markers alone cannot be used to assess response. 
If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.  
 
12.2.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.2.3.7 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
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:  


 
                              
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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. 
 
 
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 
 


 
                              
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Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
12.2.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note: If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, 
not a single lesion increase. 
 
12.2.5 Overall Response Assessment 
 
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥ 28 days Confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
≥ 28 days Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once ≥ 
28 days from baseline 
PD 
Any 
Yes or No 
PD 
 
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. 


 
                              
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**  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
 
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Table 4: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
12.2.6 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. 
 
12.3 
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 


 
                              
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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. 
 
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 8.2 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: 


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


 
                              
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12.4.5 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 from the sequence of the 
overall response assessments as described in Table 3 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 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. 
 


 
                              
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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. 
 
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. 


 
                              
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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 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 


 
                              
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PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
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). 
 
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. 
 
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. 
 
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. The 
descriptions and grading scales found in the revised CTCAE version 5.0 will be 
used 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 


 
                              
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from 
the 
CTEP 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
Step 2:  Grade the adverse event using the NCI CTCAE version 5.0. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
There are any protocol-specific exceptions to the reporting requirements.  
 
Note:  This includes all events that occur within 30 days of the last dose of protocol 
treatment.  Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the 
agent(s) must also be reported according to the instructions in the table 
below. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
 


 
                              
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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 hrs 
7 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol-specific exceptions to expedited reporting of serious adverse events are found below under the 
section entitled “Additional Instructions or Exceptions.” 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific 
expedited adverse event reporting exclusions. 
 


 
                              
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• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 
birth defects must be reported via CTEP-AERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 1 
Trials Utilizing an Agent under a CTEP-IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not clearly due 
to progressive disease must be reported via CTEP-AERS for an agent under a CTEP or non-CTEP 
IND agent per the timelines outlined in the table above. 
 
• Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), does 
not require expedited reporting, unless it is associated with hospitalization. 
Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD/LYMPHATICS DISORDERS 
Anemia 
 
• 
Grade 1 and 2 adverse events listed in the table below do not require expedited reporting via CTEP-
AERS: 
 
Category 
Adverse Events 
BLOOD AND LYMPHATIC 
SYSTEM DISORDERS 
Edema (limbs) 
GASTROINTESTINAL DISORDERS 
Constipation 
GASTROINTESTINAL DISORDERS 
Diarrhea 
GASTROINTESTINAL DISORDERS 
Dry mouth 
GASTROINTESTINAL DISORDERS 
Nausea 
GASTROINTESTINAL DISORDERS 
Vomiting 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS 
Fatigue 
GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS 
Fever 
GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS 
Neck pain 
GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS 
Headache 


 
                              
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GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS 
Febrile Neutropenia 
INVESTIGATIONS 
Alanine aminotransferase increased 
INVESTIGATIONS 
Aspartate aminotransferase increased 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
METABOLISM AND NUTRITION DISORDERS 
Dehydration 
MUSCULOSKELETAL AND 
CONNECTIVE TISSUE DISORDERS 
Myalgia 
NERVOUS SYSTEM DISORDERS 
Dizziness 
PSYCHIATRIC DISORDERS 
Insomnia 
RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS 
Dyspnea 
RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS 
Cough 
SKIN AND SUBCUTANEOUS 
TISSUE DISORDERS 
Rash 
 
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) to NCI via 
the web at http://ctep.cancer.gov (telephone CTEP at: 301-897-7497 within 24 hours of 
becoming aware of the event if the CTEP-AERS 24-Hour Notification web-based 
application is unavailable) and by telephone call to the Study Chair. Once internet 
connectivity is restored, a 24-hour notification phoned in must be entered electronically 
into CTEP-AERS by the original submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 
• 
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page https://eapps-
ctep.nci.nih.gov/ctepaers. 
 
13.3 
Expedited Reporting Methods  
 
13.3.1 CTEP-AERS Reporting 
To report adverse events in an expedited fashion use the CTEP Adverse Event 
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 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm. 
If prompted to enter a sponsor email address, please use: 
PEPCTNAERS@childrensoncologygroup.org. 
Email supporting documentation to the ADVL1515 COG Research Coordinator. 


 
                              
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ALWAYS include the ticket number on all emailed documents. 
 
13.4 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG case report 
forms and do not alter the guidelines for CTEP-AERS reporting. 
 
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) 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). 
 
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 to the 
Investigational Drug Branch (IDB) of the NCI Cancer Therapy Evaluation Program 
(CTEP) 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. 
 
 


 
                              
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Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
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 
ADVL1515 COG Study Assigned Research Coordinator along with any additional medical 
information (Appendix III). 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 
• 
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. 
 


 
                              
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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 pregnancy or pregnancy 
in partners 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.  
 
 
 
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 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data. Reports are due January 31, April 30, July 31 
and October 31. Instructions for submitting data using the CDUS can be found on the CTEP 
Website (http://ctep.cancer.gov/reporting/cdus.html). 


 
                              
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Note: If this study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified 
above. If this study has been assigned to CDUS-abbreviated reporting, no adverse 
event reporting (routine or expedited) is required to be reported via CTEP-AERS. 
This is not a responsibility of institutions participating in this trial. 
 
 
14.3 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.3.1 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 chairs will be responsible for working with the study statistician to 
prepare study reports for review by the DSMC. The DSMC will provide 
recommendations to the COG PEP-CTN Chair and the Group Chair for each study 
reviewed to change the study or to continue the study unchanged. Data and Safety 
Committee reports for institutional review boards can be prepared using the public 
data monitoring report as posted on the COG Web site. 
 
14.3.2 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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REFERENCES 
 
1. 
Kastan MB: DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes 
Memorial Award Lecture. Mol Cancer Res 6:517-24, 2008 
2. 
Ferrao PT, Bukczynska EP, Johnstone RW, et al: Efficacy of CHK inhibitors as single agents in MYC-driven 
lymphoma cells. Oncogene 31:1661-72, 2012 
3. 
Bucher N, Britten CD: G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of 
cancer. Br J Cancer 98:523-8, 2008 
4. 
Tang Y, Dai Y, Grant S, et al: Enhancing CHK1 inhibitor lethality in glioblastoma. Cancer Biol Ther 13:379-
88, 2012 
5. 
Zachos G, Gillespie DA: Exercising restraints: role of Chk1 in regulating the onset and progression of 
unperturbed mitosis in vertebrate cells. Cell Cycle 6:810-3, 2007 
6. 
Feijoo C, Hall-Jackson C, Wu R, et al: Activation of mammalian Chk1 during DNA replication arrest: a role 
for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. J Cell Biol 154:913-23, 2001 
7. 
Liu Q, Guntuku S, Cui XS, et al: Chk1 is an essential kinase that is regulated by Atr and required for the 
G(2)/M DNA damage checkpoint. Genes Dev 14:1448-59, 2000 
8. 
Takai H, Tominaga K, Motoyama N, et al: Aberrant cell cycle checkpoint function and early embryonic death 
in Chk1(-/-) mice. Genes Dev 14:1439-47, 2000 
9. 
Zachos G, Rainey MD, Gillespie DA: Chk1-dependent S-M checkpoint delay in vertebrate cells is linked to 
maintenance of viable replication structures. Mol Cell Biol 25:563-74, 2005 
10. 
Niida H, Tsuge S, Katsuno Y, et al: Depletion of Chk1 leads to premature activation of Cdc2-cyclin B and 
mitotic catastrophe. J Biol Chem 280:39246-52, 2005 
11. 
McNeely S, Conti C, Sheikh T, et al: Chk1 inhibition after replicative stress activates a double strand break 
response mediated by ATM and DNA-dependent protein kinase. Cell Cycle 9:995-1004, 2010 
12. 
Vera J, Raatz Y, Wolkenhauer O, et al: Chk1 and Wee1 control genotoxic-stress induced G2-M arrest in 
melanoma cells. Cell Signal 27:951-60, 2015 
13. 
Maya-Mendoza A, Petermann E, Gillespie DA, et al: Chk1 regulates the density of active replication origins 
during the vertebrate S phase. EMBO J 26:2719-31, 2007 
14. 
Petermann E, Woodcock M, Helleday T: Chk1 promotes replication fork progression by controlling 
replication initiation. Proc Natl Acad Sci U S A 107:16090-5, 2010 
15. 
Wu W, Bi C, Bence AK, et al: Abstract 1776: Antitumor activity of Chk1 inhibitor LY2606368 as a single 
agent in SW1990 human pancreas orthotopic tumor model. Cancer Research 72:1776, 2012 
16. 
McNeely SC, Burke TF, DurlandBusbice S, et al: Abstract A108: LY2606368, a second generation Chk1 
inhibitor, inhibits growth of ovarian carcinoma xenografts either as monotherapy or in combination with 
standard-of-care agents. Molecular Cancer Therapeutics 10:A108, 2011 
17. 
Calvo E, Chen VJ, Marshall M, et al: Preclinical analyses and phase I evaluation of LY2603618 administered 
in combination with pemetrexed and cisplatin in patients with advanced cancer. Invest New Drugs 32:955-
68, 2014 
18. 
Ganzinelli M, Carrassa L, Crippa F, et al: Checkpoint kinase 1 down-regulation by an inducible small 
interfering RNA expression system sensitized in vivo tumors to treatment with 5-fluorouracil. Clin Cancer 
Res 14:5131-41, 2008 
19. 
King C, Diaz HB, McNeely S, et al: LY2606368 Causes Replication Catastrophe and Antitumor Effects 
through CHK1-Dependent Mechanisms. Mol Cancer Ther 14:2004-13, 2015 
20. 
Carrassa L, Damia G: Unleashing Chk1 in cancer therapy. Cell Cycle 10:2121-8, 2011 
21. 
Eli Lilly: LY2606368 Investigator's Brochure. November 2014 
22. 
May CD, Beckmann R, Blosser W, et al: Targeting checkpoint kinase 1 (CHK1) with the small molecule 
inhibitor LY2606368 mesylate monohydrate in models of high risk pediatric cancer yields significant anti-
tumor effects. AACR, #2458, 2016.  
23. 
Cole KA, Huggins J, Laquaglia M, et al: RNAi screen of the protein kinome identifies checkpoint kinase 1 
(CHK1) as a therapeutic target in neuroblastoma. Proc Natl Acad Sci U S A 108:3336-41, 2011 
24. 
Grabauskiene S, Bergeron EJ, Chen G, et al: CHK1 levels correlate with sensitization to pemetrexed by 
CHK1 inhibitors in non-small cell lung cancer cells. Lung Cancer 82:477-84, 2013 
25. 
Bryant C, Rawlinson R, Massey AJ: Chk1 inhibition as a novel therapeutic strategy for treating triple-
negative breast and ovarian cancers. BMC Cancer 14:570, 2014 
26. 
Skolnik JM, Barrett JS, Jayaraman B, et al: Shortening the timeline of pediatric phase I trials: the rolling six 
design. J Clin Oncol 26:190-5, 2008 


 
                              
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27. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
 
 
 


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


 
                              
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APPENDIX II: CORRELATIVE STUDIES GUIDE 
 
 
 
 
 
 
Correlative Study 
 
 
Appendix 
Sample Volume 
 
 
Tube Type 
Volume per 
sample 
Total  
Cycle 1 
PK 
V 
2 - 3 ml 
22 -33 ml 
EDTA tubes 
PBMC 
VIII 
5 ml 
10 ml 
CPT tubes 
Tumor Tissue 
(Required) 
See Section 8.4 for details 
VI 
- 
- 
- 
Total Blood Volume 
32 - 43 ml 
 


 
                              
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APPENDIX III: PREGNANCY INFORMATION FORM 
 
Attach to CTEP-AERS 5-Day Report 
 
NOTE: For initial reporting email both the Pregnancy CTEP-AERS Report and this additional Pregnancy Information 
Form to the ADVL1515 COG Study Assigned Research Coordinator. For follow-up reporting, email only this Pregnancy 
Information Form to the ADVL1515 COG Study Assigned Research Coordinator (See Section 13.7). 


 
                              
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APPENDIX IV: MEDICATIONS ASSOCIATED WITH PROLONGED QTC  
 
The use of the following medications should be avoided during protocol therapy if reasonable alternatives 
exist. This is not an inclusive list. Because the lists of these agents are constantly changing, it is important 
to regularly consult frequently updated medical references. For the most current list of medications, please 
refer to the following reference: 
Woosley, RL and Romero, KA, www.Crediblemeds.org, QTdrugs List, Accession Date December 2nd, 
2016, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ 85755 
 
 
Medications that prolong QTc 
Amiodarone 
Flecainide 
Anagrelide 
Fluconazole 
Arsenic trioxide 
Haloperidol 
Azithromycin 
Ibutilide 
Chloroquine 
Methadone 
Chlorpromazine 
Moxifloxacin 
Ciprofloxacin 
Ondansetron 
Citalopram 
Pentamidine 
Clarithromycin 
Pimozide 
Disopyramide 
Procainamide 
Dofetilide 
Propofol 
Domperidone 
Quinidine  
Droperidol 
Sevoflurane 
Dronedarone 
Sotalol 
Erythromycin 
Thioridazine  
Escitalopram 
Vandetanib  
 
 
 
Medications that MAY prolong QTc 
Aripiprazole 
Lapatinib 
Bortezomib 
Lenvatinib 
Bosutinib 
Leuprolide 
Ceritinib 
Mirtazapine 
Clomipramine 
Nicardipine 
Crizotinib 
Nilotinib 
Dabrafenib 
Olanzapine 
Dasatinib 
Osimertinib 
Degarelix 
Pazopanib 
Desipramine 
Promethazine 
Dolasetron 
Risperidone 
Eribulin mesylate 
Sorafenib 
Famotidine 
Sunitinib 
Foscarnet 
Tacrolimus 
Gemifloxacin 
Vemurafenib 
Granisetron 
Venlafaxine 
Isradipine 
Vorinostat 


 
                              
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APPENDIX V:  PHARMACOKINETIC STUDY FORM 
 
COG Pt ID # _______________ 
 
 
 
Cycle 1, Day 1 Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg  
 
Body Surface Area: ______m2  
 
LY2606368 Dose Level: ______mg/m2    
LY2606368 Total Daily Dose: ______mg 
 
Blood samples (2 – 3 ml) will be collected in EDTA tubes at the following time points: Day 1 (pre-infusion, 1 
hr., 1.5 hrs., 2 hrs., 4 hrs., and 8 hrs. after beginning the infusion), Day 2 (24 hrs. [± 2 hrs.] after beginning the 
Day 1 infusion), Day 5 (96 hrs. [± 24 hrs.] after beginning the Day 1 infusion), Day 8 (during CBC evaluation), 
and Day 15 (pre-infusion and 1 hr. after beginning the Day 15 infusion) of Cycle 1. 
 
Record the exact time the sample is drawn along with the exact time LY2606368 is given on Days 1 and 15.  
 
 
 
 
 
 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time 
Sample Collected 
(24-hr clock) 
1 
Day 1 
Prior to Day 1 LY2606368 infusion 
___/___/___ 
|__|__| : |__|__| 
LY2606368 Infusion on Day 1  Date:___/___/___   Start Time: |__|__| : |__|__|   
End Time: |__|__| : |__|__| 
2 
Day 1 
1 hr. after beginning Day 1 
LY2606368 infusion 
___/___/___ 
|__|__| : |__|__| 
3 
Day 1 
1.5 hrs. after beginning Day 1 
LY2606368 infusion 
___/___/___ 
|__|__| : |__|__| 
4 
Day 1 
2 hrs. after beginning Day 1 
LY2606368 infusion 
___/___/___ 
|__|__| : |__|__| 
5 
Day 1 
4 hrs. after beginning Day 1 
LY2606368 infusion 
___/___/___ 
|__|__| : |__|__| 
6 
Day 1 
8 hrs. after beginning Day 1 
LY2606368 infusion 
___/___/___ 
|__|__| : |__|__| 
7 
Day 2 
24 hrs. (± 2 hrs.) after beginning Day 1 
LY2606368 infusion 
___/___/___ 
|__|__| : |__|__| 
8 
Day 5 
96 hrs. (± 24 hrs.) after beginning Day 
1 LY2606368 infusion 
___/___/___ 
|__|__| : |__|__| 
9 
Day 8 
During CBC evaluation 
___/___/___ 
|__|__| : |__|__| 
10 
Day 15 
Prior to Day 15 LY2606368 infusion 
 
 
LY2606368 Infusion on Day 15    Date:___/___/___        Start Time: |__|__| : |__|__| 
End Time: |__|__| : |__|__| 
11 
Day 15 
1 hr. after beginning Day 15 
LY2606368 infusion 
___/___/___ 
|__|__| : |__|__| 
 
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should be sent with 
the samples to the address listed in Section 8.3.6. See Section 8.3 for detailed guidelines for packaging and shipping 
PK samples. 
 
Signature: _________________________________________          Date:___________________  
(site personnel who is responsible for research sample collection) 
 
 
 


 
                              
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APPENDIX VI:  TISSUE STUDY FORM (REQUIRED TISSUE) 
 
COG Pt ID # _______________ 
 
 
 
Cycle 1, Day 1 Date: _____________ 
 
Please do not write patient names on this form or on samples. 
 
Body Surface Area: ______m2  
 
LY2606368 Dose Level: ______mg/m2  
 
 
LY2606368 Total Daily Dose: ________mg 
 
Tumor Sample Labeling: 
Samples should be labeled with the following information: 
 
Protocol number: ADVL1515 
Institution:        _________________ 
Patient ID #:     _________________ 
Accession #:     _________________ 
Sample Date:    _________________ 
Site of Acquired Tissue:  __________________ 
 
Tissue obtained at (check one option below): 
Diagnosis      Relapse 
 
Shipment of Tumor Tissue: 
Paraffin-embedded tumor specimens must be packaged appropriately and shipped at room temperature to 
Dr. Cynthia Wetmore (at the address below). If a tumor block is not available, please send as many scrolls 
from the tumor block and/or a minimum of 10 unstained slides may be shipped instead. Please indicate 
above the date of the sample, site of tissue acquisition and whether it was obtained at diagnosis or relapse. 
Shipments should be sent Monday through Thursday only for priority overnight delivery using the COG 
FedEx account (do not ship on Friday). One copy of this form should be uploaded into RAVE.  
 
A second copy should be sent with the tissue sample to the lab address below. 
 
Attn: Cynthia Wetmore, M.D., Ph.D. 
Phoenix Children's Hospital 
Center for Cancer and Blood Disorders 
Room 25117 
1919 E Thomas Road 
Phoenix AZ 85016  
Notes:    ___________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
 
Signature: ___________________________________________             Date:______________________ 
 
 
(site personnel who is responsible for research sample collection) 
 


 
                              
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APPENDIX VII:  PHARMACODYNAMIC STUDY FORM 
 
COG Pt ID # _______________ 
 
 
 
Cycle 1, Day 1 Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Body Surface Area: ______m2   
 
LY2606368 Dose Level: ______mg/m2   
 
 
LY2606368 Total Daily Dose: _____mg 
 
Blood samples (5 ml) will be collected in consenting patients in CPT tubes during Cycle 1 at the following 
time points: Day 1 (pre-infusion) and Day 2 (24 hrs. after start of Day 1 infusion). 
 
Record the exact time the sample is drawn along with the exact time LY2606368 is given on Day 1. 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time 
Actual Date 
Sample 
Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle 1, Day 1 
prior to LY2606368 infusion 
 
|__|__| : |__|__| 
LY2606368 Infusion on Day 1       Date:___/___/___       Start Time: |__|__| : |__|__| 
End Time: |__|__| : |__|__| 
2 
Cycle 1, Day 2 
24 hrs. after start of Day 1 LY2606368 
infusion 
 
|__|__| : |__|__| 
 
One copy of this Pharmacodynamic Study Form should be uploaded into RAVE. A second copy should be 
sent with the samples to the address listed in Section 8.5.6. See Section 8.5 for detailed guidelines for 
packaging and shipping PD samples. 
 
Record any notes for Sample Storage Conditions below. 
 
Notes:    __________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
 
Signature: _________________________________________                    Date:___________________ 
 
 
(site personnel who is responsible for research sample collection) 
 
 
 


 
                              
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APPENDIX VIII:  ISOLATION OF PBMCS AND PLASMA FOR CORRELATIVE 
STUDIES 
 
 
 
Isolation and Storage of Peripheral Blood Mononuclear Cells (PBMCs) 
 
a) Purpose 
 
To isolate Peripheral Blood Mononuclear Cells (PBMCs) for long term storage. 
 
 
b) Equipment and Material Required 
 
• 
Whole blood samples to be processed (freshly collected into 
CPT) 
• 
Cell preparation tubes (CPT) 
• 
Centrifuge (capable of centrifugation at 1,600 × rcf) 
• 
Pipette and tips 
• 
0.5 ml and 2.0 ml cryo tubes (capable of being stored at -80˚C or 
-150˚C) 
• 
Extra collection tubes (to counterbalance during centrifugation) 
• 
1 x PBS (room temperature) 
 
 
c) Procedure 
 
1. Gently invert CPT tubes 5 times before placing in the centrifuge 
2. Counter balance extra collection tubes for centrifugation 
3. Centrifuge the samples for 20 minutes at 1,600 × rcf at room temperature 
***Ensure that tubes will not hit inside of centrifuge rotor once centrifugation begins 
4. Remove tubes from centrifuge, ensuring that tubes are kept in the upright position so as not to 
disturb layers. 
5. Aliquot plasma into labeled 2 ml aliquots, as appropriate (see SOP Processing Blood Samples 
Step 4 - 5) 
***Be careful not to disrupt the cell layer while aspirating plasma (see image above) 
6. Transfer small amount of remaining plasma and cells from CPT tubes into a 15 ml conical tube 
7. Rinse CPT tubes using 5 ml of 1 × PBS (gently pipette up and down) 
***Be careful not to disturb the gel matrix. Rinsing should remove most of the cells from 
the gel matrix. The wash may be reddish in color. 
8. Transfer the rinse mixture into the same 15 ml conical tube (one tube per patient sample) 
9. Discard the rinsed CPT tubes in the biohazard waste 
10. Bring the total volume, in the 15 ml conical tube, to 15 ml using 1 × PBS  


 
                              
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11. Mix the cells by gently inverting the tube 5 times 
12. Centrifuge at 300 × rcf for 15 minutes at room temperature 
13. Aspirate and discard the supernatant, being careful not to disturb the cell pellet 
14. Add 200-500 µl of PBS to the cell pellet and pipette gently to resuspend pellet (use smallest 
volume of PBS to fully resuspend pellet) 
15. Aliquot resuspended cells into 0.5 ml labeled cryo tubes and place in -80˚C freezer until 
shipment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
                              
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APPENDIX IX: TOXICITY-SPECIFIC GRADING 
 
Bilirubin 
 
Grade 1: 
≤ 1.5X 
Grade 2: 
> 1.5X- 3X 
Grade 3: 
> 3X-10X 
Grade 4: 
> 10X 
 
ALT: For the purpose of this study, the ULN for ALT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
≤ 135 
Grade 2: 
136- 225 
Grade 3: 
226- 900 
Grade 4: 
> 900 
 
AST: For the purpose of this study, the ULN for AST is 50 U/L regardless of baseline. 
 
Grade 1: 
≤ 150 
Grade 2: 
151-250 
Grade 3: 
251-1000 
Grade 4: 
> 1000 
 
GGT: 
 
Grade 1: 
≤ 2.5X 
Grade 2: 
> 2.5X- 5X 
Grade 3: 
> 5X-20X 
Grade 4: 
> 20X 
 
 
 


 
                              
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APPENDIX X: 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. 
 
Sites 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 ADVL1515 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.