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: 33
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of nanoparticle albumin-bound rapamycin when given together with temozolomide and irinotecan hydrochloride in treating pediatric patients with solid tumors that have come back after treatment and a period of time during which the tumor could not be detected or has not responded to treatment. Nanoparticle albumin-bound rapamycin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as temozolomide and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nanoparticle albumin-bound rapamycin, temozolomide, and irinotecan hydrochloride may cause the cancer to stop growing or shrink for a period of time and may lessen the symptoms that are caused by the cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of nanoparticle albumin-bound rapamycin (ABI-009) administered as an intravenous infusion over 30 minutes on days 1 and 8 of a 21-day cycle, in combination with temozolomide and irinotecan hydrochloride (irinotecan) (administered on days 1-5) in pediatric patients with recurrent or refractory solid tumors, including central nervous system (CNS) tumors.

II. To define and describe the toxicities of single-agent ABI-009 administered as an intravenous infusion over 30 minutes on days 1 and 8 of a 21-day cycle in pediatric patients with recurrent or refractory solid tumors, including CNS tumors.

III. To define and describe the toxicities of ABI-009 administered as an intravenous infusion over 30 minutes on days 1 and 8 of a 21-day cycle in combination with temozolomide and irinotecan (administered on days 1-5) in pediatric patients with recurrent or refractory solid tumors, including CNS tumors.

IV. To characterize the pharmacokinetics of ABI-009 in pediatric patients with recurrent or refractory solid tumors, including CNS tumors.

SECONDARY OBJECTIVE:

I. To preliminarily define the antitumor activity of ABI-009 in combination with temozolomide and irinotecan within the confines of a phase 1 study.

EXPLORATORY OBJECTIVE:

I. To assess the biologic activity of ABI-009 by examining S6K1 and 4E-BP1 expression status in archival tumor tissue from solid tumor pediatric patients using immunohistochemistry.

OUTLINE: This is a dose-escalation study of nanoparticle albumin-bound rapamycin.

Patients receive nanoparticle albumin-bound rapamycin intravenously (IV) over 30 minutes on days 1 and 8 beginning on cycle 1. Patients also receive temozolomide orally (PO) and irinotecan hydrochloride PO on days 1-5 beginning on cycle 2. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.

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

Arms:
arm 1: Patients receive nanoparticle albumin-bound rapamycin IV over 30 minutes on days 1 and 8 beginning on cycle 1. Patients also receive temozolomide PO and irinotecan hydrochloride PO on days 1-5 beginning on cycle 2. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Irinotecan Hydrochloride intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study intervention 4: Sirolimus Albumin-bound Nanoparticles intervention 5: Temozolomide
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies intervention 4: Given IV intervention 5: Given PO

Protocol document:
Prot_SAP_000.pdf: 
ADVL1514 
 
 
Version Date: 06/19/2020 
 
1 
 
Activated: 
7/24/17 
Version Date: 
06/19/20 
Closed: 
   8/13/21 
Amendment #: 
4C 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
ADVL1514 
 
A PHASE 1 STUDY OF ABI-009 (NAB-RAPAMYCIN) 
 IN PEDIATRIC 
PATIENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS, INCLUDING CNS 
TUMORS AS A SINGLE AGENT AND IN COMBINATION WITH TEMOZOLOMIDE AND 
IRINOTECAN 
 
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 
 
TABLE OF CONTENTS 
2 
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 Aim 
9 
1.3 
Exploratory Aim 
9 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development 
9 
2.2 
Preclinical Studies 
13 
2.3 
Adult Studies 
13 
2.4 
Pediatric Studies 
14 
2.5 
Overview of Proposed Pediatric Study 
14 
2.6 
Rationale for Amendment #4 (Addition of Dose Level -2 and modification of the definition 
of hematological DLT) 
15 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
16 
3.1 
Current Study Status 
16 
3.2 
IRB Approval 
17 
3.3 
Patient Registration 
17 
3.4 
Reservation and Contact Requirements 
18 
3.5 
Informed Consent/Assent 
18 
3.6 
Screening Procedures 
18 
3.7 
Eligibility Checklist 
18 
3.8 
Institutional Pathology Report 
18 
3.9 
Study Enrollment 
18 
3.10 
Dose Assignment 
19 
4.0 
PATIENT ELIGIBILITY 
19 
4.1 
Inclusion Criteria 
19 
4.2 
Exclusion Criteria 
23 
5.0 
TREATMENT PROGRAM 
25 
5.1 
Overview of Treatment Plan 
25 
5.2 
Criteria for Starting Subsequent Cycles 
27 
5.3 
Dose Escalation Schema 
27 
5.4 
Grading of Adverse Events 
27 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
28 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
29 
6.1 
Dose Modification Guidelines for Cycle 1, Day 8 
29 
6.2 
Dose Modification Guidelines for Cycle 1 
31 
6.3 
Dose Modification Guidelines for Cycle 2 or greater 
34 
6.4 
Dose Modifications for Elevated Fasting Triglycerides 
35 


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6.5 
Dose Modifications for Elevated Fasting Cholesterol 
36 
6.6 
Dose Modifications for Hyperglycemia 
36 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
37 
7.1 
Concurrent Anticancer Therapy 
38 
7.2 
Investigational Agents 
38 
7.3 
Supportive Care 
38 
7.4 
Growth Factors 
38 
7.5 
Concomitant Medications (Study Specific) 
38 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
38 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
38 
8.2 
Radiology Studies 
40 
8.3 
Pharmacology (required) 
40 
8.4 
Tissue Studies (required) 
43 
9.0 
AGENT INFORMATION 
44 
9.1 
ABI-009       (11/25/19) 
44 
9.2 
CEFIXIME 
51 
9.3 
IRINOTECAN 
52 
9.4 
TEMOZOLOMIDE - ORAL 
55 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
57 
10.1 
Criteria for Removal from Protocol Therapy 
57 
10.2 
Off Study Criteria 
58 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
58 
11.1 
Sample Size and Study Duration 
58 
11.2 
Definitions 
59 
11.3 
Dose Escalation and Determination of MTD 
60 
11.4 
Inclusion of Children, Women and Minorities 
61 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
62 
12.0 
EVALUATION CRITERIA 
63 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
63 
12.2 
Response Criteria for Patients with Solid Tumors 
63 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
69 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
69 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
71 
12.6 
Response Criteria for Patients with CNS Tumors 
72 
12.7 
Best Response 
73 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
74 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
75 
13.2 
When to Report an Event in an Expedited Manner 
78 
13.3 
Expedited Reporting Methods 
78 
13.4 
Definition of Onset and Resolution of Adverse Events 
78 
13.5 
Other Recipients of Adverse Event Reports 
79 
13.6 
Reporting Secondary AML/MDS 
79 
13.7 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
80 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
81 
14.1 
Categories of Research Records 
81 
14.2 
Access to Rave for Data Submission/Data Reporting 
81 


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14.3 
CDUS 
82 
14.4 
Data and Safety Monitoring Plan 
82 
REFERENCES 
83 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
86 
APPENDIX II: CORRELATIVE STUDIES GUIDE 
87 
APPENDIX III: PREGNANCY INFORMATION FORM 
88 
APPENDIX IV: TEMOZOLOMIDE DOSING NOMOGRAM FOR TEMOZOLOMIDE 125 
MG/M2/DOSE 
89 
APPENDIX V: INSTRUCTIONS FOR TEMOZOLOMIDE PREPARATION, ADMINISTRATION 
AND SAFE HANDLING FOR PATIENTS WHO ARE UNABLE TO SWALLOW 
CAPSULES 
90 
APPENDIX VI: PARENT GUIDELINES FOR ADMINISTRATION OF ORAL IRINOTECAN 
91 
APPENDIX VII: INSTRUCTIONS FOR IRINOTECAN PREPARATION, ADMINISTRATION AND 
SAFE HANDLING 
92 
APPENDIX VIII: PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
93 
APPENDIX IX: MEDICATION DIARY 
95 
APPENDIX X: UNACCEPTABLE ENZYME-INDUCING AND RECOMMENDED NON-ENZYME 
INDUCING ANTICONVULSANTS 
96 
APPENDIX XI-A: PHARMACOKINETIC STUDY FORM FOR ABI-009 
97 
APPENDIX XI-B: PHARMACOKINETIC STUDY FORM FOR IRINOTECAN 
99 
APPENDIX XII: TISSUE STUDY FORM (REQUIRED TISSUE) 
100 
APPENDIX XIII: POTENTIAL DRUG INTERACTIONS 
101 
APPENDIX XIV: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
102 
APPENDIX XV: TOXICITY-SPECIFIC GRADING 
104 
APPENDIX XVI: CTEP AND CTSU REGISTRATION PROCEDURES 
105 
APPENDIX XVII:  PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
107 
 


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STUDY COMMITTEE, CONT. 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
For PEP-CTN Operations and Data/Statistics 
Contacts see: 
 
http:members.childrensoncologygroup.org 
 
 
 
AGENT NSC# AND IND#’s 
 
 
 
Agent Supplied by AADi: 
 
ABI-009 (nab-rapamycin; nab-sirlolimus) (NSC# 
791518, 
 
 
 
Commercial Agents: 
 
Temozolomide (Temodar®, Temodal®; NSC# 362856) 
 
Irinotecan (Camptosar®; NSC# 616348) 
 
Cefixime (Suprax®) NSC# NA 
 
 
 
 
 
IND Sponsor: COG 
 
 
 
 
 
SEE SECTIONS 8.3.6 AND 8.4.2 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 
 
Relapsed/refractory pediatric solid and CNS tumors are a major cause of morbidity and mortality in pediatric 
oncology with few effective treatment options. Both preclinical and clinical studies involving pediatric solid 
and CNS tumors have shown an aberration of the mammalian target of rapamycin (mTOR) pathway. In 
addition, these studies have demonstrated that inhibition of the mTOR pathway has significant efficacy 
impeding growth of these tumors. ABI-009, also known as nab-Rapamycin, is a novel human albumin-bound 
preparation of rapamycin, a potent mTOR inhibitor. Albumin nanoparticle technology encapsulates lipophilic 
drugs into nanoparticles by combining drug and human serum albumin in a water-based solvent under high 
pressure. This technology enhances permeability and retention (EPR), allowing accumulation of 
macromolecules in solid tumors. In the adult phase 1 trial, ABI-009 was well tolerated with the most common 
toxicities including thrombocytopenia, mucositis, fatigue, rash, diarrhea, and hypertriglyceridemia. We will 
conduct a phase 1 trial of ABI-009 in combination with irinotecan and temozolomide in children with 
recurrent solid and CNS tumors using the Rolling Six design. The aims of the trial will be to establish the 
maximum tolerated pediatric dose of ABI-009, and to investigate the toxicities, pharmacokinetics, and 
pharmacodynamics of ABI-009 in children with these tumors. 
 
 
 


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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
Cycle 1 – Single Agent – 21-Day Duration 
 
 
 
 
 
Day 1                Day 8                Day 21 
 
 
Cycle 2+      Combination Therapy      21 Day Duration 
Day -2 
Cefixime 
 
 
 
PJP Prophylaxis 
Day -1 
 
 
 
 
Day 1 
 
TEMO  
IRIN 
ABI-009 
Day 2 
 
TEMO 
IRIN 
 
Day 3 
 
TEMO  
IRIN 
 
Day 4 
 
TEMO 
IRIN 
 
Day 5 
 
TEMO  
IRIN 
 
Day 6 
 
 
 
 
Day 7 
 
 
 
 
Day 8 
 
 
 
ABI-009 
Day 9-19 
 
 
 
 
Day 201 
Cefixime 
 
 
 
Day 212 
 
Evaluation 
 
 
TEMO: Temozolomide 
IRIN: Irinotecan 
PJP: Pneumocystis pneumonia 
 
1 Day 20 equals Day -2 of the following cycle. 
2 Day 21 equals Day -1 of the following cycle. 
 
 
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). 
 
 
 
ABI-009 IV 
over 30 
minutes 
ABI-009 IV 
over 30 
minutes 
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 
(RP2D) of ABI-009 administered as an intravenous infusion over 30 minutes on 
Days 1 and 8 of a 21-day cycle, in combination with temozolomide and irinotecan 
(administered on Days 1-5) in pediatric patients with recurrent or refractory solid 
tumors, including CNS tumors. 
 
1.1.2 
To define and describe the toxicities of single-agent ABI-009 administered as an 
intravenous infusion over 30 minutes on Days 1 and 8 of a 21-day cycle in pediatric 
patients with recurrent or refractory solid tumors, including CNS tumors. 
 
1.1.3 
To define and describe the toxicities of ABI-009 administered as an intravenous 
infusion over 30 minutes on Days 1 and 8 of a 21-day cycle in combination with 
temozolomide and irinotecan (administered on Days 1-5) in pediatric patients with 
recurrent or refractory solid tumors, including CNS tumors. 
 
1.1.4 
To characterize the pharmacokinetics of ABI-009 in pediatric patients with recurrent 
or refractory solid tumors, including CNS tumors. 
 
1.2 
Secondary Aim 
 
1.2.1 
To preliminarily define the antitumor activity of ABI-009 in combination with 
temozolomide and irinotecan within the confines of a Phase 1 study. 
 
1.3 
Exploratory Aim 
 
1.3.1 
To assess the biologic activity of ABI-009 by examining SK61 and 4E-BP1 
expression status in archival tumor tissue from solid tumor pediatric patients using 
immunohistochemistry. 
 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
 
2.1.1 
ABI-009 and the mTOR Pathway 
ABI-009, also known as nab-Rapamycin, is a novel human albumin-bound preparation 
of rapamycin, a potent mammalian target of rapamycin (mTOR) inhibitor. Rapamycin 
interacts with the 12 kDa FK506-binding protein (FKBP12) and forms a gain-of-
function complex, resulting in inhibition of mTOR function.1 Aberration of the mTOR 
pathway occurs in numerous adult and pediatric cancers as a result of gain-of-function 
mutations in oncogenes and/or loss-of-function mutations in tumor suppressors.1 The 
deregulation of the mTOR pathway is not only confined to cancer, but also observed 
in obesity, type 2 diabetes, and neurodegeneration.2 
 


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mTOR, a serine/threonine protein kinase, belongs to the phosphoinositide 3-kinase 
(PI3K)-related protein kinase family because of the homology its C-terminus shares 
with the catalytic domain of PI3K.2 It is composed of two functionally separate protein 
complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), that have varying 
upstream inputs and downstream outputs as well as sensitivity to rapamycin, with 
mTORC1 being the more sensitive complex.3 Once activated, mTORC1 directly 
phosphorylates the translation regulators p70 ribosomal S6 kinase 1 (S6K1) and 
eukaryotic inhibition factor eIF4E binding protein 1 (4E-BP1) resulting in nucleotide 
and protein synthesis.4 Additionally, phosphorylation status of S6K and 4E-BP1 are 
frequently used to assess mTORC1 activity in vivo.3 Conversely, the underpinnings of 
mTORC2 role and function are yet to be fully understood. mTORC2 is thought to be 
rapamycin insensitive; however, long-term exposure in certain cell types reduces 
mTORC2 signaling.5 
 
2.1.2 
mTOR Signaling in Cancer 
The mTOR pathway has numerous roles in cancer pathogenesis. Aberrant activation 
of this pathway, either by gain-of-function mutations in oncogenes and/or loss-of-
function mutations in tumor suppressors, results in tumor growth, angiogenesis, 
resisting cell death, and metastasis.6 One signaling pathway altered in multiple cancer 
types is the PI3K/AKT kinase cascade, which is the key kinase acting upstream of both 
mTORC1 and mTORC2. The PI3K/AKT signaling cascade is deregulated by multiple 
mechanisms some which include mutations in PI3K, mutations or amplifications of 
AKT, overexpression of growth factor receptors human epidermal growth factor 
receptor 2 (HER-2), insulin-like growth factor receptor (IGFR), and platelet-derived 
growth factor receptor (PDGFR), or loss of phosphatase and tensin homolog (PTEN) 
function.3,6 mTOR downstream effectors S6K1, 4EBP1, and eIF4E are also implicated 
in tumorigenesis; however, their exact mechanisms of tumorigenesis are yet to be 
elucidated. Tumor formation is not only a consequence of aberrant activation of the 
mTOR pathway, but is also a result of familial cancer syndromes that interact upstream 
from this pathway; specifically, Peutz-Jeghers syndrome (mutation of the serine 
threonine kinase 11 (Lkb1)), Tuberous Sclerosis (mutations in the TSC1 or TSC2), and 
Cowden disease (loss of PTEN function).3 
 
The overall survival for advanced stage or refractory pediatric intracranial and extra-
cranial solid tumor malignancies remains dismal.7 The PI3K/AKT/mTOR pathway has 
been implicated in several pediatric solid tumor malignancies. These findings are 
outlined below: 
 
• 
Neuroblastoma (NB): Overexpression of PI3K p85, PI3K p110, p-Akt, and 
p-mTOR, and decreased PTEN expression, as well as, Akt activation have 
been identified as poor prognostic indicators.8,9  
 
• 
Osteosarcoma (OS): The PI3K/AKT pathway has been shown to be 
deregulated in a majority of localized OS and in 100% of advanced-stage 
disease.10 In addition amplification of the oncogene c-Myc is seen in 
approximately 10% of OS and upregulated by Akt phosphorylation, while 
cyclin D1 is overexpressed in 20% of OS and is a downstream target of 
mTORC1.11 Investigators have also shown that in vitro mTOR inhibition 
decreases proliferation, while in vivo delays tumor progression and pulmonary 
metastasis.12  


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• 
Ewing Sarcoma (EWS): EWS has a distinctive karyotypic abnormality 
involving the EWSR1 locus forming a fusion product with Fli-1, ERG, ETV1, 
or E1AF. These fusion proteins act as aberrant transcription factors and in in 
vitro studies have been shown to interact with insulin like growth factor 1 
(IGF-1). IGF-1 indirectly activates PI3K through Ras signaling and via insulin 
receptor substrate 1 (IRS-1) leading to downstream activation of mTOR 
signaling.13 All EWS family of tumors express the IGF-1 receptor and this 
suggests a potential role for IGF-1 in tumorigenesis.13 
 
• 
Rhabdomyosarcoma (RMS): The chromosomal translocation involving the 
FOXO1 gene and the PAX3 or PAX7 gene occur in approximately 80% of 
alveolar RMS (ARMS), and are known to play a vital role in cell cycle 
dysregulation and tumorgenesis.14 The PAX3-FOXO1 translocation decreases 
PTEN expression resulting in PI3K/Akt activation.13 The Children’s Oncology 
Group analyzed 64 primary RMS tumors via microarray and noted 
phosphorylated mTOR levels were increased in 60% of ARMS and 68% of 
embryonal RMS (ERMS) cases.13  
 
• 
Medulloblastoma (MB): Recent studies have linked the sonic hedgehog 
(SHH) signaling pathway as an important mediator in the activation of the 
mTOR pathway and its downstream effectors S6K and eIF4E.15   
 
• 
Gliomas: The signaling pathways that trigger the pathogenesis of pediatric 
gliomas have yet to be understood. Mueller et al. investigated the 
PI3K/Akt/mTOR pathway in low- and high-grade pediatric gliomas. Their 
study revealed that 80% of high-grade pediatric gliomas and 40% of low-grade 
gliomas showed activation of the PI3K/Akt/mTOR pathway and also 
suggested the tumor grade correlated negatively with PTEN expression.16 
 
• 
Renal Tumors: Currently, initial treatment for metastatic renal cell carcinoma 
involves mTOR inhibition.17 mTOR’s role in Wilms’ tumor is less defined; 
however, one study did reveal activation of the mTOR-signaling pathway in a 
metastatic lung lesion in a patient with Wilms’ tumor.18 
 
• 
Hepatic Tumors: Both hepatoblastoma and hepatocellular have deregulation 
of PI3K/Akt/mTOR signaling pathways resulting in tumorgenesis.19,20 
 
2.1.3 
Rapamycin vs. ABI-009 (nab-Rapamycin) 
Rapamycin (sirolimus) is a potent allosteric inhibitor of mTORC1; yet, it has low oral 
bioavailability, poor solubility, and dose-limiting intestinal toxicity.1,21 Temsirolimus, 
a prodrug of rapamycin and the only current intravenous “rapalog” preparation, has 
low water-solubility requiring formulation in surfactants and solvents; when infused, 
temsirolimus can potentially cause hypersensitivity reactions and decreased drug 
efficacy.21 ABI-009, nab-Rapamycin, is a novel human albumin-bound intravenous 
preparation of rapamycin. Albumin nanoparticle technology encapsulates lipophilic 
drugs into nanoparticles by combining drug and human serum albumin in a water based 
solvent under high pressure, resulting in nanoparticle size in the range of 100-200 
nM.22 This technology enhances permeability and retention (EPR) allowing 
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This increased permeability and retention is important due to the underlying 
pathophysiology of tumor tissue defined by angiogenesis, defective lymphatic 
drainage, and abnormal vascular architecture.22 ABI-009 is formulated in saline, has 
low anaphylaxis potential, and may improve drug delivery and efficacy.21 
 
Proof of this concept has been demonstrated in preclinical studies comparing albumin-
bound paclitaxel nanoparticles (nab- paclitaxel or ABI-007) vs. paclitaxel. Improved 
drug accumulation and antitumor response, as well as, enhanced biodistribution and 
increase in the maximum tolerated dose (MTD) was observed in the ABI-007 treated 
mice compared to those treated with paclitaxel.22 Adult phase 1, 2 and 3 clinical studies 
of ABI-007 showed no hypersensitivity reactions when compared to paclitaxel; ABI-
007 showed increased response rates (33% vs. 19%) and prolonged tumor progression 
(22 vs. 16.9 weeks) in patients with metastatic breast cancer.22 
 
2.1.4 
Rationale for Combination Therapy and Starting Dose 
There have been numerous clinical trials evaluating mTOR inhibition in combination 
with a variety of chemotherapy backbone regimens in both adult and pediatric trials. 
Specifically, COG has investigated mTOR inhibition in combination with 
cyclophosphamide and vinorelbine (ARST0921) and in combination with irinotecan 
(IRN) and temozolomide (TMZ) (ADVL0918).23,24 Of the combinations noted above, 
IRN and TMZ is of most interest due to its activity in heavily pretreated patients. The 
COG study ANBL0421, evaluated this backbone in patients with recurrent or 
refractory neuroblastoma. In this cohort, eight of the first 50 evaluable patients had 
objective responses to treatment.25 In addition to evaluating this combination in 
neuroblastoma, other studies have investigated this backbone in relapsed Ewing 
sarcoma, rhabdomyosarcoma, and other difficult to treat solid tumors suggesting its 
feasibility in children. 
 
These studies contributed to the development of a COG Phase 1 trial (ADVL0918) 
evaluating temsirolimus (TEM) in combination with IRN and TMZ. This was a dose 
finding study evaluating escalating doses of intravenous TEM, oral TMZ, and oral 
IRN. Seventy-one eligible patients were enrolled with a variety of solid tumor 
diagnoses, including CNS. Dose limiting toxicities included elevated serum alanine 
aminotransferase and triglycerides, anorexia, and thrombocytopenia. The MTD was 
identified as TEM 35 mg/m2 weekly on Days 1, 8, and 15 with IRN 90 mg/m2 and 
TMZ 125 mg/m2 on Days 1-5 of a 21-day cycle. Of the seventy-one patients enrolled, 
six patients had objective responses with three of those having sustained responses for 
≥ 14 cycles of therapy.23 
 
To further delineate a starting dose of ABI-009, a review of published adult PKs of 
temsirolimus26 and ABI-00921 noted a starting dose of 45 mg/m2. When administered 
temsirolimus produces the sirolimus metabolite, and the AUC of temsirolimus + 
sirolimus metabolite from temsirolimus at a dose of 45 mg/m2 is 3414 + 11740 = 
15,154 ng•h/ml. Since the molecular weight of temsirolimus (1030 g/mol) is similar to 
the molecular weight of sirolimus (914 g/mol), AUCs were summed without 
adjustment. The AUC of sirolimus from ABI-009 at 45 mg/m2 is 24,564 (ng•h/ml) 
which is at least twice the total exposure compared to temsirolimus based on sirolimus 
alone. Thus the AUC of sirolimus from ABI-009 is substantially higher than that from 
temsirolimus at an equal dose (45 mg/m2) of both drugs. A similar higher exposure of 
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of 35 mg/m2. Given that in the ADVL0918 study, the dose of 35 mg/m2 of temsirolimus 
was well tolerated in combination, the starting dose for ABI-009 was extrapolated to 
start at 35 mg/m2, understanding that this would roughly double the exposure of 
temsirolimus. 
 
Furthermore, the phase 1 trial evaluating ABI-009, determined that the majority of 
missed doses (83%) occurred on day 15 (the 3rd dose of every 4-week schedule) (data 
unpublished). As a result, AADi has recently started two new phase 2 studies that 
incorporate the 2-dose, 3-week schedule. Based upon this information, the starting dose 
for this pediatric trial will mimic ADVL0918 on a Day 1 and Day 8 schedule. This will 
allow for rapid translation of the results of this trial into disease specific studies within 
COG. 
 
 
2.2 
Preclinical Studies 
 
The activity of the combination of chemotherapy and mTOR inhibition was studied in 
preclinical models. 
 
2.2.1 
Antitumor Activity 
Biochemical and functional characterization of ABI-009 has been undertaken in 
preclinical studies. These studies have suggested exceptional drug efficacy and safety, 
as well as decreased cancer cell viability and downstream signaling in several 
xenograft cancer models, including pancreatic, colorectal, breast cancer, and multiple 
myeloma.27-30 Significant antitumor activity was observed across all tumor models 
tested at 40 mg/kg.28 
Increased antitumor activity was noted when ABI-009 was used in combination with 
either ABI-007, doxorubicin, SAHA, erlotinib or perifosine.27-30 
 
2.2.2 
Animal Toxicology 
One study evaluated overall toxicity of ABI-009 in breast and colon xenograft models 
at dose levels of 0, 15, 30, 45, 90 and 180 mg/kg on an every 4 days times 3 schedule; 
pharmacokinetic properties were evaluated at dose levels of 1, 15, 30, and 45 mg/kg, 
and antitumor activity was evaluated at 40 mg/kg with a 3 times weekly for 4 weeks 
schedule. The investigators noted that ABI-009 was non-toxic at the dose level of 180 
mg/kg; no changes were noted in blood chemistry, CBC, hypercholesterolemia, or 
hypertriglyceridemia. ABI-009 showed no CNS side effects in xenograft models 
tested.27-30 
 
2.2.3 
Preclinical Pharmacokinetic Studies 
With respect to dose, ABI-009 exhibited linear Pharmacokinetics.28 
 
2.3 
Adult Studies 
 
2.3.1 
Phase 1 Studies 
The first in-human trial of ABI-009 administered at 5 dose levels (45, 56.25, 100, 125, 
and 150 mg/m2) on a weekly schedule for 3 weeks followed by 1 week of rest in 
patients with advanced solid tumors. The maximum tolerated dose (MTD) was 100 
mg/m2 with the most common toxicities including thrombocytopenia (58%), 
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nausea (19%), anemia (19%), hypophosphatemia (19%), neutropenia (15%), and 
hypertriglyceridemia (15%). The study initially dose escalated from 100 mg/m2 to 150 
mg/m2 which resulted in 4 dose-limiting toxicities (DLTs), two at 150 mg/m2 and two 
at 125 mg/m2; these were grade 3 AST elevation and grade 4 thrombocytopenia and 
grade 3 suicidal ideation and grade 3 hypophosphatemia, respectively (CTCAE v.4). 
The MTD had only 1 grade 3 non-hematologic event (dyspnea) and 1 grade 3 
hematologic event (anemia) after cycle 1 (CTCAE v4). Twenty-seven patients were 
enrolled on this trial; however, only 19 were evaluable for efficacy. There was 1 patient 
with adenocarcinoma of the kidney with a partial response, two patients with stable 
disease (mesothelioma and neuroendocrine tumor) with prolonged stabilization for 1 
year and 238 days, respectively.21 
 
2.3.2 
Phase 2 Studies 
No Phase 2 studies have been conducted to date. 
 
2.3.3 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
The pharmacokinetic analysis showed an almost proportional increase of the maximum 
concentration (Cmax) and area under the curve (AUC) with the outlier being a 
moderately low AUC at 125 mg/m2. The Cmax of ABI-009 was 3227.61 ng/mL that is 
significantly higher than levels achieved in other studies evaluating oral rapamycin and 
intravenous temsirolimus.31,32 The half-life was 40–91 hours across the tested dose 
range and was 63 hours at the MTD of 100 mg/m2. Circulating levels of the biomarkers 
S6K1 and 4EBP1 were significantly inhibited by ABI-009 and inhibition was 
maintained for several days after administration at dose levels greater than 56.25 
mg/m2. 
 
 
2.4 
Pediatric Studies 
 
No pediatric studies of ABI-009 have been conducted. The Pediatric Preclinical Testing 
Program (PPTP) evaluated rapamycin in their xenograft models and noted a broad antitumor 
activity, with a significant activity in sarcoma models.33 The Children’s Oncology Group 
(COG) evaluated, in a Phase 2 trial (ARST0921), bevacizumab and temsirolimus in 
combination with vinorelbine (V) and cyclophosphamide (C) for initial relapse/progression 
for patients with RMS. Patients were randomized between the bevacizumab plus VC arm vs. 
temsirolimus plus VC arm. Patients that were randomized to the temsirolimus arm had a 
significantly improved EFS compared to the bevacizumab arm, 65% vs. 50%, respectively.24 
In addition, there have been multiple Phase 1 and 2 trials evaluating mTOR inhibitors 
including oral rapamycin, everolimus and temsirolimus alone or in combination in pediatric 
patients.13 
 
 
2.4.1 
Prior Experience in Children 
There have been no pediatric studies of ABI-009. 
 
 
2.5 
Overview of Proposed Pediatric Study 
 
We propose to conduct a Phase 1 study of ABI-009 in children with relapsed/refractory solid 
tumors using the rolling 6 design. Cycle 1 will aim to establish tolerability and safety and to 


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obtain pharmacokinetics of ABI-009 as a single agent dosed on days 1 and 8 of a 21-day 
cycle. Additionally, Cycle 2+ will aim to determine the MTD and/or RP2D of ABI-009 in 
combination with temozolomide and irinotecan. The ABI-009 starting dose will be 35 mg/m2 
as a single agent during Cycle 1, while Cycle 2+ dosing and scheduling in combination with 
irinotecan (90 mg/m2) and temozolomide (125 mg/m2) will mimic the Phase 1 pediatric trial 
ADVL0918.23 
 
2.6 
Rationale for Amendment #4 (Addition of Dose Level -2 and modification of the 
definition of hematological DLT) 
With Amendment #4, an additional Dose Level -2 of 15 mg/m2 has been added. To date 
(08/21/19), 18 patients have enrolled onto the study. Five patients enrolled at Dose Level 1 
(35 mg/m2); two of these patients experienced a DLT of platelet count decrease within the 
first one to three cycles of protocol therapy. An additional 13 patients enrolled at Dose Level 
-1 (20 mg/m2) of which 7 patients are inevaluable. There were 2 DLTs (platelet count 
decrease) observed among the 6 evaluable patients. This amendment will provide a dose 
reduction to 15 mg/m2 (Dose Level -2). We have reviewed our PK data for both Dose Level 
1 (35 mg/m2) and Dose Level -1 (20 mg/m2). The data notes the median AUC for Dose Level 
1 and Dose Level -1 to be 11,561 (ng•h/mL) and 8,599 (ng•h/mL), respectively. These 
median AUCs at these dose levels are well above the published AUCs for both temsirolimus 
and sirolimus. A Pediatric phase 1 trial evaluated weekly temsirolimus in refractory/recurrent 
solid tumors at doses of 10, 25, 75, and 150 mg/m2 on days 1, 8, and 15.34 The reported PK 
data indicates a median AUC for temsirolimus at doses of 10, 25, 75, and 150 mg/m2 to be 
1670, 3570, 2810, and 5190 (ng•h/mL), respectively.34 In addition, sirolimus PK data was 
also investigated in this trial as following administration temsirolimus produces the sirolimus 
metabolite.34 The median AUCs for sirolimus in this study at the above doses were 2560, 
4520, 7670, and 8660 (ng•h/mL), respectively.34 Review of the nab-rapamycin 
pharmacokinetics in adults demonstrates high variability (% coefficient of variation (CV), 
up to 40%) in both Cmax and AUC.21 In addition, for children and adolescent who received 
nab-rapamycin on this trial, PK parameters also had significantly variability (CV at least 
35%). At Dose Level -1 (20mg/m2): Cmax (mean 374 µg/L, median 368 µg/L, CV 39%); 
AUCinf (mean 10113 µg•h/L, median 9749 µg•h/L, CV 37%); Clearance (mean 2.2 
L/h/m2, median 2 L/h/m2, CV 35%). As noted previously, initial dosing for this study 
mimic the MTD in ADVL0918.23 This study evaluated temsirolimus at 15mg/m2 in 
combination with irinotecan and temozolomide, thus further validating this suggested dose 
reduction.23 In addition, Raymond et al, noted in their trial evaluating the safety and efficacy 
of CCI-779, a novel mTor inhibitor, a partial response in a patient with renal cell carcinoma 
at a dose of 15 mg/m2. Thus, based upon the information, above, a dose reduction of ABI-
009 to 15 mg/m2 is likely to yield a higher AUC then noted in the previous pediatric phase 1 
trial of temsirolimus and that this dose would be in the therapeutic range. Given the 
significant variability in exposures as dose reduction to 15 mg/m2 (Dose Level -2) ensures 
an adequate margin of safety with potential for clinical benefit. 
 
In addition, careful review of the dose limiting thrombocytopenia experienced during the trial 
to date, indicates that the platelet threshold (>75,000/mm3) for administration of day 8 
protocol therapy is the primary reason for declaration of DLT.  Based on the platelet nadir 
and recovery of patients with dose limiting thrombocytopenia, the platelet threshold for 
administration of day 8 protocol therapy has been modified to platelet count > 50,000/mm3.  
In addition, grade 4 thrombocytopenia (<25,000/mm3) ≥ 7 days duration and grade 3 
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significant bleeding, petechiae or purpura, or that persists for ≥ 7 days, and/or that requires 
platelet transfusion are considered dose limiting. 
 
Acc 
# 
Stratum 
Dose 
Level 
DLT 
Criteria 
DLT 
Cycle 
Subject Summary 
DLT Details 
1 
Stratum 
1 
DL1 
Gr. 4 Platelet 
count 
2 
Completed courses 1 and 
2; evaluable for DLT, 
and experienced DLT. 
Cycle 2, Day 8 platelet count was 
78,000; Gr 3 plt started Cycle 1, Day 
13; plt nadir 22,000, Gr 4, (Cycle 2 Day 
31). Transfused x 3 in 7 day period (2 
on Cycle 2, Day 15 and 1 on Cycle 2,  
Day 22); 100,000 by Cycle 2, Day 41.  
4 
Stratum 
1 
DL1 
Gr. 3 Platelet 
count day 8, 
not resolve to 
grade ≤2 by 
day 11 
1 
Completed course 1. 
evaluable for DLT, and 
experienced DLT 
Cycle 1, Day 8 platelets were 63,000, 
platelet nadir 35,000 on Cycle 1 Day 11; 
recovered to 118,000 by Cycle 1, Day 
15; no transfusion given.   
8 
Stratum 
1 
DL-1 
Gr. 3 Platelet 
count day 8 not 
resolve grade≤  
2 by day 11 
1 
Patient received one dose 
of study drug during Cycle 
1 experienced DLT. 
Removed from protocol 
therapy at the end of C1. 
Cycle 1, Day 8 platelets were 68,000; 
nadir platelet 32,000 on (Cycle 1, Day 
13), platelet transfusion was given; 
Cycle 1, Day 21 platelet count was 
65,000.   
18 
Stratum 
1 
DL-1 
Gr. 3 Platelet 
count day 8, 
not resolved 
grade ≤ 2 by 
day 11 
1 
Patient received one dose 
of study drug during Cycle 
1, experienced DLT. 
Removed from protocol 
therapy during C1. 
Cycle 1, Day 8 platelets were 49,000; 
nadir platelet 35,000 on (Cycle 1, Day 
11), platelet transfusion was given; 
Cycle 1, Day 11.   
 
 
Due to the fact that all of the DLTs experienced thus far in this study have been hematologic DLTs, 
no patients with known bone marrow involvement will be enrolled (Stratum 2). Therefore, all 
enrolled participants will be evaluable for hematological toxicity.  DL-2 will be evaluated with 
modified definitions of hematological DLT.  Based on experience to date and the DLT evaluation 
period including both cycle 1 and cycle 2, we have increased the accrual ceiling to include a 30% 
rate of patients who are not evaluable for toxicity, rather than 20%. 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in conjunction 
with the Oncology Patient Enrollment Network (OPEN), a web-based registration system available 
on a 24/7 basis. It is integrated with the NCI Cancer Trials Support Unit (CTSU) Enterprise System 
for regulatory and roster data and, upon enrollment, initializes the patient position in the RAVE 
database. 
 
Access requirements for OPEN:  
Investigators and site staff will need to be registered with CTEP and have a valid and active Cancer 
Therapy Evaluation Program-Identity and Access Management (CTEP-IAM) account (check at < 
https://ctepcore.nci.nih.gov/iam/index.jsp>). This is the same account (user id and password) used 
for credentialing in the CTSU members web site (refer to Appendix XVI 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  


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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. 
 
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. 
For general (non-regulatory) questions, call the CTSU General Helpdesk at 1-888-823-5923 
or contact CTSU by e-mail 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 


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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 
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. 
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start must be no later than five (5) calendar days after the date of study enrollment. Patients 
must not receive any protocol therapy prior to enrollment. 
 
3.10 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
 
4.0 
PATIENT ELIGIBILITY 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy. Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging studies 
must be obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging if 
necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th. 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01). All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient’s 
medical or research record which will serve as the source document for verification at the time 
of audit. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Age: Patients must be ≥ 12 months and ≤ 21 years of age at the time of study 
enrollment. 
 
4.1.2 
Body Surface Area: Patients must have a BSA of ≥ 0.2 m2 at the time of study 
enrollment. 
 
4.1.3 
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 patients with pineal tumors and elevations of CSF or serum 
tumor markers including alpha-fetoprotein or beta-HCG.  
 
4.1.4 
Disease Status: 
Patients must have either measurable or evaluable disease (see Sections 12.2 and 
12.3 for definitions). 
 
4.1.5 
Therapeutic Options: Patient’s current disease state must be one for which there is 


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no known curative therapy. 
  
4.1.6 
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. 
 
4.1.7 
Prior Therapy 
 
4.1.7.1 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, 
the patient is considered to have recovered adequately. 
 
a. Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive. See DVL homepage for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 
of this interval must be discussed with the Study Chair and the study-
assigned Research Coordinator prior to enrollment. 
• 
≥ 21 days after the last dose of cytotoxic or myelosuppressive 
chemotherapy (42 days if prior nitrosourea). 
 
b. Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥ 7 days after the last 
dose of agent. See DVL homepage for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 
of this interval must be discussed with the study chair and the study-
assigned Research Coordinator prior to enrollment.  
 
c. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1. 
 
d. Corticosteroids: See Section 4.2.2.1. 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 after 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 Hematopoetic 
Growth Factors): ≥ 21 days after the completion of interleukins, 


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interferon or cytokines (other than Hematopoetic Growth Factors ) 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥ 84 days 
after infusion and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion:  ≥ 42 days. 
 
h. Cellular Therapy: ≥ 42 days after the completion of any type of cellular 
therapy (e.g. modified T cells, NK cells, dendritic cells, etc.) 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days after local 
XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to ≥ 50% 
of the pelvis; ≥ 42 days if other substantial BM radiation. 
 
j. 
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): 
≥ 42 days after systemically administered radiopharmaceutical therapy. 
 
k. Irinotecan, temozolomide and mTOR inhibitor exposure: 
i. 
Patients who have received prior single agent therapy with 
irinotecan, temozolomide, or an mTOR inhibitor, excluding 
ABI-009, are eligible. 
ii. Patients who have received prior therapy with ABI-009 are not 
eligible. 
iii. Patients who have previously received irinotecan and 
temozolomide in combination without progressive disease 
while on therapy are eligible. 
iv. Patients who have previously received irinotecan and 
temozolomide in combination and had significant toxicity with 
these two drugs are not eligible. 
v. Patients who have received prior therapy with all three agents in 
combination (i.e. irinotecan, temozolomide, and an mTOR 
inhibitor) are not eligible. 
 
4.1.8 
Organ Function Requirements 
 
4.1.8.1 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 
- 
Platelet count ≥ 100,000/mm3 (transfusion independent, defined as 
not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
- 
Hemoglobin ≥ 8.0 g/dL at baseline (may receive RBC transfusions) 
 
4.1.8.2 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: 


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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. 
 
4.1.8.3 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT) ≤ 3 × ULN = 135 U/L. For the purpose of this study, the 
ULN for SGPT is 45 U/L. 
- 
Serum albumin ≥ 2 g/dL. 
 
4.1.8.4 Adequate Pulmonary Function Defined as: 
- 
Pulse oximetry > 94% on room air if there is clinical indication for 
determination (e.g. dyspnea at rest). 
 
4.1.8.5 Adequate Neurologic Function Defined as: 
- 
Patients with seizure disorder may be enrolled if on non-enzyme 
inducing anticonvulsants (see Appendix X) and well controlled. 
- 
Nervous system disorders (NCI CTCAE version 5.0) resulting from 
prior therapy must be ≤ Grade 2 with the exception of decreased tendon 
reflex (DTR). Any grade of DTR is eligible. 
 
4.1.8.6 Adequate Metabolic Function Defined as: 
- 
Serum triglyceride level ≤ 300 mg/dL 
- 
Serum total cholesterol level ≤ 300 mg/dL 
- 
Random or fasting blood glucose ≤ the upper normal limits for age. If 
the initial blood glucose is a random sample that is outside of the 
normal limits, then follow-up fasting blood glucose can be obtained and 
must be ≤ the upper normal limits for age. 
 
4.1.8.7 Adequate Coagulation Defined as: 
- 
INR ≤ 1.5 
- 
Not currently receiving anticoagulation therapy 
 
4.1.9 
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. 
 
4.1.10 Tissue blocks or slides must be sent for all patients per Section 8.4. If tissue blocks 
or slides are unavailable, the study chair must be notified prior to enrollment. 
 
 


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4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study due to risks of 
fetal and teratogenic adverse events as seen in animal/human studies. 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 6 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 4.1.7.1.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 cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease post bone marrow transplant are not 
eligible for this trial. 
 
4.2.2.5 Anticonvulsants: Patients must not have received enzyme-inducing 
anticonvulsants for at least 7 days prior to enrollment (see Appendix X for a 
list of enzyme-inducing and non enzyme-inducing anticonvulsants). 
 
4.2.2.6 Anticoagulants: Patients who are currently receiving therapeutic 
anticoagulants (including aspirin, low molecular weight heparin, and others) 
are not eligible. 
 
 
4.2.2.7 CYP3A4 or P-gp-active agents: Patients must not be receiving any strong 
CYP3A4 or P-gp inducers or inhibitors within 7 days prior to enrollment 
(see Appendix XIV). Moderate inducers or inhibitors of CYP3A4 and P-gp 
should also be avoided during ABI-009 treatment, if possible.  
 
 
4.2.3 
Study Specific: 
 
a. Pulmonary Dysfunction: 
• 
Patients with interstitial lung disease and/or pneumonitis are not 
eligible. 
 


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b. Allergic reactions: 
• 
Patients with a history of allergic reactions attributed to 
compounds of similar composition, including macrolide and 
ketolide antibiotics, temsirolimus/other mTOR inhibitors, 
temozolomide or irinotecan are not eligible. 
• 
Patients with hypersensitivity to albumin are not eligible. 
 
c. Surgery: 
• 
Patients who have had or are planning to have the following 
invasive procedures are not eligible: 
 Major surgical procedure, laparoscopic procedure, open 
biopsy or significant traumatic injury within 28 days prior 
to enrollment.  
 Subcutaneous port placement or central line placement is 
not considered major surgery. External central lines must be 
placed at least 3 days prior to enrollment and subcutaneous 
ports must be placed at least 7 days prior to enrollment.  
 Core biopsy within 7 days prior to enrollment. 
 Fine needle aspirate within 7 days prior to enrollment. 
NOTE: For purposes of this study, bone marrow aspirate and 
biopsy are not considered surgical procedures and therefore 
are permitted within 14 days prior to start of protocol therapy. 
 
d. Coagulation: 
• 
Patients with current deep vein thrombosis or deep vein 
thrombosis within the past 6 months are not eligible. 
 
e. Psychiatric Disorders: 
• 
Patients with a history of, or current grade 4 depression are not 
eligible. 
 
4.2.4 
Infection: Patients who have an uncontrolled infection are not eligible. 
 
4.2.5 
Patients who have received a prior solid organ transplantation are not eligible. 
 
4.2.6 
Patients who have known bone marrow involvement are not eligible. 
 
4.2.7 
Patients who in the opinion of the investigator may not be able to comply with the 
safety monitoring requirements of the study are not eligible. 
 
 
 
 


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5.0 
TREATMENT PROGRAM 
 
5.1 
Overview of Treatment Plan 
 
 
Cycle 1 – Single Agent – 21-Day Duration 
 
 
 
 
 
Day 1                Day 8                Day 21 
 
 
Cycle 2+      Combination Therapy      21 Day Duration 
Day -2 
Cefixime 
 
 
 
PJP Prophylaxis 
Day -1 
 
 
 
 
Day 1 
 
TEMO  
IRIN 
ABI-009 
Day 2 
 
TEMO 
IRIN 
 
Day 3 
 
TEMO  
IRIN 
 
Day 4 
 
TEMO 
IRIN 
 
Day 5 
 
TEMO  
IRIN 
 
Day 6 
 
 
 
 
Day 7 
 
 
 
 
Day 8 
 
 
 
ABI-009 
Day 9-19 
 
 
 
 
Day 201 
Cefixime 
 
 
 
Day 212 
 
Evaluation 
 
 
TEMO: Temozolomide 
IRIN: Irinotecan 
PJP: Pneumocystis pneumonia 
 
1 Day 20 equals Day -2 of the following cycle. 
2 Day 21 equals Day -1 of the following cycle. 
 
 
A cycle of therapy is considered to be 21 days. A cycle may be repeated for a total of 35 
cycles, up to a total duration of therapy of approximately 24 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.  
 
5.1.1 
Cycle 1 
Pre-Amendment #4: ABI-009 will be administered intravenously over 30 minutes on Days 
1 and 8 of Cycle 1 (beginning at Dose Level 1 = 35 mg/m2/dose; see dose escalation table in 
Section 5.3.1). The use of in-line filters is NOT necessary. Upon completion of infusion, the 
infusion catheter should be flushed with normal saline. 
ABI-009 IV 
over 30 
minutes 
ABI-009 IV 
over 30 
minutes 
Evaluation 


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Amendment #4: ABI-009 will be administered intravenously over 30 minutes on Days 1 
and 8 of Cycle 1 (beginning at Dose Level -2 = 15 mg/m2/dose; see dose escalation table in 
Section 5.3.1). The use of in-line filters is NOT necessary. Upon completion of infusion, the 
infusion catheter should be flushed with normal saline. 
 
 
5.1.2 
Cycle 2 and subsequent cycles 
Temozolomide will be administered orally at 125 mg/m2/dose (maximum 250 mg/dose) once 
daily x 5 on Days 1-5 of each cycle. The dosing nomogram is included in Appendix IV. If 
emesis occurs within 30 minutes of taking a dose of temozolomide, then the dose may be 
repeated once. If emesis occurs after 30 minutes, the dose should not be repeated. Instructions 
for administration of oral temozolomide to young children are included in Appendix V. 
Irinotecan will be administered orally at 90 mg/m2/dose once daily x 5 on Days 1-5 of each 
cycle. Irinotecan should be administered one hour after the administration of temozolomide. 
If emesis occurs within 30 minutes of taking a dose of irinotecan, then the dose may be 
repeated once. If emesis occurs after 30 minutes, the dose should not be repeated. Guidelines 
for the administration of oral irinotecan are included in Appendix VI. Instructions for the 
preparation and administration of oral irinotecan are included in Appendix VII. 
If a dose of temozolomide or irinotecan is missed and less than 6 hours have passed since the 
scheduled dosing time, the dose should be taken immediately. If more than 6 hours have 
passed since the scheduled dosing time, the patient should not take the missed dose but should 
wait and take the next regularly scheduled dose. 
Aprepitant is a substrate and moderate inhibitor of CYP3A4. Single aprepitant or 
fosaprepitant doses appear to only weakly inhibit CYP3A4 and are permitted. However, 
longer regimens (aprepitant administered on 2 or more consecutive days) may cause 
moderate CYP3A4 inhibition and should be avoided if reasonable alternatives exist. 
Pre-Amendment #4: ABI-009 will be administered intravenously over 30 minutes on Day 
1 and Day 8 of each cycle (beginning at Dose Level 1 = 35 mg/m2/dose; see dose escalation 
table in Section 5.3.1). ABI-009 should be given within 8 hours following administration of 
temozolomide and irinotecan. The use of in-line filters is NOT necessary. Upon completion 
of infusion, the infusion catheter should be flushed with normal saline. 
 
Amendment #4: ABI-009 will be administered intravenously over 30 minutes on Day 1 and 
Day 8 of each cycle (beginning at Dose Level -2 = 15 mg/m2/dose; see dose escalation table 
in Section 5.3.1). ABI-009 should be given within 8 hours following administration of 
temozolomide and irinotecan. The use of in-line filters is NOT necessary. Upon completion 
of infusion, the infusion catheter should be flushed with normal saline. 
Cefixime or an available equivalent antibiotic will be used as diarrheal prophylaxis for cycles 
2+. Initiation of antibiotic treatment two days prior to the start of irinotecan is required, and 
will continue during, and 3 days after the last dose of irinotecan of each cycle. This antibiotic 
therapy will continue throughout protocol therapy. Cefixime will be dosed at 8 mg/kg PO 
once daily (max: 400 mg/day). If cefixime is not available, cefpodoxime can be used as an 
alternative at 5 mg/kg/dose PO twice daily (10 mg/kg/day in two divided doses; max: 200 
mg/dose). 


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Note: Patients must also receive pneumocystis prophylaxis during study therapy for cycles 
2+. 
 
5.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 21 days if the patient has again met laboratory parameters as 
defined in the eligibility section, Section 4.0, or is eligible to continue agent administration 
per the requirements in Section 6.0. For cycles 3 and later, patients must also have at least 
stable disease while meeting the criteria established in Section 4.0 and meets the 
requirements presented in Section 6.0.  
 
5.3 
Dose Escalation Schema 
 
5.3.1 
Inter-Patient Escalation 
The starting dose of ABI-009 will be 35 mg/m2 (dose level 1) with dose levels for 
subsequent groups of patients as follows. 
 
Dose Level 
Cycle 1 
Cycle 2+ 
ABI-009 
(mg/m2) 
ABI-009 
(mg/m2) 
Irinotecan 
(mg/m2) 
Temozolomide
** 
(mg/m2) 
-2^ 
15 
15 
90 
125 
-1 
20 
20 
90 
125 
1* 
35 
35 
90 
125 
2 
45 
45 
90 
125 
3 
55 
55 
90 
125 
* Pre-Amendment #4: Starting dose level is the RP2D from COG study 
ADVL0918. 
** Maximum temozolomide dose = 250 mg/dose 
^ Amendment #4: Starting dose level 
 
There will be no planned escalations beyond dose level 3 (55 mg/m2), as previous 
pediatric Phase 1 studies have rarely defined an MTD greater than 160% of the adult 
MTD. However, if evaluation of PK and toxicity data as well as additional data from 
adult studies suggest higher doses are required to achieve maximal potential benefit, 
an amendment to the trial will be considered to add additional dose levels. 
 
Amendment #4: 
DL- 2 will be evaluated with modified definitions of hematological DLT, and there 
will be no planned escalations beyond dose level -2. If DL -2 is not well tolerated 
further de-escalation will not occur. The study will be closed to accrual.  
 
5.3.2 
Intra-Patient Escalation 
Intra-patient dose escalation is not allowed. 
 
5.4 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website (http://ctep.cancer.gov). Any suspected or confirmed 
dose-limiting toxicity should be reported immediately (within 24 hours) to the Study Chair. 


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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 Cycles 1 and 2 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 
protocol therapy 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, regardless of baseline. 
See Appendix XV for values that represent thresholds between CTCAE 
grades for ALT, AST, GGT and bilirubin. 
• 
Grade 3 fever  
• 
Grade 3 infection 
• 
Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to supplementation. 
• 
Grade 3 or 4 hypertriglyceridemia that returns to Grade ≤ 2 prior to the 
start of the next treatment cycle. The severity (grade) of 
hypertriglyceridemia is based upon fasting levels. If Grade 3 or 4 
triglycerides are detected when routine (non-fasting) laboratory studies 
are performed, the test should be repeated within 3 days in the fasting 
state to permit accurate grading (see Section 6.4). 
• 
Grade 3 hyperglycemia that returns to a fasting glucose value ≤ 250 
mg/dL or a fasting glucose of value ≤ 13.9 mmol/L (with or without the 
use of insulin or oral diabetic agents) prior to the start of the next 
treatment cycle. Medical management of hyperglycemia should be based 
on fasting levels.  If routine (non-fasting) laboratory studies are 
performed and indicate the potential for intervention, the test should be 
repeated within 3 days in the fasting state to permit accurate medical 
management and grading (see Section 6.6).  
• 
Grade 3 or 4 hypercholesterolemia that returns to ≤ Grade 2 after 
initiation of lipid lowering medication prior to the next treatment cycle. 
The severity (grade) of hypercholesterolemia is based upon fasting levels. 
If Grade 3 or 4 hypercholesterolemia is detected when routine (non-
fasting) laboratory studies are performed, the test should be repeated 
within 3 days in the fasting state to permit accurate grading (see Section 
6.5). 
 
5.5.1.2 Non-hematological toxicity that causes a delay of > 21 days between 
treatment cycles. 
 
5.5.1.3 Note: Allergic reactions that necessitate discontinuation of study drug will 


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not be considered a dose-limiting toxicity. 
 
5.5.2 
Hematological dose limiting toxicity 
In patients evaluable for hematological toxicity (see Section 4.1.8.1), hematological 
dose-limiting toxicity is defined as: 
• 
Day 8: 
o Grade 4 neutropenia or platelets < 50,000/mm3 on Day 8 that does 
not resolve to ANC ≥ 750/mm3 and platelets ≥ 50,000/mm3 
(transfusion independent) by Day 11 will be considered dose-
limiting (see Section 6.1). 
• 
Grade 4 thrombocytopenia (platelet count < 25,000/mm3) for ≥ 7 days 
• 
Grade 4 anemia, not due to malignant infiltration. 
• 
Grade 4 neutropenia that lasts for > 7 days 
• 
Grade 3 thrombocytopenia with clinically significant bleeding, petechiae 
or purpura, or that persists for ≥ 7 days, and/or that requires platelet 
transfusion. 
• 
Myelosuppression that causes a delay of > 21 days between treatment 
cycles. 
 
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 Modification Guidelines for Cycle 1, Day 8 
 
For Patients Evaluable for Hematological Toxicity: 
 
Hematological 
Toxicity on Day 8: 
Thrombocytopenia 
Action 
Platelets ≥ 
50,000/mm3 
• 
Continue protocol therapy. 


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Platelets < 
50,000/mm3 without 
clinically significant 
bleeding, petechial 
or purpura 
• 
Patients who have platelets < 50,000/mm3 on Day 8 will have the 
dose of ABI-009 withheld.  
• 
If the toxicity resolves to platelets ≥ 50,000/mm3 (transfusion 
independent) by Day 11, the Day 8 dose of ABI-009 may be given.  
• 
If the toxicity does not resolve to platelets ≥ 50,000/mm3 by Day 
11, the Day 8 dose of ABI-009 will be omitted and this will be 
considered a DLT. Patients should receive subsequent cycles of 
ABI-009 but at the next lower dose level or if the patient is being 
treated on the lowest dose level, protocol therapy should be 
discontinued. 
 
Platelets < 
50,000/mm3 with 
clinically significant 
bleeding, petechial 
or purpura 
• 
If Grade 3 thrombocytopenia with clinically significant bleeding, 
petechial or purpura, omit Day 8 dose of ABI-009, and this will be 
considered a DLT. Patients should receive subsequent cycles of 
ABI-009 but at the next lower dose level or if the patient is being 
treated on the lowest dose level, protocol therapy should be 
discontinued.  
• 
If persists for ≥ 7 days, patients should receive subsequent doses of 
ABI-009 at the next lower dose level or if the patient is being treated 
on the lowest dose level, protocol therapy should be discontinued. 
Other 
thrombocytopenia 
DLTs per Section 
5.5.2 on Day 8 
• 
As above, per platelet grade and bleeding. 
 
 
Hematological 
Toxicity on Day 8: 
Neutropenia 
Action 
Grade 1-3 
• 
Continue protocol therapy. 


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Grade 4 
• 
Patients who have Grade 4 neutropenia on Day 8 will have the dose 
of ABI-009 withheld. If the toxicity resolves to ANC ≥ 750/mm3 by 
Day 11, the Day 8 dose of ABI-009 may be given.  
• 
If the toxicity does not resolve to ANC ≥ 750/mm3 by Day 11, the 
Day 8 dose of ABI-009 will be omitted and this will be considered 
a DLT. Patients should receive subsequent cycles of ABI-009 but at 
the next lower dose level or if the patient is being treated on the 
lowest dose level, protocol therapy should be discontinued. 
• 
 Patients who require that their Day 8 dose of ABI-009 be omitted 
for Grade 4 neutropenia after one dose reduction (if starting at DL -
1) or if the patient is being treated on the lowest dose level, protocol 
therapy should be discontinued. 
 
Other 
neutropenia 
DLTs per Section 
5.5.2 on Day 8 
• 
As above in Grade 4 neutropenia. 
 
 
Non-Hematological 
Toxicity on Day 8 
Action 
Grade 1-2 
• 
Continue protocol therapy. 
Grade 3-4 
• 
Patients who have Grade 3 or Grade 4 non-hematological toxicity 
attributable to the study drug prior to the Day 8 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 8, 
the dose of ABI-009 may be given but at the next lower dose level. 
 
• 
Patients who have Grade 3 or Grade 4 non-hematological toxicity 
attributable to the study drug on Day 8 prior to dosing (with the 
exception of the DLT exclusions in Section 5.5.1.1) will have their 
dose of ABI-009 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 11, the Day 8 dose of ABI-009 may be 
given but at the next lower dose level. If the toxicity does not resolve 
by Day 11, the Day 8 dose of ABI-009 will be omitted. Patients 
should receive subsequent cycles of ABI-009 but with dose 
modifications according to Section 6.2 and Section 6.3. 
 
 
6.2 
Dose Modification Guidelines for Cycle 1 
 


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Hematological 
Toxicity: 
Thrombocytopenia 
Action 
Thrombocytopenia 
DLTs per Section 
5.5.2 
• 
Patients who have dose-limiting thrombocytopenia as defined in 
Section 5.5.2 should receive subsequent cycles at the next lower 
dose level of ABI-009; if the patient is being treated on the lowest 
dose level, protocol therapy should be discontinued.  
• 
Patients who experience dose-limiting thrombocytopenia after one 
dose reduction (if starting at DL -1) or if the patient is being treated 
on the lowest dose level, protocol therapy should be discontinued.  
• 
Patients who require that their Day 8 dose of ABI-009 be omitted 
for platelets < 50,000/mm3 (Section 6.1) after one dose reduction (if 
starting at DL -1) or if the patient is being treated on the lowest dose 
level, protocol therapy should be discontinued. 
 
 
 
 
 
 
 
Hematological 
Toxicity: 
Neutropenia 
Action 


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Neutropenia DLTs 
per Section 5.5.2 
• 
Patients who have dose-limiting neutropenia as defined in Section 
5.5.2 with no other dose-limiting toxicity should receive the same 
dose of ABI-009 in the next cycle with myeloid growth factor 
support administered the next day after the Day 8 dose of ABI-009 
is given during subsequent cycles (See Section 7.4). [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 of 
ABI-009 followed by myeloid growth factor support beginning the 
next day after the Day 8 dose of ABI-009 is given for subsequent 
cycles (See Section 7.4).  
• 
Patients who experience dose-limiting neutropenia after the addition 
of myeloid growth factor and one dose reduction of ABI-009 must 
be removed from protocol therapy. 
• 
Patients who experience early dose-limiting neutropenia requiring 
the omission of the Day 8 dose of ABI-009 (as defined in Section 
6.1) should receive subsequent cycles of protocol therapy but at the 
next lower dose level of ABI-009 or if the patient is being treated 
on the lowest dose level, protocol therapy should be discontinued.  
• 
Patients who require that their Day 8 dose of ABI-009 be omitted 
for Grade 4 neutropenia after one dose reduction (if starting at DL -
1) or if the patient is being treated on the lowest dose level, protocol 
therapy should be discontinued. 
 
 
 
Other 
Hematological 
Toxicity 
Action 
Other hematologic 
DLTs per Section 
5.5.2 
• 
Patients who have a dose-limiting hematological toxicity that does 
not resolve to meet eligibility or baseline parameters within 21 days 
after the planned start of the next treatment cycle must be removed 
from protocol therapy. 
 
 
 
 
 
 
Non-Hematological 
Toxicity 
Action 


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Non-hematological 
DLTs per Section 
5.5.1 
• 
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 of ABI-009. 
• 
If any non-hematological dose-limiting toxicity recurs after one 
dose reduction of ABI-009, the patient must be removed from 
protocol therapy. 
• 
Patients who have a dose-limiting non-hematological toxicity that 
does not resolve to baseline or eligibility within 21 days after the 
planned start of the next treatment cycle must be removed from 
protocol therapy. 
 
 
6.3 
Dose Modification Guidelines for Cycle 2 or greater 
 
Hematological 
Toxicity: 
Thrombocytopenia 
Action 
Platelets ≥ 
75,000/mm3 
• 
Continue protocol therapy. 
Platelets < 
75,000/mm3 
• 
ABI-009 as per Section 6.1 & Section 6.2. 
• 
Irinotecan & temozolomide will be continued at full dose. 
Platelets < 
50,000/mm3 
• 
ABI-009 as per Section 6.1 & Section 6.2. 
• 
Irinotecan & temozolomide will be continued at full dose. 
Other 
thrombocytopenia 
DLTs per Section 
5.5.2 on Day 8 
• 
ABI-009 as per Section 6.1 & Section 6.2. 
• 
Irinotecan & temozolomide will be continued at full dose. 
 
 
 
Hematological 
Toxicity: 
Neutropenia 
Action 
Grade 1-3 
• 
Continue protocol therapy. 
Grade 4 
• 
ABI-009 as per Section 6.1 & Section 6.2. 
• 
Irinotecan & temozolomide will be continued at full dose. 
Other 
neutropenia 
DLTs per Section 
5.5.2 on Day 8 
• 
ABI-009 as per Section 6.1 & Section 6.2. 
• 
Irinotecan & temozolomide will be continued at full dose. 


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Non-Hematological 
Toxicity  
Action 
Grade 1-2 
• 
Continue protocol therapy. 
Grade 3-4 
• 
ABI-009 as per Section 6.1 & Section 6.2. 
• 
Irinotecan & temozolomide will be continued at full dose. 
 
 
 
Non-Hematological 
Toxicity 
Action 
Non-hematological 
DLTs per Section 
5.5.1 
• 
ABI-009 as per Section 6.1 & Section 6.2. 
• 
Irinotecan & temozolomide will be continued at full dose. 
• 
Patients who experience dose-limiting non-hematological dose-
limiting toxicity after one dose reduction (if starting at DL -1) or if 
the patient is being treated on the lowest dose level, protocol therapy 
should be discontinued. 
• 
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. 
 
6.4 
Dose Modifications for Elevated Fasting Triglycerides 
The following guidelines should be used for patients who develop elevated fasting 
triglycerides. 
Continue irinotecan and temozolomide at full dose for cycles 2 or greater. 
 
Grade 
Action 
Grade 2 
• 
Continue ABI-009; if triglycerides are between 301 and 400 
mg/dL consider treatment with an HMG-CoA reductase inhibitor 
depending upon recommendations of institutional hyperlipidemia 
consultants. HMG-CoA reductase inhibitor is recommended if 
triglycerides are between 401 and 500 mg/dL 
Grade 3-4 
• 
Hold ABI-009 until recovery to ≤ Grade 2 
• 
An HMG-CoA reductase inhibitor should be started, and dosages 
should be adjusted based upon recommendations from 
institutional hyperlipidemia consultants 
• 
Upon retreatment at the same dose level, if Grade 3 or 4 toxicity 
recurs, lipid lowering medication should be adjusted in 
consultation with institutional hyperlipidemia consultants. ABI-
009 should be held until recovery to ≤ Grade 2. 
• 
Upon retreatment with ABI-009 concurrent with an HMG-CoA 
reductase inhibitor, if Grade 3 or 4 elevations recur, ABI-009 
should be held until recovery to ≤ Grade 2. Further lipid lowering 


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medication options should be discussed with institutional 
hyperlipidemia consultants. Upon recovery to ≤ Grade 2, ABI-
009 should be restarted at the next lower dose level. If the patient 
is being treated on the lowest dose level, protocol therapy should 
be discontinued. 
 
 
6.5 
Dose Modifications for Elevated Fasting Cholesterol 
The following guidelines should be used for patients who develop elevated fasting 
cholesterol. 
Continue irinotecan and temozolomide at full dose for cycles 2 or greater. 
 
Grade 
Action 
Grade 2 
• 
Continue ABI-009; consider treatment with an HMG-CoA 
reductase inhibitor depending upon recommendations of 
institutional hyperlipidemia consultants. 
Grade 3 
• 
An HMG-CoA reductase inhibitor should be started, and dosages 
adjusted 
based 
upon 
recommendations 
of 
institutional 
hyperlipidemia consultants. 
• 
It is expected that optimal effects of the lipid lowering medication 
will be observed 2-4 weeks after its initiation. Treatment with 
ABI-009 is to be restarted at the same dose level when recovery 
of hypercholesterolemia to ≤ Grade 2 is observed. 
Grade 4 
• 
Hold ABI-009. 
• 
An HMG-CoA reductase inhibitor should be started, and dosages 
should be adjusted based upon recommendations from 
institutional hyperlipidemia consultants. 
• 
It is expected that optimal effect of the lipid lowering medication 
will be observed 2-4 weeks after initiation. ABI-009 is to be 
restarted at the same dose level when recovery to ≤ Grade 2 
cholesterol is observed. 
• 
Upon retreatment with ABI-009 concurrent with an HMG-CoA 
reductase inhibitor, if Grade 4 elevations recur, ABI-009 should 
be held until recovery to ≤ Grade 3. Further lipid lowering 
medication options should be discussed with institutional 
hyperlipidemia consultants. Upon recovery to ≤ Grade 3 
cholesterol, ABI-009 should be restarted at the next lower dose 
level. If the patient is being treated on the lowest dose level, 
protocol therapy should be discontinued. 
 
6.6 
Dose Modifications for Hyperglycemia 
The following guidelines should be used for patients who develop hyperglycemia based 
on fasting glucose levels. 
 
Grade 
Action 
Grade 1-2 
• 
Continue ABI-009.  Grade 2 may initiate oral antiglycemic 
agent*. 
Grade 3 
• 
Initiate insulin therapy  as indicated. 
• 
Hold ABI-009 until fasting serum glucose is consistently ≤ 250 


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mg/dL or  ≤ 13.9 mmol. 
• 
Resume ABI-009 at same dose IF patient is asymptomatic, AND 
fasting serum glucose is consistently ≤ 250 mg/dL or  ≤ 13.9 
mmol ) without glycosuria. The patient may continue to receive 
concomitant insulin or an oral diabetic agent for the management 
of hyperglycemia while receiving ABI-009. 
• 
If the fasting serum glucose value of  ≥ 250 – 500 mg/dL or > 
13.9 – 27.8 mmol/L recurs and does not return to a fasting value 
≤ 250 mg/dL or ≤ 13.9 mmol/L despite a stable dose of insulin 
and an oral diabetic agent Insulin and anoral diabetic agents 
should be tried before declaring a patient’s hyperglycemia 
refractory to therapy. If the fasting serum glucose value of ≥ 250 
mg/dL or > 13.9 mmol/L recurs and does not return to a fasting 
value ≤ 250 mg/dL or ≤ 13.9 mmol/L  despite the use of insulin 
and an oral diabetic agent, subsequent doses of ABI-009 should 
be decreased to the next lower dose level. 
• 
If a patient experiences recurrence of a fasting serum glucose ≥ 
250 mg/dL or > 13.9 mmol/L  which does not return to ≤ 250 
mg/dL or  ≤ 13.9 mmol despite insulin, an oral diabetic agent 
AND the dose reduction, patient should be taken off protocol 
therapy. If the patient was already being treated at the lowest dose 
level, or if hyperglycemia > 250 mg/dL or > 13.9 mmol/L  has 
recurred despite reduction of ABI-009 to the lowest dose level, 
the patient should be taken off protocol therapy. 
Grade 4 
• 
Hold ABI-009 until resolution to fasting serum glucose is 
consistently ≤ 250 mg/dL or  ≤ 13.9 mmol. 
• 
Resume ABI-009 with one dose level reduction IF patient is 
asymptomatic AND serum glucose is consistently consistently ≤ 
250 mg/dL or  ≤ 13.9 mmol  without glycosuria. The patient may 
continue to receive concomitant insulin or an oral diabetic agent 
for the management of hyperglycemia while receiving ABI-009. 
• 
If Grade 4 hyperglycemia recurs and does not return to 
consistently ≤ 250 mg/dL or  ≤ 13.9 mmol (despite a stable dose 
of insulin, an oral diabetic agent, and dose reduction to the next 
lower dose level, then subsequent doses of ABI-009 should be 
reduced again so that the new dose is two dose levels below the 
patient’s starting dose. If the patient was already being treated at 
the lowest dose level, or if the fasting serum glucose is > 250 
mg/dL or  > 13.9 mmol has recurred despite reduction of ABI-
009 to the lowest dose level, the patient should be taken off 
protocol therapy. 
*Recommended guidelines for use of oral diabetic agents: 
Initiation of treatment for hyperglycemia should occur under the guidance of a pediatric 
endocrinologist at the local institution. Metformin or other oral anti-hyperglycemia agent may 
be used per local endocrinologist’s recommendations. Insulin therapy should be directed by 
specialists in pediatric diabetes, with the goal of normal fasting blood sugars < 126 mg/dL and 
HgbA1C < 8%. 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 


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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 (except aprepitant), fluids, electrolytes and 
general supportive care are to be used as necessary. See Appendix VIII for information on 
management of irinotecan-induced diarrhea. See Appendix X, Appendix XIII, and Appendix 
XIV for drugs that should not be used concomitantly due to potential interactions with ABI-009, 
irinotecan, or temozolomide. 
 
Please refer to COG Supportive Care Guidelines found under the Protocol Reference Materials 
tab under Standard Sections for Protocols at 
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. 
 
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 or for culture proven bacteremia or invasive 
fungal infection. The Study Chair should be notified before growth factors are initiated. 
 
7.5 
Concomitant Medications (Study Specific) 
 
a. HMG-CoA reductase inhibitors may be used to treat elevated fasting triglycerides 
and cholesterol. See Section 6.4 and Section 6.5. 
 
While on study, the following BCRP inhibitors (cyclosporine, eltrombopag, 
gefitinib) should be avoided if possible, and concomitant use of UGT1A1 
inhibitors, such as diclofenac, ketoconazole, probenecid, silibinin, nilotinib and 
atazanavir, should be avoided because of potential for increased irinotecan toxicity. 
 
Because rapamycin is a substrate for both CYP3A4 and P-gp, concomitant 
administration with inhibitors or inducers of CYP3A4 and P-gp may alter the 
pharmacokinetics of ABI-009. Inhibitors of CYP3A4 may decrease the metabolism 
of rapamycin and increase rapamycin concentrations, while inducers of CYP3A4 
may increase the metabolism of rapamycin and decrease rapamycin concentrations. 
Drugs that may increase rapamycin blood concentrations include antifungal agents 
(e.g., voriconazole, itraconazole, posaconazole), macrolide antibiotics (e.g., 
clarithromycin, telithromycin), and other drugs (e.g., HIV-protease inhibitors). 
Drugs that may decrease rapamycin concentrations include anticonvulsants (e.g., 
carbamazepine, phenobarbital, phenytoin), and antibiotics (e.g., rifabutin, 
rifampin). See Appendix XIV for more information on CYP3A4 inducers and 
inhibitors. 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation 


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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 must be 
obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging if 
necessary). 
 
STUDIES TO BE OBTAINED 
Pre-Study 
Cycles 1 & 2 
Prior to Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
Height, weight, BSA 
X 
Prior to Cycle 2 
X 
Performance Status 
X 
Prior to Cycle 2 
X 
CBC, differential, platelets 
X 
Twice Weekly 
(every 3 to 4 days)3 
Weekly4 
Pharmacokinetics1 
X 
X 
 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO43-, 
Mg++, glucose11 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Albumin 
X 
Prior to Cycle 2 
X 
INR 
X 
 
 
Total Cholesterol, Triglycerides10 
X 
Weekly 
X 
Amylase, Lipase 
X 
Prior to Cycle 2 
X 
Pregnancy Test2 
X 
 
 
Tumor Disease Evaluation 
X 
End of Cycles 112 & 
2 
Every other cycle x 2 
then q 3 cycles5 
Bone Marrow Evaluation7 
X 
 
 
Medication Diary6 
 
Cycle 2 
X 
Oxygen Saturation 
X 
Weekly 
X8 
Tumor Tissue Studies9 
X 
 
 
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
See Section 8.3 for timing of PK studies. 
2 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; 
sexually active patients must use an acceptable method of birth control.  Abstinence is an 
acceptable method of birth control. 
3 
If patients have Grade 4 neutropenia then CBCs should be checked at least every 2-3 days until 
recovery to Grade 3 or until meeting the criteria for dose limiting toxicity. 
4 
If patients develop Grade 4 neutropenia or Grade 4 thrombocytopenia 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 


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patient has progressed based on clinical or laboratory evidence, he/she may opt not to confirm 
this finding radiographically. 
6 
Medication diary (see Appendix IX) should be reviewed after completion of each treatment cycle 
and uploaded into RAVE. 
7 
As appropriate for disease, to confirm bone marrow involvement at enrollment, or as clinically 
indicated. 
8 
Required prior to each cycle; weekly for subsequent cycles only if clinically indicated. 
9 
See Section 8.4 and Appendix XII for details of Tumor Tissue studies. 
10 If Grade 3 or 4 hypercholesterolemia or Grade 3 or 4 hypertriglyceridemia is detected when 
routine (non-fasting) laboratory studies are performed, the tests should be repeated within 3 days 
in the fasting state to permit accurate grading. 
11 If the initial blood glucose is a random sample that is outside of the normal limits, then follow-
up fasting blood glucose can be obtained and must be within the upper normal limits for age. If  
blood glucose is ≥ 250 – 500 mg/dL or > 13.9 – 27.8 mmol/L when routine (non-fasting) 
laboratory studies are performed, the test should be repeated within 3 days in the fasting state to 
permit accurate grading. 
12 Patients experiencing progressive disease (defined in Section 12.6.4) in Cycle 1 can continue to 
Cycle 2 as long as 1) they have not experienced a DLT in Cycle 1, 2) they have not met any off 
study criteria listed in section 10.2, and 3) they meet all guidelines established in section 5.2. 
Patients must have at least stable disease to continue to Cycles 3 and later. 
 
8.2 
Radiology Studies 
 
8.2.1 
Central Radiology Review for Response: Patients who respond (CR, PR) to therapy 
or have long term stable disease (SD) (≥ 6 cycles) on protocol therapy will be 
centrally reviewed. COG Operations Center will notify the Imaging Center of any 
patient requiring central review. The Imaging Center will then request that the 
treating institution forward the requested images for central review. The central 
image evaluation results will be entered into RAVE for review by the COG 
Operations Center and for data analysis.  
 
The images are to be forwarded electronically to the Imaging Research Center at 
Children’s Hospital Los Angeles via the ImageInBox. 
 
COG institutions that are not connected via the ImageInBox can send the images on 
CD ROM or USB flash drive. Submitted imaging studies should be clearly marked 
with the COG patient ID, study number (ADVL1514) and date and shipped to Syed 
Aamer at the address below: 
 
 
 
 
 
 
 
 
8.3 
Pharmacology (required) 
 


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8.3.1 
Description of Studies and Assay 
 
• 
ABI-009 concentrations will be determined by a validated LC/MS/MS 
method (AADi). 
• 
Irinotecan and SN-38 concentrations will be determined using a validated 
HPLC assay with fluorescence detection (Dr. Joel Reid/Mayo Clinic). 
 
8.3.2 
Sampling Schedule (See Appendix XI-A and Appendix XI-B) 
Whole blood samples (2 ml) will be obtained prior to drug administration and at the 
following time points: 
 
8.3.2.1 ABI-009 Sampling Schedule during Cycle 1 (Single Agent) and Cycle 2 
(Combination Therapy): 
 
• 
Day 1: Pre-dose, end of infusion, and then 1, 2, 4, and 8 hrs after beginning 
of infusion. 
• 
Day 2: 24 hours post-Day 1 ABI-009 dose. 
• 
Day 4 (± 1 day): 72 hours ( ± 24 hours) post- Day 1 ABI-009 dose 
• 
Day 8: Pre-ABI-009 dose. 
 
8.3.2.2 Irinotecan/SN-38 Sampling Schedule during Cycle 2 (Combination 
Therapy): 
 
• 
Day 1: Pre-dose, and then 10 min, 1 hr, 3 hrs, and 6 hrs post-irinotecan dose. 
• 
Day 2: Pre-Day 2 irinotecan dose (24 hours after Day 1 irinotecan dose). 
 
8.3.3 
Sample Collection and Handling Instructions 
 
8.3.3.1 ABI-009 
Blood samples (2 ml) will be collected in EDTA tubes at a site distant from 
the infusion for pharmacokinetic evaluation. Samples cannot be drawn from 
the 2nd lumen of a multi-lumen catheter through which drug is being 
administered. Record the exact time that the sample is drawn along with the 
exact time that the infusion is started and stopped. 
If the duration of infusion is changed, the sample should be collected 
immediately before termination of the infusion. 
 
8.3.3.2 Irinotecan 
Blood samples (2 ml) will be collected in heparinized tubes at a site distant 
from the infusion for pharmacokinetic evaluation. Samples cannot be drawn 
from the 2nd lumen of a multi-lumen catheter through which drug is being 
administered. Record the exact time that the sample is drawn along with the 
exact time that the drug is administered. 
 
8.3.4 
Sample Processing 
 


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8.3.4.1 ABI-009 
 
• 
After drawing blood into EDTA tubes, gently mix by inversion 8-
10 times. 
• 
Keep on wet ice until frozen; freeze as soon as possible. 
• 
Samples can be placed on dry ice for short-term storage; however, 
must be placed in the appropriate freezer within 24 hours of the 
draw-time (storage in -80 °C is preferred; storage at -20 °C for no 
more than 60 days is acceptable). 
 
8.3.4.2 Irinotecan 
Blood collected into sodium heparin tubes should be gently mixed by 
immediately inverting the tubes. Blood samples will then be centrifuged 
immediately for 15 minutes in a refrigerated centrifuge set at 805 g. Next, 
remove the plasma using a transfer pipette and transfer the plasma into two 
separate 3.5 mL polypropylene tubes. Next, immediately freeze the tubes at 
-80 °C and store until delivery to the Mayo Clinic (see Section 8.3.6 for 
shipping instructions). 
 
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 exact 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 
 
8.3.6.1 ABI-009 
Samples should be batched per patient and shipped frozen on dry ice in 
opaque containers at the end of Cycle 2. 
 
Samples should be shipped using FedEx priority overnight to: 
 
AIT Bioscience 
Attn: Sample Receipt 
7840 Innovation Blvd. 
Indianapolis, IN 46278 
 
On the day of each shipment, notify samples@aitbioscience.com of the 
pending shipment, including tracking information. 
 
8.3.6.2 Irinotecan 
Samples will be held until all samples have been obtained and then sent as a 
single batch. Batched samples should be sent frozen on dry ice by FedEx 
priority overnight to: 
 
 
 


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A copy of the irinotecan pharmacokinetics specimen transmittal form should 
accompany the shipment and another copy should be faxed to 507-293-0107. 
Samples should only be shipped on a Monday-Thursday to allow for 
weekday 
delivery. 
Avoid 
holiday 
shipments. 
Email 
 
 
(
) with the tracking number at the time of sample 
shipment. 
 
8.4 
Tissue Studies (required) 
The key objective of the tumor molecular profiling is to identify specific markers related to 
the mTOR pathway that may be predictive of response to ABI-009. 
Archival tumor tissue (or unstained tissue slides) 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 Study of S6K1 
Tumor tissue will be analyzed by immunohistochemistry. Antibody to be 
used for pS6(S235) is obtained from Cell Signaling, Catalog #2211S. 
 
8.4.1.2 Study of 4E-BP1 
Tumor tissue will be analyzed by immunohistochemistry. Antibody to be 
used for p4EBP1 is obtained from Cell Signaling, Catalog #2855S. 
 
8.4.2 
Sample Collection, Handling, and Shipment 
Paraffin-embedded tissue blocks or slides will be shipped to the Histopathology Core 
of the Brigham and Women’s Hospital. If sending tissue slides, it is preferred that 8-
10 unstained slides (minimum: 6) are being sent. Detailed instructions regarding 
collection, handling, and shipping of tissue samples are located in the Tissue Study 
Form (Appendix XII). 
 
8.4.2.1 Tumor Block Instructions 
• 
Paraffin-embedded tumor specimens must be packaged appropriately and 
shipped at room temperature in the tumor block bags provided. 
• 
Ensure that the specimen is labeled with the subject ID, both on the block and 
on the block bag. 
 
8.4.2.2 Tumor Slides Instructions 
• 
Cut 8-10 (minimum: 6) tissue sections 4-5 microns thick and mount on 
positively charged slides. 
• 
Number sequentially; write the subject ID and original block ID on frosted end 
of slide. 
• 
Place the slides in the pre-labeled slide holders provided and write the subject 
ID on the label. 
 


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All samples must be shipped under ambient conditions, Monday – Thursday ONLY 
with a corresponding pathology report containing the subject ID and the block ID. 
Ensure to de-identify the pathology report. 
 
Before shipping, a “Work Request for Processing, Sectioning & Staining” and a “Work 
Request for Standardized Immunohistochemistry Services” must be submitted online 
at http://pathcore.hms.harvard.edu. Please follow the instructions posted on the 
protocol page of the COG website. 
 
Samples should be shipped to:  
 
Specialized Histopathology Core 
Brigham and Women’s Hospital 
20 Shattuck Street 
Thorn Building, Rm 603C 
Boston, MA 02115 
 
 
Please contact phase1@childrensoncologygroup.org or the COG study-specific 
research coordinator with protocol or work order related questions. 
 
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). 
 
 
 
9.0 
AGENT INFORMATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.2 
CEFIXIME 
(Suprax®) NSC# NA 
 
 
 
 
 
 
(11/17/17) 
 
9.2.1 
Source and Pharmacology 
Cefixime is a third generation cephalosporin antibiotic for oral administration that 
inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding 
proteins and interfering with the final transpeptidation step of peptidoglycan synthesis. 
Its spectrum of activity is similar to other third-generation agents, including 
Enterobacteriaceae, and β-lactamase producing H. influenzae and N. gonorreae, and 
Staph. aureus. When taken orally, it is about 40%-50% absorbed whether administered 
with or without food. The area under the time versus concentration curve is greater by 
approximately 10%-25% with the oral suspension than with the tablet after doses of 
100 to 400 mg, when tested in normal adult volunteers. This increased absorption 
should be taken into consideration if the oral suspension is to be substituted for the 
tablet. Cefixime serum half-life is approximately 3-4 hours. It is excreted primarily by 
the kidney. There is no evidence of metabolism of cefixime in vivo. 
 
9.2.2 
Toxicity 
 
Incidence 
Toxicities 
Common 
(>20% of patients) 
None known 
Occasional 
(4-20% of patients) 
 
Diarrhea, nausea, flatulence, loose or frequent stools 
 


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Incidence 
Toxicities 
Rare 
(<3% of patients) 
Erythema multiforme, pruritus, rash maculo-papular, 
Stevens-Johnson syndrome, toxic epidermal necrolysis, 
urticaria, 
angioedema, 
abdominal 
pain, 
pseudomembranous colitis, dyspepsia; transient white 
blood cell decrease, neutrophil count decreased, platelet 
count 
decreased; 
transient 
jaundice, 
alanine 
aminotransferase increased, aspartate aminotransferase 
increased, bilirubin increased; anaphylaxis, allergic 
reaction; dizziness, headache, seizure, acute kidney 
injury, creatinine increased, vaginal infection, vomiting. 
Pregnancy & Lactation 
Pregnancy Category B 
Teratogenic effects were not observed in animal 
reproduction studies. Cefixime crosses the placenta and 
can be detected in the amniotic fluid. There are no well-
controlled studies of cefixime in pregnant women; 
effects of cefixime on the fetus are unknown. An increase 
in most types of birth defects was not found following 
first trimester exposure to cephalosporins. It is not known 
whether cefixime is excreted in human milk. 
 
9.2.3 Formulation and Stability 
Cefixime is available in scored 400 mg film coated tablets, 400 mg capsules, 100 mg 
chewable tablets, and 200 mg chewable tablets.  The chewable tablets are tutti-frutti 
flavor and contain aspartame and fd&c red #40 aluminum lake.  Cefixime is also 
available in two strengths as a powder for oral suspension, which when reconstituted, 
provides either a 100 mg/5mL or 200 mg/5 mL suspension. The powder for oral 
suspension is strawberry flavored and contains sodium benzoate, sucrose, and xanthan 
gum. After reconstitution, suspension may be stored for 14 days at room temperature 
or under refrigeration. 
 
Cefixime tablets and powder for oral suspension are stored at 20 - 25°C (68 - 77°F). 
Do not freeze. The suspension bottle should be kept tightly closed. 
 
9.2.4 
Guidelines for Administration 
See Treatment and Dose Modification sections of the protocol. 
 
Cefixime may be administered with or without food. Administration with food may 
decrease abdominal distress. Shake the suspension prior to withdrawing dose or 
administration. 
 
9.2.5 
Supplier 
Commercially available from various manufacturers. See package insert for further 
information  
 
 
9.3 
IRINOTECAN 


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[CPT-11,Camptothecin-11,7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-
camptothecin), Camptosar®], NSC #616348 
 
 
 
(03/07/17) 
 
9.3.1 
Source and Pharmacology 
Irinotecan is a semisynthetic water-soluble analog of camptothecin (a plant alkaloid 
isolated from Camptotheca acuminata). Irinotecan is a prodrug that requires 
conversion, by the carboxylesterase enzyme to the topoisomerase-I inhibitor, 
SN-38 in order to exert anti-tumor activity. SN-38 is approximately 1000 times 
more potent than irinotecan. Camptothecins interact specifically with the enzyme 
topoisomerase I which relieves torsional strain in DNA by inducing reversible 
single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the 
topoisomerase I-DNA complex and prevent religation of these single-strand breaks. 
Current research suggests that the cytotoxicity of irinotecan is due to double-strand 
DNA damage produced during DNA synthesis when replication enzymes interact 
with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or 
SN-38. Renal excretion is a minor route of elimination of irinotecan. The majority 
of the drug is metabolized in the liver. SN-38 is conjugated to glucuronic acid and 
this metabolite has no anti-tumor activity. The extent of conversion of SN-38 to its 
glucuronide has been inversely correlated with the risk of severe diarrhea, because 
the other major route of SN-38 excretion is biliary excretion by canalicular 
multispecific organic anion transporter (cMOAT) which presumably leads to 
mucosal injury. In addition, APC and NPC are oxidative metabolites of irinotecan 
dependent on the CYP3A4 isoenzyme. After intravenous infusion of irinotecan in 
humans, irinotecan plasma concentrations decline in a multiexponential manner, 
with a mean terminal elimination half-life of about 6 to 12 hours. The mean 
terminal elimination half-life of the active metabolite SN-38 is about 
10 to 20 hours. Irinotecan is 30% to 68% bound to albumin and SN-38 is 
approximately 95% bound to albumin. 
 
9.3.2 
Toxicity 
 


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Incidence 
Toxicities 
Common 
(> 20% of patients)  
• 
Anemia 
• 
Thrombocytopenia 
• 
Neutrophil count decreased 
• 
White blood cell count decreased 
• 
Nausea 
• 
Vomiting 
• 
Constipation 
• 
Anorexia 
• 
Fever 
• 
Asthenia 
• 
Cholinergic symptoms: (rhinitis, increased salivation, miosis, lacrimation, 
diaphoresis, flushing, and intestinal hyperperistalsis that can cause 
abdominal cramping and diarrhea) 
• 
Alopecia 
• 
Bilirubin increased 
• 
Mucositis 
• 
Dyspnea 
• 
Cough 
• 
Weight loss 
• 
Pain 
Occasional 
(4-20% of patients)  
• 
Abdominal fullness 
• 
Flatulence 
• 
Vasodilation 
• 
Hypotension 
• 
Dehydration 
• 
Edema 
• 
AST increased 
• 
Alkaline phosphatase increased 
• 
Ascites 
• 
Jaundice 
• 
Febrile neutropenia 
• 
Infection 
• 
Headache 
• 
Dizziness 
• 
Chills 
• 
Insomnia 
• 
Rash 
• 
Dyspepsia 
• 
Somnolence 
• 
Thromboembolic events 
• 
Pneumonia 
Rare 
(≤ 3% of patients)  
• 
Anaphylaxis 
• 
Bradycardia 
• 
Disorientation/confusion 
• 
Colitis 
• 
Renal failure (secondary to severe dehydration) 


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• 
Ileus 
• 
Pancreatitis 
• 
Pneumonitis (L) 
Pregnancy & 
Lactation 
Fetal toxicities and teratogenic effects of irinotecan have been noted in animals at 
doses similar or less than those used in humans. Toxicities include: decreased 
skeletal ossification, multiple anomalies, low birth weight and increased fetal 
mortality. It is not known if irinotecan is excreted into breast milk but it is 
excreted into rat milk. 
(L) Toxicity may also occur later 
 
 
9.3.3 
Formulation & Stability 
Each mL of irinotecan injection contains 20 mg irinotecan (on the basis of the 
trihydrate salt), 45 mg sorbitol, and 0.9 mg lactic acid. When necessary, pH has been 
adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. 
Irinotecan is available in single-dose amber glass vials in 40 mg (2 mL),100 mg 
(5 mL), 300 mg (15 mL), and 500 mg (25 mL). Store at controlled room temperature 
15°-30°C (59°-86°F). Protect from light. It is recommended that the vial (and 
backing/plastic blister) should remain in the carton until the time of use. 
9.3.4 
Guidelines for Administration 
See Treatment and Dose Modifications sections of the protocol. 
 
For oral use, the appropriate volume of irinotecan solution (20 mg/ml) is drawn up 
undiluted into a plastic oral syringe. Each dose is to be mixed with juice (crangrape, 
cranapple, cranberry, or other “cran” juice or juice cocktail) immediately before 
administration. The oral syringes containing undiluted irinotecan are stable for 21 days 
when stored in a refrigerator. Irinotecan has a very unpleasant flavor, therefore, the 
juice will be used to mask the drug taste (See Appendix VI). See protocol for pre-
medication and supportive care measures. 
 
9.3.5 
Supplier 
Commercially available from various manufacturers. See package insert for more 
detailed information. 
 
 
9.4 
TEMOZOLOMIDE - ORAL 
(Temodar, Temodal) NSC #362856 
 
 
 
 
(06/26/18) 
 
9.4.1 
Source and Pharmacology: 
An orally administered alkylating agent, a second generation imidazotetrazine. A 
prodrug of MTIC, temozolomide spontaneously decomposes to MTIC at physiologic 
pH. Exerts its effect by cross-linking DNA. This is likely a site-specific alkylation at the 
O6-position of guanine with some effect at the N7-position. Temozolomide reaches its 
peak concentration in 1 hour. Food reduces the rate and extent of absorption. It has an 
elimination half-life of 1.13 hr (intraperitoneally) and 1.29 hr (orally) with an oral 
bioavailability of 0.98. Total apparent body clearance is 100 mL/min/m2 and plasma 
elimination half-life is ~ 100 minutes. 
 


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9.4.2 
Toxicity 
 
The table below lists the anticipated toxicity profile of temozolomide (oral): 
Incidence 
Toxicities 
Common 
(>20% of patients) 
Constipation, nausea, vomiting, diarrhea, anorexia, alopecia, alanine 
aminotransferase increased, aspartate aminotransferase increased, ataxia, anxiety, 
depression, insomnia, nervous system disorders – other: hemiparesis or paresis, 
dizziness, gait disturbance, amnesia, paresthesia, somnolence, headache, seizure, 
fatigue 
Occasional 
(4-20% of patients) 
Edema limbs, localized edema, rash maculopapular, dysphagia, mucositis oral, 
anemia, platelet count decreased, white blood cell count decreased, lymphocyte 
count decreased, aplastic anemia, blood bilirubin increased, urinary frequency, 
cough, upper respiratory infection, sinusitis 
Rare 
(≤ 3% of patients) 
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, 
hypercalcemia, lower gastrointestinal hemorrhage, upper gastrointestinal 
hemorrhage, cholecystitis, alkaline phosphatase increased, myelodysplastic 
syndrome, leukemia secondary to oncology chemotherapy, infections and 
infestations – other: Pneumocystis pneumonia, pulmonary fibrosis, anaphylaxis, 
allergic reaction, hepatic failure 
Pregnancy & 
Lactation 
Pregnancy Category D 
Adequate, well-controlled studies have not been conducted in humans. Women of 
childbearing potential should be advised against becoming pregnant while taking 
temozolomide and for at least 6 months following the end of therapy. 
Temozolomide administration to rats and rabbits at 3/8 and 3/4 the human dose 
resulted in the development of malformations of the external organs, soft tissues, 
and skeleton. These animal studies also demonstrated embryolethality (increased 
resorptions) at similar doses. There is no information available regarding the 
transmission of temozolomide during lactation; women should avoid breastfeeding 
while receiving temozolomide. 
 
9.4.3 
Formulation and Stability 
Temozolomide capsules are available in six different strengths (5, 20, 100, 140, 180, 
250 mg). The capsules vary in size, color, and imprint according to strength. In the US, 
capsules are packaged in 5-count and 14-count bottles. In other countries 
temozolomide may be packaged in 5-count, 14-count or 20-count bottles. 
Temozolomide capsules are stored at controlled room temperature. 
 
9.4.4 
Guidelines for Administration 
See Treatment and Dose Modification sections of the protocol. 
 
There is a potential for medication errors involving temozolomide capsules resulting 
in drug overdosages, which may have been caused by dispensing/taking the wrong 
number of capsules per day and/or product usage exceeding the prescribed dosing 
schedule. 


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When dispensing, it is extremely important that prescribing and dispensing include 
clear instructions on which capsules, and how many of each capsule(s) are to be taken 
per day. Only dispense what is needed for the course, and clearly indicate how many 
days of dosing the patient will have and how many days are without temozolomide 
dosing. When counseling patients, it is important for each patient/parent to understand 
the number of capsules per day and the number of days that they take temozolomide. 
It is also important for the patient/parent to understand the number of days that they 
will be off the medication.  
 
Each strength of temozolomide must be dispensed in a separate vial or in its original 
container (e.g., bottle or sachet). Based on the dose prescribed, determine the number 
of each strength of temozolomide capsules needed for the full course as prescribed by 
the physician. For example, 275 mg/day for 5 days would be dispensed as five 250 mg 
capsules, five 20 mg capsules, and five 5 mg capsules. Label each container with the 
appropriate number of capsules to be taken each day. Dispense to the patient/parent, 
making sure each container lists the strength (mg) per capsule and that he or she 
understands to take the appropriate number of capsules of temozolomide from each 
bottle or vial to equal the total daily dose prescribed by the physician. Institutions that 
have the capability to dispense temozolomide as daily doses in a blister pack may do 
so, taking specific precautions to ensure that the appropriate dose is provided and that 
the patient is educated to understand the daily dosing regimen. 
 
For children unable to swallow the capsules whole, the oral capsules may be formulated 
into a suspension. To prepare a 10 mg/mL suspension triturate the contents of ten 100 
mg capsules (1000 mg), 500 mg povidone K-30 and 25 mg anhydrous citric acid 
dissolved in 1.5 mL purified water in a glass mortar to form a uniform paste. To the paste 
add 50 mL of Ora-Plus® by adding a small amount, mixing, and then adding the balance. 
Transfer to a glass graduated cylinder. Add Ora-Sweet® or Ora-Sweet® SF to a total 
volume of 100 mL by rinsing the mortar with small amounts of the syrup (Ora-Sweet® 
or Ora-Sweet® SF). Rinse at least four times. Package in an amber plastic prescription 
bottle. The packaged suspension should be stored in the refrigerator at 2°-8°C (36-46°F) 
for no more than 2 weeks after preparation. The suspension should be shaken well 
before each use. Procedures for proper handling and disposal of cytotoxic drugs should 
be used when preparing the suspension.35 
 
Alternatively, the capsules can be opened and mixed with apple sauce or juice, which 
should be used immediately after mixing or must be used in 2 hours after mixing (See 
Appendix V). 
 
9.4.5 
Supplier: 
Commercially available. See package insert for further information. 
 
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). 


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b) 
Adverse Events requiring removal from protocol therapy (See Section 6.0). 
c) 
Refusal of protocol therapy by patient/parent/guardian 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Completion of 35 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 
ABI-009 (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
 
Patients who are removed from protocol therapy during cycle 1 should continue to have 
the required observations in Section 8.1 until the originally planned end of the cycle or 
until all adverse events have resolved per Section 13.4.4, whichever happens LATER. 
The only exception is with documentation of the patient’s withdrawal of consent. 
Patients who are removed from protocol therapy in subsequent cycles should have the 
necessary observations to ensure adequate clinical care.  
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Ongoing adverse events, or adverse events that emerge after the patient 
is removed from protocol therapy, but within 30 days of the last dose of investigational agent, 
must be followed and reported via RAVE and CTEP-AERS (if applicable).  Follow-up data 
will be required unless consent is withdrawn. 
 
10.2 
Off Study Criteria 
 
a) 
Thirty days after the last dose of the investigational agent. 
b) 
Death 
c) 
Lost to follow-up 
d) 
Withdrawal of consent for any required observations or data submission. 
e) 
Enrollment onto another COG therapeutic (anti-cancer) study  
f) 
Patient did not receive protocol treatment after study enrollment 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
A minimum of 4 patients will be enrolled in this study if the first two patients develop DLTs 
at DL1 and DL-1. The projected maximum number of evaluable patients is 24. This includes 
6 evaluable patients at each of DL 1-3 and 6 additional evaluable patients in a PK expansion 
cohort. Therefore, the projected maximum number of patients enrolled into this study 
allowing for 20% inevaluability is 29, and this number is expected to be accrued over 15-29 
months. The study design includes several contingencies that may increase the maximum 
sample size if all contingencies are needed to estimate the MTD. A maximum of 51 patients 
may be possible in the unlikely scenario that all dose levels require expansion to 12 patients 
plus 6 additional patients for pharmacokinetic analysis and a 20% inevaluable rate. The 
maximum sample size of 51 patients could accrue over 26-51 months. 


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11.1.1 Amendment #4  
The projected maximum number of additional (i.e., in addition to the 18 already 
enrolled) evaluable patients required to complete the study with this amendment is 
12. This includes 6 evaluable patients at DL -2 and 6 additional evaluable patients 
in a PK expansion cohort. Therefore, the projected maximum number of additional 
patients enrolled into the study allowing for 30% inevaluability is 18, and this 
number is expected to be accrued over 9-18 months. The overall study will have an 
expected maximum of 36 patients. 
The study design includes several contingencies that may increase the maximum 
sample size if all contingencies are needed to estimate the MTD. A maximum of 26 
additional patients may be possible in the unlikely scenario that DL-2 requires 
expansion to 12 patients plus 6 additional patients for pharmacokinetic analysis and 
a 30% inevaluable rate. The maximum sample size of 26 additional patients could 
accrue over an additional 13-26 months. The overall study will have an absolute 
maximum enrollment of 44 patients. 
11.2 
Definitions 
 
11.2.1 Evaluable For Adverse Events 
Any patient who receives at least one dose of the study drug(s) or who experiences 
a dose-limiting toxicity is considered evaluable for Adverse Events. In addition, for 
the dose-escalation portion during Cycles 1 and 2, patients must receive at least 85% 
of the prescribed dose of protocol therapy per protocol guidelines in Cycle 1 and 
85% of the prescribed dose of protocol therapy in Cycle 2, 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 a DLT (See Section 5.5) during Cycles 1 and 2 of therapy. 
 
• 
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.  


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11.3 
Dose Escalation and Determination of MTD 
 
The rolling six phase 1 trial design will be used for the conduct of this study36. Two to six 
patients can be concurrently enrolled onto a dose level, dependent upon (1) the number of 
patients enrolled at the current dose level, (2) the number of patients who have experienced 
DLT at the current dose level, and (3) the number of patients entered but with tolerability 
data pending at the current dose level.  Accrual is suspended when a cohort of six has enrolled 
or when the study endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in the cohort, 
the number of DLTs observed, and the number of participants at risk for developing a DLT 
(i.e., participants enrolled but who are not yet assessable for toxicity). For example, when 
three participants are enrolled onto a dose cohort, if toxicity data is available for all three 
when the fourth participant entered and there are no DLTs, the dose is escalated and the 
fourth participant is enrolled to the subsequent dose level. If data is not yet available for one 
or more of the first three participants and no DLT has been observed, or if one DLT has been 
observed, the new participant is entered at the same dose level. Lastly, if two or more DLTs 
have been observed, the dose level is de-escalated. This process is repeated for participants 
five and six. In place of suspending accrual after every three participants, accrual is only 
suspended when a cohort of six is filled. When participants are inevaluable for toxicity, they 
are replaced with the next available participant if escalation or de-escalation rules have not 
been fulfilled at the time the next available participant is enrolled onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the current dose 
level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the study is 
suspended to accrual: 
 
 
# Pts 
Enrolled 
# Pts 
with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
 
 
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 


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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. 
 
11.3.1 Amendment #4 
Patients will be enrolled at DL -2 using the rolling 6 study design. If DL -2 is 
determined to be safe (at most 1 out of 6 evaluable patients with DLT), then up to 6 
more patients will be enrolled at DL -2 in a PK expansion cohort. If DL -2 is 
determined to not be tolerable (2 or more dose limited patients out of 6 evaluable 
patients), the study will be closed to accrual. 
 
 
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 
1 
1 
0 
0 
2 
Native 
Hawaiian 
or Other 
Pacific 
Islander 
0 
0 
0 
0 
0 
Black or 
African 
American 
2 
4 
0 
0 
6 
White 
9 
14 
4 
1 
28 
More Than 
One Race 
0 
0 
0 
0 
0 
Total 
12 
19 
4 
1 
36 
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 ABI-009 as a single agent and 
in combination with temozolomide and irinotecan 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 ABI-009, 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 correlative biology study 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 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 current 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).37 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 
evaluable. 


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


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All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
12.2.3.1 Clinical lesions:  Clinical lesions will only be considered measurable when 
they are superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 
10 mm diameter as assessed using calipers (e.g., skin nodules).  In the case 
of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  
 
12.2.3.2 Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
 
12.2.3.3 Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans). Ideally, 
the same type of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans.  
 
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. 
 


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12.2.3.7 FDG-PET: While FDG-PET response assessments need additional study, 
it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly 
possible 'new' disease). New lesions on the basis of FDG-PET imaging can 
be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up 
is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD. If the positive FDG-PET at follow-up is 
not confirmed as a new site of disease on CT, additional follow-up CT 
scans are needed to determine if there is truly progression occurring at 
that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to 
a pre-existing site of disease on CT that is not progressing on the basis 
of the anatomic images, this is not PD. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid with 
an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image. 
 
 
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 


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has PD if there is an overall level of substantial 
worsening in non-target disease such that the 
overall tumor burden has increased sufficiently to 
merit discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
12.2.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to 
be considered in complete clinical response. 
 
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-
No 
SD 
documented at least once 
≥ 28 days from baseline 


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PD/not 
evaluated 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion. 
**  In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so 
to assign this category when no lesions can be measured is not advised 
 
 
Table 3: 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 


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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 12.8 
from a sequence of overall response assessments. 
 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
12.3.1 Evaluable Disease 
The presence of at least one lesion, with no lesion that can be accurately measured 
in at least one dimension. Such lesions may be evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers or other reliable 
measures.  
 
12.3.2 Complete Response 
Disappearance of all evaluable disease. 
 
12.3.3 Partial response 
Partial responses cannot be determined in patients with evaluable disease 
 
12.3.4 Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), or 
Progressive Disease. 
 
12.3.5 Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, clinical, or 
radiographic progression. 
 
12.3.6 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect. Best response is determined as outlined in Section 12.8 
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 


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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: 
 
 
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 


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Table 5: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease 
Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly 
identified lesion by CT/MRI that occurs during therapy would be considered 
progressive disease. 
 
 
MIBG 
CT/MRI 
Bone Scan 
Bone 
Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 
12.4.5 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 12.8. 
 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
12.5.1 Bone Marrow Involvement  
Bone marrow obtained within 28 days prior to study enrollment with tumor cells 
seen on routine morphology (not by immunohistochemical staining only) of bilateral 
aspirate or biopsy on one bone marrow sample. 
 
Bone Marrow responses are determined by H&E Staining of bilateral bone marrow 
biopsies and aspirates. 
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at study 
enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone marrow 
by morphology have progressive disease if there is a 
doubling in the amount of tumor in the marrow AND a 
minimum of 25% tumor in bone marrow by morphology. 
(For example, a patient entering with 5% tumor in marrow 
by morphology must increase to ≥ 25% tumor to have 
progressive disease; a patient entering with 30% tumor must 
increase to > 60%). 
 


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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 12.8. 
 
12.6 
Response Criteria for Patients with CNS Tumors 
 
12.6.1 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, for 
CNS tumors. 
 
12.6.2 Evaluable Disease  
Evaluable disease is defined as at least one lesion, with no lesion that can be 
accurately measured in at least one dimension. Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures. 
 
12.6.3 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered a 
“target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect (e.g., 
8 mm lesion for a 4 mm slice). 
 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
12.6.4 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in other 
lesions – e.g., when multiple lesions show opposite responses, the progressive 
disease takes precedence. Response Criteria for target lesions: 
 
• 
Complete Response (CR): Disappearance of all target lesions. 
 
• 
Partial response (PR): ≥ 50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements. 


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• 
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. 
 
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 12.8 
from a sequence of overall response assessments. 
 
12.7 
Best Response 
 
12.7.1 Evaluation of Best Overall Response 


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The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
Table 1.  Sequences of overall response assessments with corresponding best 
response. 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
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 


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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 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 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. 
 
 
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 
 


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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 


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• 
Any medical event equivalent to CTCAE version 5.0 grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-specific 
expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 
birth defects must be reported via CTEP-AERS if the event occurs following treatment with an agent 
under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 1 Trials 
Utilizing an Agent under a CTEP-IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational agent 
which can be attributed (possibly, probably, or definitely) to the agent and is not clearly due to 
progressive disease must be reported via CTEP-AERS for an agent under a CTEP or non-CTEP IND 
agent per the timelines outlined in the table above. 
 
• Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), does not 
require expedited reporting, unless it is associated with hospitalization. 
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 
GASTROINTESTINAL DISORDERS 
Nausea 
GASTROINTESTINAL DISORDERS 
Vomiting 
GASTROINTESTINAL DISORDERS 
Constipation 
GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS 
Fatigue 
INFECTIONS AND INFESTATIONS 
Mucosal inflammation 
INFECTIONS AND INFESTATIONS 
Thrush 
INFECTIONS AND INFESTATIONS 
Infection 
INVESTIGATIONS 
Weight loss 
INVESTIGATIONS 
Aspartate aminotransferase increased 
METABOLISM AND NUTRITION 
DISORDERS 
Hypokalemia 
METABOLISM AND NUTRITION 
DISORDERS 
Hypophosphatemia 


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METABOLISM AND NUTRITION 
DISORDERS 
Hypertriglyceridemia 
RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS 
Dyspnea 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
Rash/desquamation 
 
 
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 (email the ADVL1514 COG Study Assigned Research 
Coordinator within 24 hours of becoming aware of the event if the CTEP-AERS 24-Hour 
Notification web-based application is unavailable) and by telephone call to the Study Chair. 
Once internet connectivity is restored, a 24-hour notification phoned in must be entered 
electronically into CTEP-AERS by the original submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 
• 
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event Expedited 
Reporting 
System), 
accessed 
via 
the 
CTEP 
home 
page 
https://eapps-
ctep.nci.nih.gov/ctepaers. 
 
13.3 
Expedited Reporting Methods  
 
13.3.1 CTEP-AERS Reporting 
To report adverse events in an expedited fashion use the NCI’s Adverse Event 
Expedited 
Reporting 
System 
(CTEP-AERS) 
that 
can 
be 
found 
at 
http://ctep.cancer.gov. 
 
A CTEP-AERS report must be submitted electronically via the CTEP-AERS Web-
based application located at https://ctepcore.nci.nih.gov/ctepaers. If prompted to 
enter 
a 
sponsor 
email 
address, 
please 
type 
in: 
PEPCTNAERS@childrensoncologygroup.org. 
 
Email supporting documentation to the ADVL1514 COG Study Assigned Research 
Coordinator. ALWAYS include the ticket number on all faxed and 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. 


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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 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. 
 
 
 
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.  


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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 ADVL1514 
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 SOC 
and reported as Grade 3. 
 
• 
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 Fetal Death 
• 
Pregnancy loss is defined in CTCAE version 5.0 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 
recognized any Grade 5 event as a patient death. 
 
 
13.7.3 Death Neonatal 
• 
Neonatal death, defined in CTCAE version 5.0 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. 


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• 
A neonatal death should be reported expeditiously as  “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. 
 
• 
Neonatal death should NOT be reported as “Death neonatal” under the 
General disorders and administration SOC, a Grade 5 event. If reported as 
such, the CTEP-AERS interprets this as a death of the patient being treated. 
 
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/PregnancyReport
Form.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 
Access to Rave for Data Submission/Data Reporting 
Data collection for this study will be done through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application 
to all persons with the appropriate roles assigned in Regulatory Support System (RSS). To 
access Rave via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the COG or PEP-CTN roster at the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. To 
accept 
the 
invitation, 
site 
users 
must 
log 
into 
the 
Select 
Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, 
and click on the “accept” link in the upper right-corner of the iMedidata page. Please note, 
site users will not be able to access the study in Rave until all required Medidata and study 
specific trainings are completed. Trainings will be in the form of electronic learnings 
(eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 


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Users that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ 
or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com, or by email to the COG Study Assigned Data Manager. 
 
14.3 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis by FTP burst of data. Reports are due January 31, April 30, July 31 and 
October 31. Instructions for submitting data using the CDUS can be found on the CTEP Web 
site (http://ctep.cancer.gov/reporting/cdus.html). 
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. 
 
 
14.4 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.4.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of patients 
and the scientific integrity for all Phase 1 and 2 studies. The DSMC consists of a 
chair; a statistician external to COG; one external member; one consumer 
representative; the lead statistician of the PEP-CTN  scientific committee; and a 
member from the NCI. The DSMC meets at least every 6 months to review current 
study results, as well as data available to the DSMC from other related studies. 
Approximately 6 weeks before each meeting of the Phase 1 and 2 DSMC, study 
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. 
 
14.4.2 Monitoring by the Study Chair and Developmental Therapeutics Leadership  
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the COG 
PEP-CTN Chair, Vice Chair and Statistician on a weekly conference call. 


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REFERENCES 
 
1. 
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2. 
Laplante M, Sabatini DM: mTOR signaling in growth control and disease. Cell 149:274-
93, 2012 
3. 
Populo H, Lopes JM, Soares P: The mTOR signalling pathway in human cancer. Int J Mol 
Sci 13:1886-918, 2012 
4. 
Ma XM, Blenis J: Molecular mechanisms of mTOR-mediated translational control. Nat 
Rev Mol Cell Biol 10:307-18, 2009 
5. 
Phung TL, Ziv K, Dabydeen D, et al: Pathological angiogenesis is induced by sustained 
Akt signaling and inhibited by rapamycin. Cancer Cell 10:159-70, 2006 
6. 
Faivre S, Kroemer G, Raymond E: Current development of mTOR inhibitors as anticancer 
agents. Nat Rev Drug Discov 5:671-88, 2006 
7. 
Smith MA, Seibel NL, Altekruse SF, et al: Outcomes for children and adolescents with 
cancer: challenges for the twenty-first century. J Clin Oncol 28:2625-34, 2010 
8. 
Izycka-Swieszewska E, Drozynska E, Rzepko R, et al: Analysis of PI3K/AKT/mTOR 
signalling pathway in high risk neuroblastic tumours. Pol J Pathol 61:192-8, 2010 
9. 
Opel D, Poremba C, Simon T, et al: Activation of Akt predicts poor outcome in 
neuroblastoma. Cancer Res 67:735-45, 2007 
10. 
Zhou W, Hao M, Du X, et al: Advances in targeted therapy for osteosarcoma. Discov Med 
17:301-7, 2014 
11. 
Zhai M, Cong L, Han Y, et al: CIP2A is overexpressed in osteosarcoma and regulates cell 
proliferation and invasion. Tumour Biol 35:1123-8, 2014 
12. 
Zhang J, Yu XH, Yan YG, et al: PI3K/Akt signaling in osteosarcoma. Clin Chim Acta 
444:182-192, 2015 
13. 
Loh AH, Brennan RC, Lang WH, et al: Dissecting the PI3K Signaling Axis in Pediatric 
Solid Tumors: Novel Targets for Clinical Integration. Front Oncol 3:93, 2013 
14. 
Shapiro DN, Sublett JE, Li B, et al: Fusion of PAX3 to a member of the forkhead family of 
transcription factors in human alveolar rhabdomyosarcoma. Cancer Res 53:5108-12, 1993 
15. 
Mohan AL, Friedman MD, Ormond DR, et al: PI3K/mTOR signaling pathways in 
medulloblastoma. Anticancer Res 32:3141-6, 2012 
16. 
Mueller S, Phillips J, Onar-Thomas A, et al: PTEN promoter methylation and activation of 
the PI3K/Akt/mTOR pathway in pediatric gliomas and influence on clinical outcome. 
Neuro Oncol 14:1146-52, 2012 
17. 
Barthelemy P, Hoch B, Chevreau C, et al: mTOR inhibitors in advanced renal cell 
carcinomas: from biology to clinical practice. Crit Rev Oncol Hematol 88:42-56, 2013 
18. 
Subbiah V, Brown RE, Jiang Y, et al: Morphoproteomic profiling of the mammalian target 
of rapamycin (mTOR) signaling pathway in desmoplastic small round cell tumor 
(EWS/WT1), Ewing's sarcoma (EWS/FLI1) and Wilms' tumor(WT1). PLoS One 8:e68985, 
2013 
19. 
Ashworth RE, Wu J: Mammalian target of rapamycin inhibition in hepatocellular 
carcinoma. World J Hepatol 6:776-82, 2014 
20. 
Hartmann W, Kuchler J, Koch A, et al: Activation of phosphatidylinositol-3'-kinase/AKT 
signaling is essential in hepatoblastoma survival. Clin Cancer Res 15:4538-45, 2009 


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21. 
Gonzalez-Angulo AM, Meric-Bernstam F, Chawla S, et al: Weekly nab-Rapamycin in 
patients with advanced nonhematologic malignancies: final results of a phase I trial. Clin 
Cancer Res 19:5474-84, 2013 
22. 
Kratz F: Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. 
J Control Release 132:171-83, 2008 
23. 
Bagatell R, Norris R, Ingle AM, et al: Phase 1 trial of temsirolimus in combination with 
irinotecan and temozolomide in children, adolescents and young adults with relapsed or 
refractory solid tumors: a Children's Oncology Group Study. Pediatr Blood Cancer 61:833-
9, 2014 
24. 
Mascarenhas L, Meyer WH, Lyden E, et al: Randomized phase II trial of bevacizumab and 
temsirolimus in combination with vinorelbine (V) and cyclophosphamide (C) for first 
relapse/disease progression of rhabdomyosarcoma (RMS): A report from the Children's 
Oncology Group (COG). 2014 ASCO Annual Meeting. Chicago IL, J Clin Oncol 2014, pp 
abstr 10003 
25. 
Bagatell R, London WB, Wagner LM, et al: Phase II study of irinotecan and temozolomide 
in children with relapsed or refractory neuroblastoma: a Children's Oncology Group study. 
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Raymond E, Alexandre J, Faivre S, et al: Safety and pharmacokinetics of escalated doses of 
weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J 
Clin Oncol 22:2336-47, 2004 
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Trieu VR, S.; Volk, L.; Stutzman, A.; D’Cruz, O.; Desai, N.: CNS safety, antitumor 
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the 100th American Association for Cancer Research Annual Meeting (AACR). Denver 
CO, 2009, pp abstr 136 
28. 
De TT, V.; Yim, Z.; Cordia, J.; Yang, A.; Beals, B., et al: Nanoparticle albumin-bound 
(nab) rapamycin as an anticancer agent, Proceedings of the 98th American Association for 
Cancer Research Annual Meeting (AACR). Los Angeles CA, 2007, pp abstr 4719 
29. 
Cirstea D, Hideshima T, Rodig S, et al: Dual inhibition of akt/mammalian target of 
rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces 
antitumor activity in multiple myeloma. Mol Cancer Ther 9:963-75, 2010 
30. 
Desai NDC, O.; Trieu, V: Combination regimens of nab-rapamycin (ABI-009) effective 
against MDA-MB-231 breast-tumor xenografts, Proceedings of the 32ndt Annual San 
Antonio Breast Cancer Symposium (CRTC-AACR-SABCS). San Antonio TX, 2009, pp 
abstr 6106 
31. 
Hidalgo M, Buckner JC, Erlichman C, et al: A phase I and pharmacokinetic study of 
temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to 
patients with advanced cancer. Clin Cancer Res 12:5755-63, 2006 
32. 
Jimeno A, Rudek MA, Kulesza P, et al: Pharmacodynamic-guided modified continuous 
reassessment method-based, dose-finding study of rapamycin in adult patients with solid 
tumors. J Clin Oncol 26:4172-9, 2008 
33. 
Houghton PJ, Morton CL, Kolb EA, et al: Initial testing (stage 1) of the mTOR inhibitor 
rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer 50:799-805, 
2008 
34. 
Spunt SL, Grupp SA, Vik TA, et al: Phase I study of temsirolimus in pediatric patients with 
recurrent/refractory solid tumors. J Clin Oncol 29:2933-40, 2011 


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35. 
Trissel LABRF, Zhang YB, Koontz SEPB: Temozolomide stability in extemporaneously 
compounded oral suspensions. Int J Pharm Compd 10:396-9, 2006 
36. 
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 
37. 
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 and 
Cycle 2 
Pharmacokinetic Study (PK) XI-A and XI-
B 
2 ml 
48 ml 
Preservative-free heparin 
(green top) 
Tumor Tissue 
(Required) 
See Section 8.4 for details 
XII 
- 
- 
- 
Total Blood Volume 
48 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 ADVL1514 COG Study Assigned Research Coordinator. For follow-up reporting, email only this Pregnancy 
Information Form to the ADVL1514 COG Study Assigned Research Coordinator (See Section 13.7). 
 


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APPENDIX IV: TEMOZOLOMIDE DOSING NOMOGRAM FOR TEMOZOLOMIDE 125 
MG/M2/DOSE 
 
 
Temozolomide dose assignment: 125 mg/m2 
 
BSA (m2) 
Administered daily dose (mg) 
 
0.2-0.49* 
 
4.17 mg/kg* 
0.50-0.53 
65 
0.54-0.59 
70 
0.60-0.65 
80 
0.66-0.69 
85 
0.70-0.75 
90 
0.76-0.81 
100 
0.82-0.85 
105 
0.86-0.91 
110 
0.92-0.97 
120 
0.98-1.01 
125 
1.02-1.07 
130 
1.08-1.15 
140 
1.16-1.23 
150 
1.24-1.31 
160 
1.32-1.39 
170 
1.40-1.47 
180 
1.48-1.55 
190 
1.56-1.67 
200 
1.68-1.83 
220 
1.84-1.95 
240 
1.96-2.00 
250 
> 2.0 
250 
 
*Dosing for patients with BSA <0.5 m2 is by mg/kg, rounded to the nearest 5 mg 
 
 


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APPENDIX V: INSTRUCTIONS FOR TEMOZOLOMIDE PREPARATION, ADMINISTRATION 
AND SAFE HANDLING FOR PATIENTS WHO ARE UNABLE TO SWALLOW CAPSULES 
 
Patient Name: ___________________________        Cycle#: _____         Date Range: _______________ 
 
Temozolomide is an oral medicine for the treatment of cancer. This 
information sheet will help you prepare, administer, store, and 
dispose of the medicine. Please read the information before preparing 
and giving the medicine. If you have any questions, please 
contact:_______________ 
 
 
WHAT DO I NEED?  
 
 
Your Temozolomide dose is: ________mg 
You should use the following number of capsules for each dose: 
 
Number of temozolomide capsules per dose 
5 mg 
20 mg 
100 mg 
140 mg 
180 mg 
250 mg 
 
 
 
 
 
 
Give each dose by mouth one time each morning for 5 days in a 
row  
You should take the temozolomide on the following 
days:_________________________ 
 
Supplies: 
Temozolomide capsules (see the table above) 
Disposable pad or paper towels  
Disposable gloves and mask and a pair of goggles (eye protection) 
Disposable cup and disposable spoon 
A container to collect waste (zip top plastic bag or medical waste 
bag or container) 
A small amount of applesauce or apple juice  
o 
Two teaspoons (10 mL) should be enough. A single-
serving container of applesauce may be used, but the 
patient must be able to eat the entire contents of the 
container to ensure the full dose is taken.  
o 
Food should be cool or close to room temperature when 
administered; do not use hot or boiling food 
 
 
HOW DO I STORE THE MEDICINE AND WASTE?  
 
Store the medication in the original bottle away from food and 
out of the reach of children or pets. Store the waste container out 
of the reach of children or pets. Return the container to the clinic 
during your next visit. 
 
 
WHAT SAFETY MEASURES SHOULD I TAKE? 
 
If the medicine gets into eyes, hold eyelids open while flushing with 
water for at least 15 minutes.  If you spilled the medicine on your 
skin, remove contaminated clothing.  Wash area with soap and large 
amount of water.  Seek medical attention if the skin becomes red, 
irritated, or if you are concerned.  Call your doctor or nurse 
immediately 
at:____________________________________________ 
and/or contact the Poison Center at 1-800-222-1222. 
 
HOW DO I PREPARE THE MEDICINE?  
 
CAUTION: If you are pregnant, could become pregnant, or are breast-
feeding, DO NOT prepare or administer this medicine.  
 
1. Choose a quiet working space away from food, windows, fans or 
heat ducts. 
2. Clean the working space with damp paper towels. 
3. Wash your hands with soap and water; dry them well. 
4. Put on disposable gloves, disposable mask, and a pair of goggles 
or eye protection. 
5. Place a disposable pad or paper towel on the clean working space 
and place all supplies on the pad or paper towel.  
6. Fill a cup with a small amount of apple juice or applesauce (or use 
pre-filled applesauce cup). 
7. Open each capsule required for the daily dose over the cup with the 
apple juice or applesauce. 
• Hold one capsule over the center of the cup.  
• To open, pinch both ends of one capsule with gentle 
pressure. Slowly rotate one end in small, back and forth 
movements while holding the other end steady until the 
capsule sections begin to separate. 
• Gently separate the ends so the powder falls into the center 
of the food. Look inside each end of the capsule. Tap and 
shake each end of the capsule until all medicine powder is 
out of the capsule. 
• Repeat the steps above for each capsule needed. 
8. The medicine will not dissolve completely if mixing in apple juice. 
Keep extra apple juice on hand to add to any remaining powder left 
at the bottom of the cup.  If you need more apple juice or 
applesauce, remove your gloves before touching the main 
container. Wear new gloves before adding the additional apple 
juice or applesauce to the medicine to prevent contaminating the 
main container with any powder that may be on your gloves. 
9. Give the medicine mixture to the patient immediately. 
 
 
HOW DO I TAKE/GIVE THE MEDICINE? 
 
• Take/give an anti-nausea medicine 30-60 minutes before the 
temozolomide only if instructed to do so by your doctor.  
• Take/give temozolomide at around the same time each day with or 
without food.  
• Take/give the temozolomide dose within 8 hours prior to receiving 
the study medicine, ABI-009. Temozolomide should be given 1 
hour before irinotecan. 
• When you are finished, place all used supplies in a plastic zip top 
bag or the waste container that was provided to you by your doctor, 
nurse, or pharmacist.  
• If the dose is vomited within 30 minutes, the dose should be 
repeated. If the dose is vomited more than 30 minutes after the 
dose, do not repeat the dose. If the patient is unable to take a dose, 
or a dose is accidentally missed, place the remaining medicine from 
this dose in the waste container, seal, and contact your doctor or 
nurse for instructions. 


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APPENDIX VI: PARENT GUIDELINES FOR ADMINISTRATION OF ORAL IRINOTECAN 
 
 
The hospital pharmacist will provide you with 5 doses of irinotecan, each in an oral syringe. Because 
irinotecan has an unpleasant taste, it is usually mixed with a small amount of juice IMMEDIATELY 
BEFORE giving the medicine to your child. 
 
The best juice to use is CranGrape Juice, although cranapple or cranberry juice or juice cocktail is 
fine as well. 
 
DO NOT mix the irinotecan in orange juice, apple juice, milk or soda. 
 
Use a disposable cup to mix the irinotecan with juice. The amount of juice used is up to you. The 
more juice used, the more the flavor of the irinotecan will be masked. However, it is critical that your 
child drink ALL of the juice mixed with irinotecan. Most parents start by mixing the irinotecan in 
about one teaspoon (5 ml) of juice.  Discard the cup when empty after the irinotecan + juice has been 
taken. 
 
Irinotecan should be mixed with juice only on the day the dose is given. The other doses should be 
stored in a REFRIGERATOR. Irinotecan will last for 21 days at a time, provided it has not been 
mixed with juice. 
 
Irinotecan is taken 1 hour after temozolomide. 
 
Use of nausea medicines (Zofran, Kytril, or Anzemet) may be helpful, and these medicines are best 
given about 30-60 minutes before the irinotecan. Please discuss this with your doctor. 
If your child is unable to take the medicine, or vomits within 30 minutes of taking the medicine, please call 
your doctor for further instructions. 
 
 


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APPENDIX VII: INSTRUCTIONS FOR IRINOTECAN PREPARATION, ADMINISTRATION 
AND SAFE HANDLING 
 
Patient Name: ___________________________ 
        Cycle#: _____   
       Date Range: _______________ 
 
Irinotecan is a chemo drug that requires safe handling. This 
information sheet will help you safely prepare, administer, and 
dispose of the drug. Please read the information before preparing and 
taking the drug. If you have any questions, please contact: 
__________________________________________ 
 
WHAT DO I NEED?  
 
Your dose is:  Irinotecan _______ mg  
• Take each dose by mouth once time each day for 5 days in a 
row.   
• You should take the irinotecan on the following 
days:_________________________________ 
• Take the dose within 8 hours prior to the study drug ABI-009 
 
Supplies:  
• Irinotecan syringe(s) from your pharmacy 
• Disposable pad or paper towels  
• Disposable gloves and mask 
• Oral syringe, medicine cup, or measuring spoon  
• Disposable cup for mixing drug with juice  
• Disposable spoon or straw to stir the mixture 
• A container to collect waste (zip-top plastic bag or medical 
waste bag or container) 
• One of the juices below: 
o Cran-Grape or Cran-Apple juice 
o Cranberry juice  
o Cranberry juice cocktail 
DO NOT use orange juice, apple juice, grapefruit juice, 
milk, or soda. 
 
 
HOW DO I STORE THE DRUG SYRINGES?  
 
Store the medication in syringes in the refrigerator away from 
food and out of the reach of children or pets.  
 
 
WHAT SAFETY MEASURES SHOULD I TAKE? 
 
If the drug gets into eyes, hold eyelids open while flushing with water 
for at least 15 minutes.  Call your doctor or nurse immediately at: 
__________________  
and/or 
contact 
the 
Poison 
Center 
at 
1-800-222-1222. 
 
If you spilled the drug on your skin, remove contaminated clothing.  
Wash area with soap and large amount of water.  Seek medical 
attention (see contact information above) if the skin becomes red or 
irritated or if you are concerned. 
 
HOW DO I PREPARE THE DRUG?  
 
 
Caution: If you are pregnant, could become pregnant, or are breast-
feeding, we suggest that you DO NOT prepare or administer this drug 
without FIRST checking with your health care provider. 
1. 
Choose a quiet working space away from food, windows, fans or 
heat ducts. 
2. 
Clean the working space with damp paper towels. 
3. 
Place a disposable pad or paper towel on the clean working space 
and place all needed items and drug on the pad or paper towel.  
4. 
Wash your hands with soap and water; dry them well. 
5. 
Put on disposable gloves and mask. 
6. 
Fill a disposable cup with 5 mL (1 teaspoon) of juice. Note: more 
juice can be used to improve the taste but you must make sure the 
entire dose is taken. 
7. 
Add the irinotecan to the cup by slowly squeezing the syringe in 
the cup. Be careful to do this slowly so the drug doesn’t splash or 
spill. 
8. 
Stir the mixture with the plastic spoon or straw. 
9. 
Take/Give the mixture to the patient immediately. 
 
HOW DO I TAKE/GIVE THE DRUG? 
 
 
• Take/Give an anti-nausea medicine 30-60 minutes before 
irinotecan if instructed to do so by your doctor. 
• Take/Give irinotecan 1 hour after temozolomide. 
• Take/Give irinotecan at around the same time each day. 
• Take/Give irinotecan on an empty stomach, at least one (1) hour 
after food. Do not eat for at least one (1) hour. 
• When you are finished, place the dirty gloves, spoon, cup, and 
other tools used to mix the drug in a plastic zip top bag or the waste 
container that was provided to you by your doctor, nurse, or 
pharmacist. 
• If the dose is vomited within 30 minutes, the patient is unable to 
take the dose, or the dose is accidentally missed, contact your 
doctor or nurse for instructions. 
 
 
WHAT SHOULD I DO WITH LEFTOVER DRUG AND USED 
SUPPLIES?  
 
 
If the patient could not take the dose or part of the dose, first place the 
remaining drug from this dose in the waste container and seal. Then call 
your doctor or nurse to let them know that some of the dose was missed. 
Store the waste container out of the reach of children or pets. Return the 
waste container to the clinic at the next visit.  
 


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APPENDIX VIII: PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
 
Guidelines for the Treatment of Diarrhea 
 
Institutional practice may be used in place of these guidelines. 
 
You should purchase or will be given a prescription for loperamide to have available to begin treatment at 
the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent 
than normally expected for the patient. Patients will also be instructed to contact their physician if any 
diarrhea occurs. Patients will be given loperamide based on body weight.  
 
Early diarrhea 
Early onset diarrhea associated with irinotecan is usually preceded by sweating and abdominal cramping. 
Patients who have the onset of these symptoms followed by diarrhea within several hours after taking 
irinotecan should contact the treating physician immediately.  The treating physician may consider treatment 
with atropine. If symptoms do not improve with administration of atropine, treatment for late diarrhea (as 
outlined below) should be started. 
 
Late diarrhea (more than 24 hours after the administration of the first dose of irinotecan) 
Each family will be instructed to have antidiarrheal medication available and begin treatment at the first 
episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than 
normally expected for the patient.  
 
Be aware of your child's bowel movements. At the first sign they become softer than usual or if your child 
has any increase in the number of bowel movements over what is normal for him/her, begin taking 
loperamide. If he/she does not start taking the loperamide right away, the diarrhea may become severe 
and last several days or require hospitalization. 
 
Please follow these directions carefully, using dosing guidelines below: 
• 
Take _____________ at the first sign of diarrhea. 
• 
Continue taking __________ every __ hours until your normal pattern of bowel movements returns. 
Repeat the same doses and frequency if the diarrhea returns. 
• 
Do not exceed ___________ in a 24 hour period. 
• 
Please call your doctor if you have any questions about taking loperamide, if your child's diarrhea is 
not under control after two days, or if he/she is feeling extremely weak, lightheaded, or dizzy. 
• 
Make an extra effort to give your child lots of fluids (several glasses of pedialyte, fruit juices, soda, 
soup, etc.) while your child is participating in this study. 
• 
Side effects may include tiredness, drowsiness or dizziness. If your child experiences these side 
effects, or if your child is urinating less frequently than usual, please contact your child's physician. 
• 
Do not give your child any laxatives without consulting with his/her physician. 
 
 
 
 


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LOPERAMIDE DOSING RECOMMENDATIONS FOR LATE DIARRHEA 
(maximum dose of Loperamide for adults is 16 mg/day) 
Weight (kg) 
ACTION 
<13 kg   
Take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral solution) after 
the first loose bowel movement, followed by 0.5 mg (2.5 mL [one-half teaspoonful 
of the 1 mg/5 mL oral solution]) every 3 hours. During the night, the patient may 
take 0.5 mg (2.5 mL [one-half teaspoonful of the 1 mg/5 mL oral solution) every 4 
hours. Do not exceed 4 mg (20 mL or 4 teaspoonfuls) per day. 
 
≥ 13 kg to < 20 kg 
Take 1 mg (5 mL [(1 teaspoonful] of the 1 mg/5 mL oral solution or one-half  tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] of 
the 1 mg/5 mL oral solution) or one-half tablet every 3 hours. During the night, the 
patient may take 1 mg (5 mL [one teaspoonful] of the 1 mg/5 mL oral solution) or 
one-half tablet every 4 hours. Do not exceed 6 mg (30 mL or 6 teaspoonfuls) per 
day. 
 
≥ 20 kg to < 30 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 tablet) after 
the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] of the 1 
mg/5 mL oral solution or one-half  tablet) every 3 hours. During the night, the patient 
may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1  tablet) 
every 4 hours. Do not exceed 8 mg (40 mL or 8 teaspoonfuls) per day. 
 
≥ 30 kg to < 43 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1  tablet) after 
the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] of the 1 
mg/5 mL oral solution or one-half  tablet) every 2 hours. During the night, the patient 
may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1  tablet) 
every 4 hours. Do not exceed 12 mg (60 mL or 12 teaspoonfuls) per day. 
 
Over 43 kg 
Take 4 mg (20 mL [4 teaspoonfuls] of the 1 mg/5 mL oral solution or 2 capsules or 
tablets) after the first loose bowel movement, followed by 2 mg (10 mL 
[2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 capsule or tablet) every 2 hours. 
During the night, the patient may take 4 mg (20 mL [4 teaspoonfuls] of the 1 mg/5 
mL oral solution or 2 capsules or tablets) every 4 hours. Do not exceed 16 mg (80 
mL or 16 teaspoonfuls) per day. 
 


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APPENDIX IX: MEDICATION DIARY 
 
COG Patient ID: ___________ ACC # : _____ Institution :________________________________ 
Please do not write patient names on this form. 
 
 
Course #:________ 
For each day, fill in the date and time temozolomide, irinotecan, and cefixime (or equivalent antibiotic to prevent diarrhea) were given. 
Irinotecan should be given one hour after administration of temozolomide. Make note of other drugs and supplements taken. Cefixime or 
an available equivalent antibiotic will be used as diarrheal prophylaxis. Initiation of antibiotic treatment at least two days prior to the start 
of irinotecan is recommended. This antibiotic therapy should continue throughout protocol therapy. Return the completed diary to your 
institution after each treatment course.  
PLEASE CAREFULLY READ THE STEPS FOR DRUG ADMINISTRATION (SEE RECOMMENDATIONS FOR 
ADMINISTRATION OF TEMOZOLOMIDE AND PARENT GUIDELINES FOR ADMINISTRATION OF ORAL 
IRINOTECAN) BEFORE GIVING DRUGS. 
Day: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date: _____ 
Cefixime  
Time:______
_ 
Dose:______
_ 
Date:____
 
 
 
Cefixime  
Time:____
__ 
Dose:_____ 
Date:_____ 
 
Temozolomide, 
Irinotecan, ABI-
009 given in 
Clinic. DO NOT 
TAKE AT HOME 
Cefixime  
Time:________ 
Dose:________ 
Date: _____ 
 
Temozolomide 
Time:________ 
Dose:________ 
Irinotecan 
Time:_______ 
Dose:_______ 
Cefixime  
Time:________ 
Dose:________ 
 
Date: _______ 
 
Temozolomide 
Time:________ 
Dose:________ 
Irinotecan 
Time:_______ 
Dose:_______ 
Cefixime  
Time:________ 
Dose:________ 
 
Date: _______ 
 
Temozolomide 
Time:________ 
Dose:________ 
Irinotecan 
Time:_______ 
Dose:_______ 
Cefixime  
Time:________ 
Dose:________ 
 
Date: ________ 
 
Temozolomide 
Time:________ 
Dose:________ 
Irinotecan 
Time:_______ 
Dose:_______ 
Cefixime  
Time:________ 
Dose:________ 
 
Date: _____ 
 
Cefixime  
Time:______
__ 
Dose:______
_ 
Date:____ 
Cefixime  
Time:____
_ 
Dose:_____ 
Date: _______ 
ABI-009 given in 
Clinic 
Cefixime  
Time:________ 
Dose:_______ 
Date: 
____________ 
Date: 
____________ 
Date: 
____________ 
 
Date: 
_____________ 
 
Date:  
__________ 
 
Date:____ 
Date: 
_____________ 
Date: 
____________ 
 
Date:  
____________ 
Date: 
____________ 
 
Date: 
_____________ 
 
Date:_____ 
Cefixime  
Time:______
_ 
Dose:______
_ 
Date:____
 
 
Cefixime  
Time:____
_ 
Dose:_____ 
 
 
 
 
 
 
NOTES: 
 
 
 
 


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APPENDIX X: UNACCEPTABLE ENZYME-INDUCING AND RECOMMENDED NON-ENZYME 
INDUCING ANTICONVULSANTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recommended Non-enzyme inducing 
anticonvulsants 
 
Clonazepam 
Diazepam 
Ethosuximide 
Ezogabine 
Gabapentin 
Lacosamide 
Lamotrigine 
Levetiracetam  
Lorazepam 
Perampanel 
Tiagabine 
Topiramate 
Valproic Acid 
Zonisamide 
 
Unacceptable Enzyme inducing 
anticonvulsants 
 
Carbamazepine 
Felbamate 
Phenobarbital 
Fosphenytoin 
Phenytoin 
Primidone 
Oxcarbazepine 
 


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APPENDIX XI-A: PHARMACOKINETIC STUDY FORM FOR ABI-009 
 
 
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  
 
ABI-009 Dose Level: ______mg/m2    ABI-009 Total Daily Dose: ______mg 
 
ABI-009 Sampling Schedule during Cycle 1 (Single Agent) and Cycle 2 (Combination Therapy): 
 
Blood samples (2 ml) will be collected in EDTA tubes (lavender top) at the following time points: Day 1 (pre-infusion, end 
of infusion, 1 hr., 2 hrs., 4 hrs., and 8 hrs. after beginning the infusion), Day 2 (24 hrs. after beginning the Day 1 infusion), 
Day 4 (72 hrs. [± 24 hrs.] after beginning the Day 1 infusion), Day 8 (pre-infusion) of Cycle 1 and 2. 
 
 
Record the exact time the sample is drawn along with the exact time ABI-009 is given on Days 1 and 8. 
 
 
 
 
 
 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time 
Sample Collected 
(24-hr clock) 
1 
Cycle 1, Day 1 
Prior to Day 1 ABI-009 infusion 
___/___/___ 
|__|__| : |__|__| 
ABI-009 Infusion on Day 1  Date:___/___/___  Start Time: |__|__| : |__|__|  Stop Time: |__|__| : |__|__| 
2 
Cycle 1, Day 1 
30 min. after beginning Day 1 ABI-
009 infusion 
___/___/___ 
|__|__| : |__|__| 
3 
Cycle 1, Day 1 
1 hr. after beginning Day 1 ABI-009 
infusion 
___/___/___ 
|__|__| : |__|__| 
4 
Cycle 1, Day 1 
2 hrs. after beginning Day 1 ABI-009 
infusion 
___/___/___ 
|__|__| : |__|__| 
5 
Cycle 1, Day 1 
4 hrs. after beginning Day 1 ABI-009 
infusion 
___/___/___ 
|__|__| : |__|__| 
6 
Cycle 1, Day 1 
8 hrs. after beginning Day 1 ABI-009 
infusion 
___/___/___ 
|__|__| : |__|__| 
7 
Cycle 1, Day 2 
24 hrs. after beginning Day 1 ABI-
009 infusion 
___/___/___ 
|__|__| : |__|__| 
8 
Cycle 1, Day 4 
72 hrs. (± 24 hrs.) after beginning 
Day 1 ABI-009 infusion 
___/___/___ 
|__|__| : |__|__| 
9 
Cycle 1, Day 8 
Prior to Day 8 ABI-009 infusion 
___/___/___ 
|__|__| : |__|__| 
ABI-009 Infusion on Day 8  Date:___/___/___  Start Time: |__|__| : |__|__|  Stop Time: |__|__| : |__|__| 
10 
Cycle 2, Day 1 
Prior to Day 1 ABI-009 infusion 
___/___/___ 
|__|__| : |__|__| 
ABI-009 Infusion on Day 1  Date:___/___/___  Start Time: |__|__| : |__|__|  Stop Time: |__|__| : |__|__| 
11 
Cycle 2, Day 1 
30 min. after beginning Day 1 ABI-
009 infusion 
___/___/___ 
|__|__| : |__|__| 
12 
Cycle 2, Day 1 
1 hr. after beginning Day 1 ABI-009 
infusion 
___/___/___ 
|__|__| : |__|__| 
13 
Cycle 2, Day 1 
2 hrs. after beginning Day 1 ABI-009 
infusion 
___/___/___ 
|__|__| : |__|__| 


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14 
Cycle 2, Day 1 
4 hrs. after beginning Day 1 ABI-009 
infusion 
___/___/___ 
|__|__| : |__|__| 
15 
Cycle 2, Day 1 
8 hrs. after beginning Day 1 ABI-009 
infusion 
___/___/___ 
|__|__| : |__|__| 
16 
Cycle 2, Day 2 
24 hrs. after beginning Day 1 ABI-
009 infusion 
___/___/___ 
|__|__| : |__|__| 
17 
Cycle 2, Day 4 
72 hrs. (± 24 hrs.) after beginning 
Day 1 ABI-009 infusion 
___/___/___ 
|__|__| : |__|__| 
18 
Cycle 2, Day 8 
Prior to Day 8 ABI-009 infusion 
___/___/___ 
|__|__| : |__|__| 
ABI-009 Infusion on Day 8  Date:___/___/___  Start Time: |__|__| : |__|__|  Stop Time: |__|__| : |__|__| 
 
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should be sent with the 
samples to the address listed in Section 8.3.6. See Section 8.3 for detailed guidelines for packaging and shipping PK samples. 
 
Signature: _________________________________________          Date:___________________  
(site personnel responsible for sample collection) 
 
 
 


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APPENDIX XI-B: PHARMACOKINETIC STUDY FORM FOR IRINOTECAN 
 
COG Pt ID # _______________ 
 
 
 
Cycle 2, Day 1 Date: _____________ 
Please do not 
write patient names on this form or on samples. 
 
Patient Weight: ______kg  
 
Body Surface Area: ______m2  
 
Irinotecan Dose Level: ______mg/m2    Irinotecan Daily Dose: ______mg 
 
 
 
Irinotecan/SN-38 Sampling Schedule during Cycle 2 (Combination Therapy): 
 
Blood samples (2 ml) will be collected in heparinized tubes (green top) at the following time points: Day 1 (pre-dose, 10 
min, 1 hrs., 3 hrs., and 6 hrs. after irinotecan dose), Day 2 (pre-dose [24 hrs. after Day 1 dose]) of Cycle 2. 
 
Record the exact time the sample is drawn along with the exact time Irinotecan is given on Days 1 and 2.  
 
 
 
 
 
 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time 
Sample Collected 
(24-hr clock) 
1 
Cycle 2, Day 1 
Prior to Day 1 irinotecan dose 
___/___/___ 
|__|__| : |__|__| 
Irinotecan Dose on Day 1       Date:___/___/___       Time: |__|__| : |__|__| 
2 
Cycle 2, Day 1 
10 min. after Day 1 irinotecan dose 
___/___/___ 
|__|__| : |__|__| 
3 
Cycle 2, Day 1 
1 hr. after Day 1 irinotecan dose 
___/___/___ 
|__|__| : |__|__| 
4 
Cycle 2, Day 1 
3 hrs. after Day 1 irinotecan dose 
___/___/___ 
|__|__| : |__|__| 
5 
Cycle 2, Day 1 
6 hrs. after Day 1 irinotecan dose 
___/___/___ 
|__|__| : |__|__| 
6 
Cycle 2, Day 2 
Prior to Day 2 irinotecan dose 
___/___/___ 
|__|__| : |__|__| 
Irinotecan Dose on Day 2       Date:___/___/___       Time: |__|__| : |__|__| 
 
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should be sent with the 
samples to the address listed in Section 8.3.6. See Section 8.3 for detailed guidelines for packaging and shipping PK samples. 
 
Signature: _________________________________________          Date:___________________  
(site personnel responsible for sample collection) 
 
 
 


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APPENDIX XII: 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  
 
ABI-009 Dose Level: ______mg/m2 
 
 
 
ABI-009 
Total Daily Dose: ________mg 
 
Tumor Sample Labeling: 
Samples should be labeled with the following information: 
 
Protocol number: ADVL1514 
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 or tissue slides must be packaged appropriately and shipped at room temperature to the Specialized 
Histopathology Core at Brigham and Women’s Hospital (at the address below). If a tumor block is not available, scrolls from the tumor 
block and/or 8-10 (minimum: 6) 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: 
Specialized Histopathology Core 
Brigham and Women’s Hospital 
20 Shattuck Street 
Thorn Building, Rm 603C 
Boston, MA 02115 
Attention: Teri Bowman, Laboratory Manager 
 
Notes:    ___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature: ___________________________________________             Date:______________________ 
 
 
(site personnel responsible for samples) 
 


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APPENDIX XIII: POTENTIAL DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or their Parents 
should be encouraged to talk to their doctors before starting any new medications, using over-the-counter medicines, or 
herbal supplements and before making a significant change in diet. 
 
Cefixime 
Drugs that may interact with cefixime 
• Aminoglycoside antibiotics (such as gentamicin, tobramycin) 
• Oral contraceptives (“birth control”) 
• Probenecid 
• Warfarin 
Food and supplements** that may interact with cefixime 
• 
Thuja 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. All forms should be avoided. 
 
Irinotecan 
Drugs that may interact with irinotecan* 
• 
Antibiotics  
o 
Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics  
o 
Clozapine, nefazodone 
• 
Antifungals  
o 
Fluconazole, itraconazole, isavuconazole, ketoconazole, posaconazole, voriconazole 
• 
Arthritis medications  
o 
Leflunomide, tofacitinib 
• 
Anti-rejection medications 
o 
Cyclosporine 
• 
Antiretrovirals and antivirals  
o 
Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, lopinavir, nelfinavir, nevirapine, 
ritonavir, saquinavir, Stribild®, telaprevir, tipranavir 
• 
Anti-seizure medications  
o 
Carbamazepine, fosphenytoin,  phenobarbital, phenytoin, primidone 
• 
Heart medications  
o 
Amiodarone, carvedilol, dronedenarone, diltiazem, propafenone, quinidine, ranolazine, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Many other drugs, including the following: 
o 
Aprepitant, bosentan, cobicistat, conivaptan, ivacaftor, mifepristone, modafinil, natalizumab 
Food and supplements that may interact with irinotecan** 
• 
Echinacea 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville orange, star fruit 
*Sometimes these drugs are used with irinotecan on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. All forms should be avoided.  
 
The list above does not include everything that may interact with your chemotherapy. Talk to your doctor before starting any new medications, over-the-counter 
medicines, or herbal supplements and before making a significant change in your diet. 
 
Temozolomide 
 
Drugs that may interact with temozolomide*  
• Clozapine, leflunomide, natalizumab, tofacitinib, valproate products  
Food and supplements that may interact with temozolomide**  
• Echinacea 
*Sometimes these drugs are used with temozolomide on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. All forms should be avoided.  
The list above does not include everything that may interact with your chemotherapy. Talk to your doctor before starting any new medications, over-the-counter 
medicines, or herbal supplements and before making a significant change in your diet. 


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APPENDIX XIV: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
This is NOT an all-inclusive list. Because the lists of these agents are constantly changing, it is important to regularly 
consult frequently updated medical references. 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong Inducers 
Moderate 
Inducers 
acalabrutinib5 
alfentanil4,5  
amiodarone4 
aprepitant/fosaprepitant 
atorvastatin 
axitinib 
bortezomib 
bosutinib5 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
mifepristone 
nilotinib 
verapamil 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
dabrafenib 
efavirenz 
etravirine 
modafinil 
nafcillin 
rifapentin 
 
 
 


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ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
nefazodone 
nilotinib 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
quetiapine5 
quinidine4  
regorafenib 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
telaprevir 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may inhibit CYP 
3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section _____ regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is concentration-, dose-, and 
preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors) 


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


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APPENDIX XVI: 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 >. 
 
 
 
CTSU Registration Procedures 


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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 ADVL1514 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.   
 
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. 
 


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APPENDIX XVII:  PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions 
with Other Drugs and Herbal Supplements  
 
Patient 
Name: 
      
Diagnosis
:  
      
Trial #: 
ADVL1514 
Study 
Doctor: 
      
Study 
Doctor 
Phone #:  
      
Study 
Drug(s): 
ABI-009 
 
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse practitioners, pharmacists), 
and tell them you are taking part in a clinical trial sponsored by the National Cancer Institute.  
 
These are the things that your healthcare providers need to know: 
ABI-009 interacts with certain specific enzyme(s) in your liver or other tissues like the gut, AND certain transport 
proteins that help move drugs in and out of cell. 
 
 
Explanation 
CYP 
isoenzymes  
The enzyme(s) in question is CYP3A4. ABI-009 is broken down by this enzyme and 
may be affected by other drugs that inhibit or induce this enzyme. 
 
Protein 
transporters  
 
The protein(s) in question is P-glycoprotein. ABI-009 is moved in and out of 
cells/organs by this transport protein. 
 
These are the things that you need to know: 
The study drug ABI-009, may interact with other drugs which can cause side effects. For this reason, it is very important 
to tell your doctors about all your medicines, including: (a) medicines you are taking before this clinical trial, (b) 
medicines you start or stop taking during this study, (c) medicines you buy without a prescription (over-the-counter 
remedy), (d) herbals or supplements (e.g. St. John’s Wort). It is helpful to bring your medication bottles or an updated 
medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered strong inducers/inhibitors of CYP3A4 enzyme and P-glycoprotein. 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain ingredients that could 
interact with your study drug.  Speak to your doctors or pharmacist to determine if there could be any side effects.  
o St. John’s Wort, graperfruit or grapefruit juice 
• Make sure your doctor knows to avoid certain prescription medications.  
o Antofungal agents (e.g., voriconazole, itraconazole, posaconazole), macrolide antibiotics (clarithromycin, 
telithromycin), anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin), and antibiotics (e.g., 
rifabutin, rifampin) and other drugs (e.g., HIV-protease inhibitors, amiodarone, dronedarone, carvedilol).  
• Your regular health care provider should check a frequently updated medical reference or call your study doctor 
before prescribing any new medicine or discontinuing any medicine.   
 
(Next page: Patient Drug Interaction Wallet Card) 
 
 
 
 
 
 


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PATIENT DRUG INTERACTION WALLET CARD 
 
 
 
EMERGENCY 
INFORMATION 
 
DRUG INTERACTIONS  
Show this card to all of 
your healthcare 
providers. Keep it with 
you in case you go to the 
emergency room. 
Tell your doctors before you start or 
stop any medicines. 
Check with your doctor or 
pharmacist if you need to use an 
over-the-counter medicine or 
herbal supplement! 
Carry this card with you at all times   
ABI-009 interacts with a specific enzyme in your liver or other 
tissues like the gut, transport proteins that help move drugs in and 
out of cells, the heart’s electrical activity, and must be used very 
carefully with other medicines. 
Patient Name:       
Use caution 
and avoid the 
following 
drugs if 
possible:  
 
amiodarone 
atazanavir 
boceprevir 
carbamazepine 
carvedilol 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
dronedarone 
enzalutamide 
fosphenytoin 
grapefruit/grape
fruit juice 
idelalisib 
indinavir 
itraconazole 
ketoconazole 
lapatinib 
 
 
 
 
 
 
lopinavir/riton
avir 
nefazodone 
nelfinavir 
phenobarbital 
phenytoin 
posaconazole 
primidone 
propafenone  
ranolazine 
rifampin 
ritonavir 
saquinavir 
St. John’s 
wort 
telaprevir 
telithromycin 
tipranavir 
verapamil 
voriconazole 
Your healthcare providers should be aware of any medicines that 
are strong inducers/inhibitors of CYP3A4 and P-glycoprotein 
transport protein. 
Diagnosis:       
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #: ADVL1514 
Before prescribing new medicines, your health care provider 
should check a frequently-updated medical reference for a list 
of drugs to avoid or contact your study doctor. 
Study Drug(S): ABI-009 
 
             Version 06/2020 
 
For more information: 1-800-4-
CANCER 
For more information: 1-800-4-
CANCER 
For more information: 1-800-4-
CANCER 
For more information: 1-800-4-
CANCER 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
 
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