Conditions: Central Nervous System Embryonal Tumor With Rhabdoid Features Central Nervous System Embryonal Tumor, Not Otherwise Specified Central Nervous System Ganglioneuroblastoma Embryonal Tumor With Multilayered Rosettes, C19MC-Altered Pineoblastoma Primary Central Nervous System Neoplasm Recurrent Childhood Central Nervous System Embryonal Neoplasm Recurrent Malignant Solid Neoplasm Recurrent Medulloblastoma Recurrent Neuroblastoma Recurrent Rhabdomyosarcoma Refractory Malignant Solid Neoplasm Refractory Medulloblastoma Refractory Neuroblastoma Refractory Rhabdomyosarcoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 76
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and best dose of adavosertib and irinotecan hydrochloride in treating younger patients with solid tumors that have come back (relapsed) or that have not responded to standard therapy (refractory). Adavosertib and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of adavosertib (AZD1755 \[MK-1775\]) administered on days 1 through 5 every 21 days, in combination with oral irinotecan (irinotecan hydrochloride), to children with recurrent or refractory solid tumors.

II. To define and describe the toxicities of AZD1755 (MK-1775) in combination with oral irinotecan administered on this schedule.

III. To characterize the pharmacokinetics of AZD1755 (MK-1775) in children with refractory cancer.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of AZD1755 (MK-1775) and irinotecan within the confines of a Phase 1 study.

II. To obtain initial phase 2 efficacy data on the anti-tumor activity of AZD1755 (MK-1775) in combination with irinotecan administered to children with relapsed or refractory neuroblastoma, in children with relapsed or refractory medulloblastoma/CNS PNET (central nervous system primitive neuroectodermal tumor) and in children with relapsed or refractory rhabdomyosarcoma.

III. To investigate checkpoint over-ride by AZD1755 (MK-1775) via the mechanism-based pharmacodynamic (PD) biomarker of decreased cyclin-dependent kinase 1 (CDK1) phosphorylation in correlative and exploratory studies.

IV. To evaluate potential predictive biomarkers of AZD1755 (MK-1775) sensitivity, including v-myc avian myelocytomatosis viral oncogene homolog (MYC), v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), phosphorylated-WEE1 G2 checkpoint kinase (p-Wee1), enhancer of zeste homolog 2 (Drosophila) (EZH2) and gamma-H2A histone family, member gamma-(H2AX) in tumor tissues in correlative and exploratory studies.

OUTLINE: This is a phase I, dose-escalation followed by a phase II study.

Patients receive irinotecan hydrochloride orally (PO) and adavosertib PO on days 1-5. Treatment repeats every 21 days for up to 18 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 irinotecan hydrochloride PO and adavosertib PO on days 1-5. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Adavosertib intervention 2: Irinotecan Hydrochloride
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO

Protocol document:
Prot_SAP_001.pdf: 
Pediatric Early Phase Clinical Trial 
Network (PEP-CTN) and  
Developmental Therapeutics (DVL) 
Chair 
Brenda J. Weigel, M.D. 
weige007@umn.edu 
 
PEP-CTN and  
Developmental Therapeutics (DVL) 
Vice Chair  
Elizabeth Fox, M.D. 
foxe@email.chop.edu 
 
PEP-CTN Operations  
Data & Statistics Center Director 
Thalia Beeles, MPH 
tbeeles@childrensoncologygroup.org 
 
PEP-CTN Statistician  
Charles G. Minard, Ph.D. 
minard@bcm.edu 
 
 
PEP-CTN and  
DVL Chair’s Office 
University of Minnesota/ 
Masonic Cancer Center 
Masonic Children’s Hospital 
420 Delaware Street, SE 
MMC 366 
Minneapolis, MN  55455 
 
P 612 626 5501 
F 612 624 3913 
 
 
Children’s Oncology Group 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
PEP-CTN Operations Data & 
Statistics Center 
222 E. Huntington Drive 
Suite 100  
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
 
A National Cancer Institute  
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
 
 
 
 
 
 
Page i 
June 2, 2020 
 
Martha Kruhm, M.S., RAC 
Head, Protocol and Information Office (PIO)  
National Institutes of Health/NCI/DCTD/CTEP/OIB/PIO 
9609 Medical Center Drive, OIB MSC 9742, Room #5W246 
Bethesda, MD 20892-9742 
 
 
 
Dear Ms. Kruhm, 
 
 
Enclosed please find Amendment #10 to ADVL1312, A Phase 1/2 Study of AZD1775 
(MK-1775) in Combination with Oral Irinotecan in Children, Adolescents, and Young 
Adults with Relapsed or Refractory Solid Tumors. 
 
The protocol has been amended in response to the Request for Rapid Amendment from 
Dr. Charles Kunos, dated May 21, 2020. 
 
SUMMARY OF CHANGES 
 
The following specific revisions have been made to the protocol and informed consent 
document. Additions are in boldfaced font and deletions in strikethrough font.  
 
SUMMARY OF CHANGES PROTOCOL DOCUMENT: 
 
# 
Section 
Page 
Comments 
1. 
General 
All 
The version date and amendment number have been 
updated throughout the protocol 
2. 
9.1.6 
36-39 
CAEPR has been updated to version 2.7, dated April 
27, 2020 
 
 
SUMMARY OF CHANGES INFORMED CONSENT DOCUMENTS: 
# 
Section 
Comments 
1. 
General 
The version date has been updated throughout 
 
2. 
Risks… 
Risks list for AZD1775 has been updated 
 


 
 
 
 
 
 
 
ADVL1312 
Page 1 
 
 
Activated: 
March 17, 2014 
Version Date: 
06/02/20 
Closed: 
Amendment #: 
10 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
ADVL1312 
 
A PHASE 1/2 STUDY OF AZD1775 (MK-1775) IN COMBINATION WITH ORAL IRINOTECAN 
IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH RELAPSED OR 
REFRACTORY SOLID TUMORS 
 
 
 
Lead Organization: Pediatric Early Phase Clinical Trials Network (PEP-CTN) 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED 
OR USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN 
THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY 
ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT 
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL 
HOSPITAL OR HEALTHCARE INSTITUTION. 
 
STUDY CHAIR 
Kristina A. Cole, MD, PhD 
Children’s Hospital of Philadelphia 
Division of Oncology  
CTRB Room 3054 
 
3501 Civic Center Blvd 
Philadelphia, PA 19104 
Phone: 
(267) 426-2285 
Fax: 
(267) 426-0685   
                                                                 E-mail: colek@email.chop.edu                    
 
                                   
For 
PEP-CTN 
Operations 
and 
Statistics 
& 
Data 
Center 
Contacts 
See: 
http://members.childrensoncologygroup.org    
 
 


 
 
 
 
 
ADVL1312 
Page 2 
Version Date: 06/02/2020 
 
TABLE OF CONTENTS 
SECTION 
PAGE 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Aims 
8 
1.2 
Secondary Aims 
8 
2.0 
BACKGROUND 
8 
2.1 
Introduction/Rationale for Development and Dosing 
8 
2.2 
Preclinical Studies 
11 
2.3 
Adult Studies 
12 
2.4 
Pediatric Studies 
14 
2.5 
Overview of Proposed Pediatric Study 
14 
2.6 
Rationale for inclusion of Part D (Amendment #4) 
14 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
15 
3.1 
Current Study Status 
15 
3.2 
IRB Approval 
15 
3.3 
Patient Registration 
16 
3.4 
Reservation and Contact Requirements 
16 
3.5 
Informed Consent/Assent 
16 
3.6 
Screening Procedures 
17 
3.7 
Eligibility Checklist 
17 
3.8 
Institutional Pathology Report 
17 
3.9 
Study Enrollment 
17 
3.10 
Dose Assignment 
17 
4.0 
PATIENT ELIGIBILITY 
17 
4.1 
Inclusion Criteria 
18 
4.2 
Exclusion Criteria 
21 
5.0 
TREATMENT PROGRAM 
22 
5.1 
Overview of Treatment Plan 
22 
5.2 
Criteria for Starting Subsequent Cycles 
23 
5.3 
Dose Escalation Schema 
23 
5.4 
Grading of Adverse Events 
24 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
24 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
25 
6.1 
Dose Modifications for Hematological Toxicity 
25 
6.2 
Dose Modifications for Non-Hematological Toxicity 
26 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
26 
7.1 
Concurrent Anticancer Therapy 
26 
7.2 
Investigational Agents 
26 
7.3 
Supportive Care 
27 
7.4 
Growth Factors 
27 
7.5 
Concomitant Medications 
27 


 
 
 
 
 
ADVL1312 
Page 3 
Version Date: 06/02/2020 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
27 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
27 
8.2 
Radiology Studies 
30 
8.3 
Pharmacokinetics (Required for Part A only) 
31 
8.4 
Pharmacodynamics (for Part A only) 
32 
8.5 
Bone marrow Studies (for Parts A, B, or C, or D) 
33 
8.6 
Tissue Studies (for Parts A, B,  C, or D) 
34 
9.0 
AGENT INFORMATION 
34 
9.1 
AZD1775  (MK-1775) 
34 
9.2 
Cefixime       (11/17/17) 
40 
9.3 
IRINOTECAN        (03/07/17) 
42 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
45 
10.1 
Criteria for Removal from Protocol Therapy 
45 
10.2 
Off Study Criteria 
45 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
45 
11.1 
Sample Size and Study Duration 
45 
11.2 
Definitions 
46 
11.3 
Dose Escalation and Determination of MTD (Part A) 
47 
11.4 
Phase 2 Evaluation in Neuroblastoma (Part B), Medulloblastoma/CNS PNET (Part C) and 
Rhabdomyosarcoma (Part D) 
48 
11.5 
Inclusion of Children, Women and Minorities 
50 
11.6 
Pharmacokinetic and Correlative Studies and Response Analysis 
50 
12.0 
EVALUATION CRITERIA 
51 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
51 
12.2 
Response Criteria for Patients with Solid Tumors 
51 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
55 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
56 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
57 
12.6 
Response Criteria for Patients with CNS Tumors 
58 
12.7 
Best Response 
60 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
63 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
63 
13.2 
When to Report an Event in an Expedited Manner 
65 
13.3 
Expedited Reporting Methods 
66 
13.4 
Definition of Onset and Resolution of Adverse Events 
66 
13.5 
Other Recipients of Adverse Event Reports 
66 
13.6 
Reporting Secondary AML/MDS 
67 
13.7 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
67 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
69 
14.1 
Categories of Research Records 
69 
14.2 
CDUS 
69 
14.3 
CRADA/CTA/CSA 
69 
14.4 
Data and Safety Monitoring Plan 
71 
REFERENCES 
72 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
74 


 
 
 
 
 
ADVL1312 
Page 4 
Version Date: 06/02/2020 
 
APPENDIX II:  UNACCEPTABLE ENZYME INDUCING AND RECOMMENDED NON-ENZYME 
INDUCING ANTICONVULSANTS 
75 
APPENDIX III:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
76 
APPENDIX IV: AZD1775 (MK-1775) DOSING NOMOGRAM 
78 
APPENDIX V:  INSTRUCTIONS FOR IRINOTECAN PREPARATION, ADMINISTRATION AND 
SAFE HANDLING 
79 
APPENDIX VI:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
80 
APPENDIX VII:  CORRELATIVE STUDIES GUIDE 
82 
APPENDIX VIII:  PHARMACOKINETIC STUDY FORM (PART A ONLY) 
83 
APPENDIX IX-A:  PHARMACODYNAMIC STUDY FORM (PART A ONLY) 
84 
APPENDIX IX-B: PD SAMPLE COLLECTION GUIDELINES 
85 
APPENDIX X:  BONE MARROW STUDY FORM (PART A, B, C OR D) 
86 
APPENDIX XI:  TISSUE STUDY FORM (PART A, B, C, OR D) 
87 
APPENDIX XII: TOXICITY-SPECIFIC GRADING 
88 
APPENDIX XIII:  MEDICATION DIARY FOR AZD1775 (MK-1775) 
89 
APPENDIX XIV:  POTENTIAL DRUG INTERACTIONS 
91 
APPENDIX XV: MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
93 
APPENDIX XVI: CTEP AND CTSU REGISTRATION PROCEDURES 
94 


 
 
ADVL1312 
 
 
 
Page 5 
Version Date: 06/02/2020 
 
STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS  
Kristina A. Cole , MD, PhD 
 
Children’s Hospital of Philadelphia 
Brenda J. Weigel, MD 
Division of Oncology 
Chair, Developmental Therapeutics  
CTRB Room 3054 
Hematology/Oncology 
3501 Civic Center Blvd. 
University of Minnesota Medical Center - Fairview 
Philadelphia, PA 19104  
Department of Pediatrics 
Phone: (267) 426-2285 
420 Delaware Street, SE  MMC 366 
Fax: 
(267) 426-0685 
Minneapolis, MN 55455 
E-mail: colek@email.chop.edu 
Phone:   (612) 626-5501 
 
Fax:  
 (612) 624-3913 
STUDY VICE CHAIR 
E-mail: weige007@umn.edu 
Elizabeth Fox, MD 
 
Vice Chair, Developmental Therapeutics 
Susan M. Blaney, MD 
Children’s Hospital of Philadelphia 
Hematology/Oncology 
Pediatrics/Division of Oncology 
Baylor College of Medicine 
CTRB Room 4016 
Clinical Care Center,  CC1410.00 
3501 Civic Center Blvd. 
6621 Fannin Street, Suite 1410 
Philadelphia, PA 19104 
Houston, TX  77030-2399 
Phone: (267) 425-3010 
Phone: (832) 822-4586 
Fax: 
(267) 425-0113 
Fax: 
(832) 825-4299 
E-mail: foxe@email.chop.edu  
E-mail: smblaney@txch.org 
 
 
SENIOR STATISTICIAN  
John M. Maris, MD 
Charles G. Minard, PhD 
Children’s Hospital of Philadelphia 
Baylor College of Medicine  
The Colket Translation Research Building 
One Baylor Plaza, Suite 100D, BCM 122 
3501 Civic Center Boulevard 
Houston, TX 77030 
Philadelphia, PA 19104 
Phone:   (713) 798-2353 
Phone: (215) 590-5244 
Fax:  
 (713) 798-2816 
Fax: 
(267) 426-0685 
E-mail: minard@bcm.edu 
 
E-mail: maris@chop.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Douglas J. Harrison, MD 
MD Anderson Cancer Center, Division of Pediatrics, 
Unit 87 
1515 Holcombe Blvd 
Houston, TX 77030-4009 
Phone: (713) 792-6620 
Fax: 
(713) 794-5042 
E-mail: djharrison@mdanderson.org 
 


 
 
ADVL1312 
 
 
 
Page 6 
Version Date: 06/02/2020 
 
 
STUDY NURSE  
Jane E. Minturn, MD, PhD 
Susan Ehling, MN ARNP 
Children’s Hospital of Philadelphia 
Seattle Children's Hospital 
Division of Oncology 
Hematology/Oncology 
CTRB 4028, 3501 Civic Center Boulevard 
4800 Sand Point Way NE 
Philadelphia, PA 19104-4318 
PO Box C5371 Hem/Onc. Mail Stop B6553 
Phone: (267) 426-5026 
Seattle, WA 98105 
Fax: 
(215) 590-9956 
Phone: (206) 987-2043 
E-mail: minturn@email.chop.edu 
Fax: (206) 987-3946 
 
E-mail: susan.ehling@seattlechildrens.org 
 
 
 
PROTOCOL COORDINATOR 
STUDY CRA 
Patrice Navrude, MS 
Marily Lesher, BS, CCRP 
Children’s Oncology Group – Operations Center 
University of Minnesota/Masonic Cancer Center 
222 E. Huntington Drive, Suite 100 
420 Delaware St SE 
Monrovia, CA  91016 
MMC 484/ Mayo D548-2 
Phone: (626) 241-1607 
Phone: (612) 626-3915 
Fax: 
(626) 445-4334 
Fax: (612) 626-2815 
E-mail: pnavrude@childrensoncologygroup.org  
E-mail: mblesher@umn.edu 
 
 
 
 
 
For PEP-CTN Operations and 
 
Statistics & Data Center (SDC) contacts see: 
 
http://members.childrensoncologygroup.org   
 
 
 
 
 
AGENT NSC# AND IND#’s 
 
 
 
NCI-Supplied Agent: 
MK-1775 (AZD1775) 
 
(NSC # 751084) 
 
 
 
Commercial Agent: 
 
Irinotecan (CPT-11, Camptosar), NSC #616348 
Cefixime (Suprax®) 
 
 
 
IND Sponsor:  [DCTD, NCI] 
 
SEE SECTION 8.3.6, 8.4.6, and APPENDIX X AND XI FOR SPECIMEN SHIPPING ADDRESSES 
 


 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. ADVL1312 
  
 
 
 
Page 7 
Version Date: 06/02/2020 
 
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 
 
Wee1 is a tyrosine kinase that is activated in response to DNA damage and plays a role in chemo-resistance 
and tolerance of oncogene induced cellular stress. The Wee1 inhibitor, AZD1775 (MK-1775), was 
developed to overcome this checkpoint and render cells more sensitive to chemotherapy, and may be more 
effective in tumors with high levels of the MYC or MYCN oncogene.  In the phase 1 portion of this study 
(Part A), patients with recurrent or refractory solid tumors including CNS tumors will receive the Wee1 
inhibitor AZD1775 (MK-1775) in combination with irinotecan. Both agents will be administered orally on 
days 1-5 of a 21-day cycle with a step-wise inter-patient dose escalation of AZD1775 (MK-1775).  Patients 
will be accrued to dose levels using a 3+3 design. Toxicity will be graded according to the CTCAE v 5.0 
and response will be assessed by RECIST criteria. There will be analysis of AZD1775 (MK-1775) 
pharmacokinetics and the mechanism-based biomarker of AZD1775 (MK-1775) induced replication 
checkpoint over-ride. Analysis of Wee1 signaling and MYC and MYCN levels will be performed from 
archival tumor tissue in patients with available tissue and from bone marrow in consenting patients with 
bone marrow involvement. Once the recommended phase 2 dose of AZD1775 (MK-1775) in combination 
with irinotecan is determined, there will be a phase 2 expansion for patients with refractory or recurrent 
neuroblastoma (Part B) for patients with refractory or recurrent medulloblastoma/CNS PNET (Part C) and 
for patients with relapsed or refractory rhabdomyosarcoma (Part D). 
 
 
EXPERIMENTAL DESIGN SCHEMA 
 
 
 
AZD1775 (MK-1775) 
Irinotecan 
   CEF: Cefixime or an available equivalent antibiotic will be administered at least 2 days prior to the first dose of 
irinotecan, during, and 3 days after irinotecan in each cycle. 
 
See Table 8.1 for required disease evaluations. Therapy will be discontinued if there is evidence of 
progressive disease or drug related dose-limiting toxicity that requires removal from therapy. Therapy may 


 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. ADVL1312 
  
 
 
 
Page 8 
Version Date: 06/02/2020 
 
otherwise continue for up to 18 cycles. 
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 
dose of AZD1775 (MK-1775) administered on days 1 through 5 every 21 days, 
in combination with oral irinotecan, to children with recurrent or refractory solid 
tumors. 
 
1.1.2 
To define and describe the toxicities of AZD1775 (MK-1775) in combination 
with oral irinotecan administered on this schedule. 
 
1.1.3 
To characterize the pharmacokinetics of AZD1775 (MK-1775) in children with 
refractory cancer. 
 
1.2 
Secondary Aims 
 
1.2.1 
To preliminarily define the antitumor activity of AZD1775 (MK-1775) and 
irinotecan within the confines of a Phase 1 study. 
 
1.2.2 
To obtain initial Phase 2 efficacy data on the anti-tumor activity of AZD1775 
(MK-1775) in combination with irinotecan administered to children with 
relapsed or refractory neuroblastoma, in children with relapsed or refractory 
medulloblastoma/CNS PNET (central nervous system primitive neuroectodermal 
tumor) and in children with relapsed or refractory rhabdomyosarcoma. 
 
1.2.3 
To investigate checkpoint over-ride by AZD1775 (MK-1775) via the 
mechanism-based pharmacodynamic (PD) biomarker of decreased CDK1 
phosphorylation in correlative and exploratory studies.  
 
1.2.4 
To evaluate potential predictive biomarkers of AZD1775 (MK-1775) sensitivity, 
including MYC, MYCN, p-Wee1, EZH2 and γ-H2AX in tumor tissues in 
correlative and exploratory studies. 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development and Dosing 
Although patients with localized solid tumors generally do well, patients with refractory 
and relapsed disease have a poor prognosis.  New therapeutic regimens that combine 
chemotherapy with targeted chemosensitizing agents merit study in this patient population. 
 
2.1.1 
Rationale for Wee1 inhibition strategies 
Wee1 is a tyrosine kinase that phosphorylates and inhibits CDK1 (the HUGO term 
for CDC2) at a conserved tyrosine 15 residue, affecting proper coordination of 
DNA replication as well as entry into mitosis.1 In the presence of DNA damage or 
replication stress (by chemotherapy, radiation or oncogenes) CDK1 activity is 
restrained by the checkpoint kinases CHK1 and Wee1, allowing for repair of DNA 
prior to mitosis and tolerance of replication stress and maintenance of tumor cell 
viability.2 Inhibition of CHK1 or Wee1 under these circumstances leads to 


 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. ADVL1312 
  
 
 
 
Page 9 
Version Date: 06/02/2020 
 
replication fork collapse or mitotic catastrophe, generation of double-strand DNA 
breaks and ultimately cellular death. Therefore, checkpoint inhibitors have been 
evaluated in clinical trials as chemotherapy and radiation sensitizers.3 The Wee1 
inhibitor MK-1775 has been evaluated in combination with gemcitabine, 
carboplatin and cisplatin, 5-FU, topotecan and cisplatin and carboplatin and 
paclitaxel.4  
 
2.1.2 
Rationale for Wee1 inhibition strategies in pediatric solid tumors 
In an effort to identify novel therapeutics for neuroblastoma, an unbiased RNA 
interference screen of the entire protein kinome was performed and the Cell Cycle 
Checkpoint Kinase 1 (CHK1) was the most potent in a panel of ten neuroblastoma 
cell lines.5 Upon examination of downstream signaling, this effect was 
phenocopied by inhibition of the CDK1 kinase, Wee1.6 Like CHK1, Wee1 was 
highly expressed in neuroblastoma, particularly tumors with MYCN amplification 
and constitutively phosphorylated in neuroblastoma cell lines and diagnostic 
primary tumors of children with advanced disease. This single agent sensitivity 
resulted in synergistic growth inhibition in combination with cytotoxic 
chemotherapy agents, including camptothecins. 6 There is also potent synergistic 
growth inhibition with dual CHK1 and Wee1 targeting.6,7 Neuroblastoma is likely 
sensitive to single agent Wee1 inhibition due to intrinsic replication stress and high 
CDK1 activity due to high levels of MYC and MYCN.2 MYCN is an oncogenic 
driver in high-risk neuroblastoma via focal genomic amplification, and tumors 
without MYCN amplification have high levels of c-MYC. Yet, both oncogenes 
have remained undruggable. As has been recently shown with MYC-induced 
lymphomas, targeting the ATR/CHK1 and Wee1 pathways in MYC-driven tumors 
may be a synthetic lethal means of targeting MYC and MYCN.8,9 As such, 
medulloblastoma is an embryonal tumor that also involves MYC / MYCN in tumor 
initiation and maintenance and marks the most clinically aggressive subset of 
medulloblastomas.10-12 Like neuroblastoma, medulloblastoma cell lines are also 
sensitive to single agent Wee1 inhibition (unpublished results). In addition, Wee1 
has been shown to be overexpressed in diffuse intrinsic pontine glioma (DIPG) 
tumors and MK-1775 was a radiation sensitizer in a mouse model of DIPG.13  
 
2.1.3 
Rationale for Chemotherapy Backbone  
In adult clinical trials, MK-1775 has been developed in combination with 
gemcitabine, cisplatin, carboplatin, 5-FU, topotecan plus cisplatin and carboplatin 
plus paclitaxel. The rationale for combining MK-1775 with irinotecan in a 
pediatric phase 1/2 clinical trial is multi-factorial. Irinotecan induces replication 
arrest and MK-1775’s mechanism of action involves replication arrest over-ride 
providing mechanistic support for this combination. There is pre-clinical data 
showing synergistic growth inhibition of MK-1775 in combination with irinotecan 
in preclinical models of neuroblastoma.6 The multiple five-day dosing regimen of 
irinotecan allows for serial dosing of MK-1775, allowing for a more prolonged 
exposure than single day dosing and irinotecan induced downregulation of CHK1. 
Finally, irinotecan containing regimens have been shown to have activity in 
combination in neuroblastoma (providing a backbone to test targeted agents) 14 and 
there is single agent activity of irinotecan in medulloblastoma (16% overall 
response rate).15 
 
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MK-1775 was combined with topotecan and cisplatin in an adult phase 1 trial for 
cervical cancer. 4  
 
2.1.4 
Rationale for Proposed MK-1775 and Irinotecan Dosing 
MK-1775 has been administered to adults as a single agent and in combination 
with several chemotherapeutics. The schedule of administration of MK-1775 was 
determined by the chemotherapy regimen and included single dosing and multiple 
day dosing regimens. 
 
The proposed starting dose, schedule and dose escalation of MK-1775 on a 5 day 
schedule were based on the following considerations: 4 
 
▪ 
Wee1 restrains CDK1 activity and is involved in the DNA damage response, 
and irinotecan causes DNA strand breaks.2  Inhibitors of Wee1 including MK-
1775 may potentiate the DNA damage in tumor cells.  However, MK-1775 
may also potentiate toxicity.  Therefore, the starting dose of irinotecan on this 
study (70 mg/m2 PO) corresponds to the recommended phase 2 dose for 
heavily pretreated patients (40 mg/m2 IV) and the starting dose used in 
combination regimens.16,17  In the absence of dose limiting toxicity, the dose 
of irinotecan will be escalated from 70 mg/m2 to 90 mg/m2. 17 
 
▪ 
Irinotecan is administered on a daily 5-day schedule every 21 days; therefore, 
the proposed administration of MK-1775 will be daily x 5 every 21 days.15 
MK-1775 has a short half-life (average of 9 hours). In dogs, the No Observed 
Adverse Effect Level (NOEL) of MK-1775 was 100 mg/m2 (5 mg/kg) daily 
for 7 days. Given the novel combination, schedule and dosing in children, a 
conservative approach was taken with dosing. The proposed starting dose of 
MK-1775 daily for 5 days on this trial is 50 mg/m2, 50% of the NOEL in dogs 
receiving MK-1775 daily x 7 days. The highest MK-1775 dose proposed on 
this study (110 mg/m2 daily x 5 days) is at the NOEL. The proposed starting 
dose on this trial (50 mg/m2) was also determined by the tolerated adult phase 
1 clinical trial that evaluated patients receiving 3 days of IV topotecan, 1 day 
of IV cisplatin and 5 days of MK-1775 (50 mg for 9 doses) every 21 days.  The 
highest proposed dose in this trial’s escalation (110 mg/m2) is based on the 
adult phase 1 multiple day dosing trials in which 5 doses of MK-1775 were 
administered over 2.5 days in combination with carboplatin and cisplatin. The 
MTD of MK-1775 was 225 mg and 200 mg, respectively, which when 
converted to 5-day single dose administration would be approximately 116 
mg/m2/day. 
 
▪ 
Preclinical data indicates that MK-1775 concentrations ≥ 0.28µM produce a 
target effect (EC50 for p-CDK1) after gemcitabine.4 Clinical studies showed 
accumulation of drug with BID dosing, but this was minimal with daily dosing. 
A single oral dose of 100 mg MK-1775 (57 mg/m2) in adults in combination 
with chemotherapy has an average Cmax of approximately 0.3 µM; therefore, 
all proposed MK-1775 doses on this study may produce a biologically relevant 
concentration. In the absence of dose limiting toxicity, MK-1775 dose 
escalation is proposed to increase the systemic exposure and prolong time 
above this threshold concentration. 
 


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2.1.5 
Rationale for Cefixime 
There are two distinct patterns of irinotecan-associated diarrhea: early and late 
onset. Early onset diarrhea occurs within 4 hours of treatment, is associated with 
cholinergic symptoms and is readily reversible with atropine. Late onset diarrhea 
develops during the second week of therapy and is one of the main dose limiting 
toxicities of irinotecan in pediatric studies.18  With the addition of antibiotics, such 
as cefixime, that selectively eradicate intestinal bacteria that would otherwise re-
activate the metabolized irinotecan, investigators have been able to improve 
tolerability of irinotecan. Using cefixime combined with as needed use of 
loperamide, Furman et al 19 were able to increase the MTD of protracted oral 
irinotecan by 50%, and a similar increase was noted with protracted IV irinotecan 
dosing.20  
 
2.2 
Preclinical Studies  
 
2.2.1 
Antitumor Activity of Irinotecan in pre-clinical models 
Irinotecan is a camptothecin prodrug whose active metabolite (SN-38) induces 
cytotoxicity in the presence of topoisomerase I. Topoisomerase I permits 
relaxation of supercoiled DNA by inducing single strand breaks, which reduces 
torsional strain during DNA replication and transcription. When an active 
topoisomerase I enzyme is present, camptothecins stabilize topoisomerase-induced 
DNA strand breaks which ultimately leads to apoptosis.  Anti-tumor activity of 
irinotecan has been demonstrated in mouse models of neuroblastoma21, 
rhabdomyosarcoma22 and CNS malignancies.22,23 
 
2.2.2 
Antitumor Activity of MK-1775 in pre-clinical models 
Kinase screening assays identified MK-1775 as a selective and potent (IC50= 5.18 
nM) inhibitor of Wee1.24 In vitro synergistic antiproliferative effects were 
observed in tumor cells treated with MK-1775 in combination with gemcitabine, 
cisplatin, carboplatin and 5-FU. In tumor bearing mouse xenografts, MK-1775 was 
administered according the chemotherapy schedule.  There was enhanced anti-
tumor efficacy, increased survival and tolerability noted in multiple xenograft 
models when MK-1775 was combined with gemcitabine, cisplatin, carboplatin, 5-
FU, radiation or capecitabine.4,24-28 
 
While MK-1775 has the potential to enhance chemotherapy sensitivity, with 
continuous dosing there is single agent activity in some tumor models. In vitro 
testing of eight sarcoma lines with MK-1775 had an average IC50 of 342 nM (± 
154 nM).29 There was anti-tumor efficacy of twice daily dosing of MK-1775 in 
mouse xenografts bearing tumors derived from non-small cell lung cancer and 
colorectal carcinoma.4 MK-1775 enhanced the radiation response in DIPG mouse 
xenografts.13 Finally, MK-1775 also had single agent antiproliferative activity in 
10 of 11 human derived neuroblastoma cell lines with an average IC50 of 300 nM 
(± 193 nM) and cell lines derived from the MYCN genetically engineered 
neuroblastoma mouse model (IC50s ~ 200 nM).6 The average IC50 in 4 
medulloblastoma cell lines treated with MK-1775 alone was 454 nM (unpublished 
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results).  MK-1775 in combination with SN-38 (the active metabolite of irinotecan) 
resulted in significant synergistic inhibition in eight of ten of the human 
neuroblastoma cell lines tested. 6  
 
 
2.2.3 
MK-1775 Toxicology4 
In the 7 day oral toxicity studies, MK-1775 was administered by 25, 75, or 300 
mg/kg in rats, and at 5 or 15 mg/kg in dogs, once daily for 7 days.  Expected 
toxicity of the hematopoietic organs and GI tract were observed in both rats and 
dogs.  In rats, however, this was associated with mortality at 75 mg/kg (450 mg/m2) 
and 300 mg/kg (1800 mg/m2). During the 2 week recovery period, MK-1775 
related changes recovered or showed a trend towards reversibility in rats dosed at 
25 mg/kg (150 mg/m2) and dogs at 15 mg/kg (300 mg/m2). In the anesthetized 
cardiovascular dog study, MK-1775 marginally prolonged QTc by an average of 
5% and 7%, at the 3 and 10 mg/kg doses, respectively. Only minimal effects on 
blood pressure (-5%) and heart rate (-5%) were observed at the 10 mg/kg dose. 
There were no effects on other cardiographic measures, i.e., QRS duration or PR 
interval, at either dose. In mice, MK-1775 had no effect on CNS function (at a dose 
of 10 mg/kg), including gross behavior, spontaneous activity, neural reflexes, or 
thermoregulation during the 24-hour post dose period. 
 
2.2.4 
Preclinical Pharmacokinetic Studies 4 
The PK studies were conducted in male Sprague-Dawley rats and Beagle dogs 
following IV and PO administration of MK-1775. MK-1775 was rapidly 
distributed and eliminated with the mean half-life (t½) 1.6 hours in rats and 1.1 
hours in dogs. MK-1775 has moderate plasma protein binding with the unbound 
fraction in rat, human and dog begin 23.2%, 40% and 39.5%, respectively. The 
major metabolic pathway of MK-1775 in human liver preparations was oxidative 
metabolism. In human hepatocytes, the major metabolites formed were an N-
desmethyl metabolite and an N-oxide derivative. All metabolites observed in 
human liver preparations were also formed in vivo in the rat and dog. Oxidative 
metabolism of MK-1775 was mediated predominantly by cytochrome P450 3A4 
(CYP3A4) and flavin-containing monooxygenase 3 (FMO3). MK-1775 was a 
weak reversible inhibitor of CYP2C8, CYP2C9, CYP2C19, and CYP3A4 (IC50 
of 51, 56, 12, and 14 μM, respectively). In addition, MK-1775 was a time-
dependent inhibitor of CYP3A4. MK-1775 is a substrate of P-glycoprotein (Pgp). 
 
2.3 
Adult Studies 
 
2.3.1 
Phase 1 Studies 4 
MK-1775 clinical data are derived from the phase 1 dose-escalation study (PN001) 
in adult patients with advanced solid tumors, sponsored by Merck.30 The study 
consists of a MK-1775 monotherapy arm and several combination therapy arms 
(MK-1775 with gemcitabine, cisplatin, or carboplatin). The study objectives 
include investigating safety, tolerability, PK, and PD of MK-1775 administered as 
monotherapy and as combination therapy. MK-1775 administered as a single agent 
at a single dose (≤ 1300 mg PO) was well tolerated, and no MTD has been 
established. A single patient experienced Grade 3 dehydration and urinary tract 
infection.  To date, a total of 176 patients have received MK-1775, 9 patients 
received MK-1775 as one dose monotherapy. Eight out of the original 9 patients 
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went on to get a combination with cisplatin, carboplatin or gemcitabine and an 
additional 35 patients were enrolled in the single-dose combination. In all, 44 
patients took part in the single-dose monotherapy/combination portion of the 
study. The MTD for single dose MK-1775 given in combination but 24 hours after 
cisplatin (75 mg/m2) or gemcitabine (1000 mg/m2) has been established at 200 mg, 
and with carboplatin (AUC5) at 325 mg. AE data is available for 43 patients. 
Among all patients receiving single dose MK-1775 in combination with 
chemotherapy, the most common classifications for drug-related AEs ≥ Grade 3 
were blood and lymphocytic system disorders (7/43), gastrointestinal disorders 
(3/43) and investigations (3/43). The MTDs for BID dosing x 5 doses of MK-1775 
with similar chemotherapy regimens were 200 mg with cisplatin and 225 with 
carboplatin. The DLTs for multiple dose cisplatin (75 mg/m2) were Grade 3 colitis 
and Grade 4 neutropenia in 3 of 4 patients at 250 mg MK-1775 BID for 2.5 days. 
The DLTs for multiple dose carboplatin (AUC 5) were Grade 3 diarrhea and 
nausea and Grade 4 neutropenia, febrile neutropenia and pancytopenia in 6 of 12 
patients at 325 mg MK-1775 BID for 2.5 days. MK-1775 in combination with 
gemcitabine is currently being evaluated on a QD × 2 schedule since the PD 
threshold was not met at the initially defined MTD on a BID schedule. 
 
The most frequent adverse events seen in the combination trials are 
myelosuppression, diarrhea, vomiting, nausea, constipation and abdominal pain. 
Investigational findings, including alterations in blood chemistry, have also been 
affected. 
 
In all, three patients had confirmed partial responses in the multiple dose 
combination study; this included two patients (squamous cell carcinoma and 
melanoma) receiving multiple doses of MK-1775 at 100 mg BID in combination 
with cisplatin, and one patient (squamous cell carcinoma) receiving single-dose 
MK-1775 at a dose of 200 mg in combination with cisplatin. In an investigator-
sponsored study, two additional refractory ovarian cancer patients receiving 225 
mg MK-1775 BID in combination with carboplatin have had confirmed partial 
responses. 
 
Merck has also sponsored trials with the combination of MK-1775 with 5-FU with 
and without cisplatin in Japanese patients, combination with topotecan plus 
cisplatin in cervical cancer and carboplatin plus paclitaxel in ovarian cancer. The 
first two studies have been discontinued as a result of prioritization efforts; no 
safety concerns were identified. The carboplatin plus paclitaxel study is ongoing. 
 
2.3.2 
Phase 2 Studies 
A phase II study of AZD1775 dosed orally twice daily over 2.5 days with 
carboplatin every 21-days, demonstrated that AZD1775 enhances carboplatin 
efficacy in patients with TP53 mutated ovarian cancers that were previously 
refractory or resistant to a platinum-based regiment.31 
 
2.3.3 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 4 
The AUC0-inf and Cmax increased approximately proportionate to dose. For the 
majority of patients, Cmax was reached ~3 hours after dosing (range 1.0-8.0 hours 
for monotherapy and 1.0-8.0 hours combination therapy). The mean terminal half-
life (t1/2) was ~9 hours (mean range 8.2-12.1 hours for monotherapy and 7.91-11.9 
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hours for combination therapy). Target engagement was assessed by 
immunohistochemical scoring for variation from baseline in pCDK1Tyr15 in a skin 
biopsy. A 50% reduction from baseline in pCDK1Tyr15 was targeted, based on 
preclinical studies demonstrating significant antitumor effects of MK-
1775/chemotherapy combinations at this level of target engagement in xenograft 
tumor samples. In the PN001 trial, 55% of patients at doses of greater than 100 mg 
showed target engagement. 
 
2.4 
Pediatric Studies 
 
2.4.1 
Prior Experience in Children 
Part A, the phase 1 dose escalation of ADVL1312, was completed in 2016.32 Thirty-one 
eligible patients, median age 14 years (range 5-20) were enrolled on Part A of ADVL1312; 
29 (93%) received prior chemotherapy (median 3 regimens) and 25 (81%) received prior 
radiation therapy. Sixteen patients had a primary CNS malignancy: malignant glioma (9), 
ependymoma (3), neuroepithelial tumor (1), medulloblastoma (2) and CNS Ewings 
sarcoma (1). Fifteen patients had extracranial solid tumors: soft tissue sarcoma (6), 
neuroblastoma (2), carcinoma (4), osteosarcoma (2) and Wilms’ Tumor (1). The most 
common toxicities were hematologic and gastrointestinal (nausea, vomiting, diarrhea). 
Two patients experienced dose limiting toxicity, one with grade 3 diarrhea and dehydration 
and the second with grade 3 dehydration at DL5 (AZD1775 110 mg/m2 and irinotecan 90 
mg/m2). Therefore, the MTD and recommended phase 2 dose from Part A of ADVL1312 
is AZD1775 (85 mg/m2/day) in combination with irinotecan (90 mg/ m2/day) daily for 
five days every 21 days (Dose Level 4). 
 
 
2.5 
Overview of Proposed Pediatric Study  
There will be four parts to the study. Part A is the phase 1 dose escalation of AZD1775 
(MK-1775) in combination with oral irinotecan for individuals with refractory or recurrent 
solid tumors. Part A will be conducted in children with refractory or recurrent solid tumors, 
including CNS tumors. AZD1775 (MK-1775) will be administered in combination with 
oral irinotecan in a 21 day cycle. Part B will be a phase 2 expansion at the recommended 
phase 2 dose of AZD1775 (MK-1775) in combination with irinotecan for patients with 
recurrent or refractory neuroblastoma.  Part C will be a phase 2 expansion at the 
recommended phase 2 dose of AZD1775 (MK-1775) in combination with oral irinotecan 
for patients with recurrent or refractory medulloblastoma/CNS PNET. Pharmacokinetics 
will be obtained in all patients in Part A of the study (see Section 8.3). Part D will be a 
phase 2 expansion at the recommended phase 2 dose of AZD1775 (MK-1775) in 
combination with oral irinotecan for patients with recurrent or refractory 
rhabdomyosarcoma.  Correlative and exploratory pharmacodynamic, tumor tissue and 
bone marrow studies will be obtained as described in Sections 8.4, 8.5, and 8.6.  
 
2.6 
Rationale for inclusion of Part D (Amendment #4) 
Since the initial protocol for ADVL1312 was developed, independent groups have shown 
that AZD1775 has promising in vitro and in vivo activity in pediatric rhabdomyosarcoma, 
supporting the addition of an expansion cohort in this disease. Kahen et al demonstrated 
that AZD1775 exhibited broad activity with high cell killing in four separate 
rhabdomyosarcoma cell lines (two embryonal and two alveolar).33 Relevant to this 
amendment, AZD1775 was synergistic with irinotecan, which is a chemotherapeutic agent 
typically used clinically in rhabdomyosarcoma. Furthermore, in vivo studies with 
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orthotopic rhabdomyosarcoma xenografts performed at St. Jude’s Children’s Research 
Hospital (SJCRH) confirmed AZD1775 to have activity in rhabdomyosarcoma. AZD1775 
in combination with irinotecan had a 42% response rate (CR + PR), an effect that was even 
greater with the addition of vincristine (70% response rate).34 Part D will be a phase 2 
expansion at the recommended phase 2 dose of AZD1775 (MK-1775) in combination with 
oral irinotecan for patients with recurrent or refractory rhabdomyosarcoma. 
 
 
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/ >). This is the same account (user id and password) used for 
credentialing in the CTSU members' web site. To perform registrations in OPEN, the site user must 
have been assigned the 'Registrar' role on the relevant Group or CTSU roster. OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. Registrars must hold a minimum of an AP registration type.   
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise 
System for regulatory and roster data and, upon enrollment, initializes the patient position in the 
Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in OPEN, the 
IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on the site’s IRB 
approval.  Please see Appendix XVI for detailed CTEP and CTSU Registration Procedures 
including: registration in Registration and Credential Repository (RCR), requirements for site 
registration, submission of regulatory documents and how to check your site’s registration status. 
 
3.1 
Current Study Status  
Investigators should refer to the COG website to determine if the study is currently open 
for accrual. If the study is listed as active, investigators should then access the page 
CTSU OPEN (Oncology Patient Enrollment Network) to ensure that a reservation for the 
study is available. To access the Slot Availability 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 


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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 email at ctsucontact@westat.com. 
 
Study centers can check the status of their registration packets by accessing the Site 
Registration Status page on the CTSU Member’s Website under the Regulatory Tab. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory 
Office.) 
 
3.3 
Patient Registration 
Prior to enrollment on study, patients must be assigned a COG patient ID number. This 
number is obtained via the COG Registry system once authorization for the release of 
protected health information (PHI) has been obtained. 
 
3.4 
Reservation and Contact Requirements 
Before enrolling a patient on study, a reservation must be made following the steps in 
Section 3.1 above 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 


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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 CTSU OPEN 
helpdesk at https://www.ctsu.org/CTSUContact.aspx. Patients must be enrolled before 
treatment begins.  The date protocol therapy is projected to start must be no later than five 
(5) calendar days after the date of study enrollment. Patients must not receive any 
protocol therapy prior to enrollment. 
 
3.10 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
4.0 
PATIENT ELIGIBILITY  
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of chemotherapy. The start of chemotherapy is defined as the 
initiation of treatment with AZD1775 (MK-1775) and irinotecan. The start of protocol therapy is 
defined as the initiation of cefixime or an available equivalent antibiotic (i.e. cefpodoxime). 
Laboratory tests need not be repeated if chemotherapy 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 chemotherapy: CBC with differential, bilirubin, ALT 
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receive protocol-prescribed chemotherapy and will be considered off protocol therapy. Imaging 
studies must be obtained within 14 days prior to start of chemotherapy (repeat the tumor imaging 
if necessary).  For patients whose disease is evaluated with a bone marrow examination, the bone 
marrow aspirates and biopsies are required within 14 days prior to the start of chemotherapy. 
  
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01).  All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient’s 
medical or research record which will serve as the source document for verification at the 
time of audit. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Age:  Patients must be > than 12 months and  21 years of age at the time of 
study enrollment. 
 
4.1.2 
Diagnosis: Patients 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.  
 
4.1.2.1 Part A: Patients with relapsed or refractory solid tumors, including 
patients with primary or metastatic CNS tumors.  
 
4.1.2.2 Part B:  Patients with relapsed or refractory neuroblastoma. 
 
4.1.2.3 Part C: Patients with relapsed or refractory medulloblastoma or CNS 
embryonal tumors formally classified as PNET (pineoblastoma, CNS 
neuroblastoma, CNS ganglioneuroblastoma, embryonal tumor with multi-
layered rosettes, medulloepithelioma, CNS embryonal tumor with 
rhabdoid features (INI1 intact) and CNS embryonal tumor, not otherwise 
specified)  
4.1.2.4 Part D: Patients with relapsed or refractory rhabdomyosarcoma. 
 
4.1.3 
Body Surface Area:  
Part A: Patients must have a body surface area ≥ 0.35 m2 at the time of study 
enrollment if enrolling on Dose Levels 1-5. Patients must have a body surface area 
≥ 0.46 m2 at the time of study enrollment if enrolling on Dose Level 0. 
 
Parts B, C, and D: Phase 2 Expansion: Patients must have a body surface area of > 
0.49 m2 at the time of study enrollment at the recommended phase 2 dose of AZD-
1775.   
4.1.4 
Disease Status: 
4.1.4.1 Part A: Patients must have either measurable or evaluable disease (see 


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Sections 12.2 and 12.3 for definitions). 
4.1.4.2 Part B: Patients must have either measurable disease (see Section 12.2 for 
definitions) or must be evaluable for MIBG response without evidence of 
RECIST measurable lesions (see Section 12.4 for definitions). Patients 
with neuroblastoma in bone marrow only are not eligible. 
4.1.4.3 Part C: Patients must have measurable disease by CT or MRI (see section 
12.6 for definitions). 
4.1.4.4 Part D: Patients must have measurable disease for Part D (see Section 
12.2 for definitions) 
 
4.1.5 
Therapeutic Options: Patient’s current disease state must be one for which there 
is no known curative therapy or therapy proven to prolong survival with an 
acceptable quality of life. 
 
 
4.1.6 
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 chemotherapy. 
 
a. Myelosuppressive chemotherapy: At least 21 days after the last dose 
of myelosuppressive chemotherapy (42 days if prior nitrosourea).  
b. Hematopoietic growth factors: At least 14 days after the last dose of a 
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting 
growth factor.  For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur.  The 
duration of this interval must be discussed with the study chair.  
c. Biologic (anti-neoplastic agent):  At least 7 days after the last dose of 
a biologic agent.  For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur.  The 
duration of this interval must be discussed with the study chair. 
d. Immunotherapy: At least 42 days after the completion of any type of 
immunotherapy, e.g. tumor vaccines. 
e. 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. 
f. XRT: At least 14 days after local palliative XRT (small port); At least 
150 days must have elapsed if prior TBI, craniospinal XRT or if  50% 
radiation of pelvis; At least 42 days must have elapsed if other 
substantial bone marrow radiation, including therapeutic doses of 
MIBG. 


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g. Stem Cell Infusion without TBI:  No evidence of active graft vs. host 
disease and at least 84 days must have elapsed after transplant or stem 
cell infusion. 
 
4.1.7.2 Patients previously treated with irinotecan are eligible for this study. 
 
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 (may receive RBC transfusions) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in 4.1.8.1.a 
(may receive transfusions provided they are not known to be 
refractory to red cell or platelet transfusions). These patients will 
not be evaluable for hematologic toxicity.  At least 2 of every 
cohort of 3 patients must be evaluable for hematologic toxicity for 
Part A, the dose escalation part of the study. If dose-limiting 
hematologic toxicity is observed, all subsequent patients enrolled 
must be evaluable for hematologic toxicity. 
 
4.1.8.2 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: 
 
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)  135 U/L.  For the purpose of this study, the ULN for 
SGPT is 45 U/L.  
- 
Serum albumin  2 g/dL. 
 


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4.1.8.4 Adequate Cardiac Function Defined As: 
- 
QTc ≤ 480 msec 
 
Note:  Patients should avoid concomitant medication known or suspected 
to prolong QTc interval or cause Torsades De Pointes. If possible, 
alternative agents should be considered. 
Patients who are receiving drugs that prolong the QTc are eligible if the 
drug is necessary and no alternatives are available. See Appendix XV for 
drugs that may prolong the QTc. 
 
4.1.9 
Adequate Neurologic Function Defined as: 
- 
Patients with seizure disorder may be enrolled if on non-enzyme inducing 
anticonvulsants and well controlled.  (See Appendix II for a list of 
recommended non-enzyme inducing anticonvulsants). 
- 
Nervous system disorders (CTCAE v5.0) resulting from prior therapy must 
be  Grade 2, with the exception of decreased tendon reflex (DTR). Any 
grade of DTR is eligible. 
 
4.1.10 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.  
 
4.1.11 Tissue blocks or slides must be sent per Section 8.6 if available, with exclusions 
as per Section 4.1.2. If tissue blocks or slides are unavailable, the study chair 
must be notified prior to study enrollment. 
 
4.1.12 Patients must be able to swallow capsules. 
 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy, Breast-Feeding, and Contraception 
a. Pregnant or breast-feeding women may not be entered on this study as there is 
yet no available information regarding human fetal or teratogenic toxicities. 
Pregnancy tests must be obtained in girls who are post-menarchal. 
b. Males or females of reproductive potential may not participate unless they 
have agreed to use an effective double barrier contraceptive method for the 
entire duration of protocol therapy and for 3 months (males) and 1 month 
(females) after study drug discontinuation. 
 
4.2.2 
Concomitant Medications 
 
4.2.2.1 Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. 
 
4.2.2.2 Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
 
4.2.2.3 Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible. 
 


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4.2.2.4 
CYP3A4 Agents: Patients who are currently receiving drugs that are 
strong or moderate inhibitors and/or inducers of CYP3A4 or sensitive 
CYP3A4 substrates and CYP3A4 substrates with a narrow therapeutic 
range are not eligible.  See Appendix III for a list of agents. The use of 
aprepitant as an antiemetic is prohibited due to early drug interaction 
data demonstrating increased exposure to AZD1775 (MK-1775).  
 
Caution should be exercised with concomitant administration of AZD1775 
(MK-1775) and agents that are sensitive substrates of CYP2C8, 2C9 and 
2C19, or substrates of this enzyme with narrow therapeutic ranges, as well 
as agents that are inhibitors or substrates of P-gp. 
 
4.2.2.5 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. 
 
4.2.2.6 Anticonvulsants: Patients must not have received enzyme inducing 
anticonvulsants for at least 14 days prior to enrollment (see Appendix II 
for a list of enzyme inducing and non-enzyme inducing anticonvulsants). 
 
4.2.3 
Cardiac Disease: Patients with cardiac diseases ongoing or in the past 6 months 
(e.g. congestive heart failure, acute myocardial infarction, significant uncontrolled 
arrhythmias) are not eligible for this trial. 
 
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 in the opinion of the investigator may not be able to comply with 
the safety monitoring requirements of the study are not eligible. 
 
4.2.7 
Patients with a history of allergic reaction to irinotecan, cephalosporins or a 
severe penicillin allergy are not eligible. 
 
4.2.8 
Patients unable to swallow capsules whole are not eligible. Nasogastric or G tube 
administration is not allowed. 
 
5.0 
TREATMENT PROGRAM 
 
5.1 
Overview of Treatment Plan 
 
Cycle 1+ 
 
Week 1 
 
Day - 2 
Day 1 
2 
3 
4 
5 
6 
7 
8 
 
Cefixime 
 
IRIN 
IRIN 
IRIN 
IRIN 
IRIN 
 
AZD1775 (MK-1775) 
AZD1775 (MK-1775) 
AZD1775 (MK-1775) 
AZD1775 (MK-1775) 
AZD1775 (MK-1775) 
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20 
21 
 
 
End of cycle 
 
 
Irinotecan (PO) will be administered 1 hour prior to AZD1775 (MK-1775) (PO) on days 
1-5, with rest on days 6-21. Cefixime or an available equivalent antibiotic (i.e. 
cefpodoxime) will be used as diarrheal prophylaxis and administered at least 2 days prior 
to the first dose of irinotecan, during, and 3 days after the last dose of irinotecan of each 
cycle. Instructions for administration of oral irinotecan are included in Section 9.3 and 
Appendix V. 
 
AZD1775 (MK-1775) should be taken on an empty stomach one hour prior or two hours after 
a meal. Capsules should be swallowed whole and not opened or manipulated.  If a dose is 
vomited it should not be repeated; resume administration with the next regularly scheduled 
dose. 
 
The doses of irinotecan and AZD1775 (MK-1775) will be as per Section 5.3.  Cefixime 
will be dosed at 8 mg/kg PO once daily (max: 400 mg/day).  If cefixime is not available, 
cefpodoxime should be dosed at 5 mg/kg/dose PO twice daily (10 mg/kg/day in two 
divided doses; max: 200 mg/dose).   
 
The treatment regimen may be repeated for a total of 18 cycles, up to a total duration of 
approximately 12 months. 
 
Drug doses should be adjusted based on the BSA calculated from height and weight 
measured within 7 days prior to the beginning of each cycle, and according to the dosing 
nomogram (see Appendix IV).    
 
5.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 21 days if the patient has at least stable disease, has again 
met laboratory parameters as defined in the eligibility criteria, Section 4.1.8, and the patient 
does not meet any of the criteria for removal from protocol therapy or off study criteria 
(Section 10.0).  
 
5.3 
Dose Escalation Schema 
 
5.3.1 
Part A : Inter-Patient Escalation 
The starting dose will be 70 mg/m2/dose of irinotecan and 50 mg/m2/dose of 
AZD1775 (MK-1775). Dose levels for subsequent groups of patients are as 
follows. 
 
Dose 
Level 
Irinotecan 
AZD1775 (MK-1775) 
mg/m2/dose orally 
mg/m2/dose orally 
0 
70 
40 
  1* 
70 
50 
2 
70 
65 
3 
90 
65 
4 
90 
85 
5 
90 
110 


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*Starting Dose Level 
 
If the MTD has been exceeded at the first dose level, then the subsequent cohort 
of patients will be treated at a dose of 70 mg/m2/dose of irinotecan and 40 
mg/m2/dose of AZD1775 (MK-1775) (dose level 0). 
 
5.3.2 
Parts B, C, and D: Phase 2 Expansion  
Patients with neuroblastoma (Part B), medulloblastoma/CNS PNET (Part C), and 
relapsed or refractory rhabdomyosarcoma (Part D) will be treated with irinotecan 
and AZD1775 (MK-1775) at the recommended phase 2 dose (RP2D) determined 
from the phase 1 component (Part A) of this trial. 
 
The MTD/RP2D of Part A was determined to be Dose Level 4 (85 mg/m2/dose 
AZD1775 and 90 mg/m2/dose irinotecan on a 21-day cycle). 
 
5.3.3 
Intra-Patient Escalation 
Intra-patient dose escalation is not allowed.  
 
5.4 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Any 
suspected or confirmed dose-limiting toxicity should be reported immediately (within 24 
hours) to the Study Chair. 
 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to the combination of irinotecan and AZD1775 (MK-1775).  The DLT 
observation period for the purposes of dose-escalation (Part A) will be the first cycle of 
therapy. 
 
Dose limiting hematological and non-hematological toxicities are defined differently.   
 
5.5.1 
Non-hematological dose-limiting toxicity 
5.5.1.1 Any Grade 3 or Grade 4 non-hematological toxicity with the specific 
exclusion of: 
• Grade 3 nausea and vomiting < 3 days duration despite maximal 
supportive care 
• Grade 3 liver enzyme elevation, including ALT/AST/GGT, that 
returns to Grade  1 or baseline prior to the time for the next 
treatment cycle. Note:  For the purposes of this study the ULN for 
ALT is defined as 45 U/L. Adverse event grades will be based on 
increases above the upper limit of normal, regardless of the subject’s 
baseline. See Appendix XII for toxicity grading table. 
• Grade 3 fever  
• Grade 3 infection 
• Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to oral supplementation. 


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• Grade 3 diarrhea ≤ 3 days duration despite maximal supportive care 
• Grade 3 mucositis or stomatitis ≤ 3 days duration 
 
5.5.1.2 Non-hematological toxicity that causes a delay of  14 days between 
treatment cycles. 
 
5.5.1.3 Note: Allergic reactions that necessitate discontinuation of study drug 
will not be considered a dose-limiting toxicity. 
 
5.5.2 
Hematological dose limiting toxicity 
5.5.2.1 Hematological dose limiting toxicity is defined as: 
 
In patients evaluable for hematological toxicity (see Section 4.1.8.1),   
• 
Grade 4 neutropenia for > 7 days 
• 
Platelet count < 20,000/mm3 on 2 separate days, at least 48 hours apart, 
or requiring a platelet transfusion on 2 separate days, within a 7 day 
period  
• 
Myelosuppression that causes a delay of > 14 days between treatment 
cycles.  
 
5.5.2.2 Note:  Grade 4 febrile neutropenia will not be considered a dose-limiting 
toxicity. 
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. 
 
6.1 
Dose Modifications for Hematological Toxicity 
 
6.1.1 
Patients who have dose-limiting thrombocytopenia should receive subsequent 
cycles at the same dose of AZD1775 (MK-1775) and a dose reduction of irinotecan 
to 65 mg/m2 if original dose assignment was 90 mg/m2, or to 50 mg/m2 if original 
dose assignment was 70 mg/m2. If dose-limiting thrombocytopenia recurs after the 
irinotecan is reduced, the AZD1775 (MK-1775) should be dose reduced to the next 
lower dose assignment indicated in the dosing nomogram (See Appx. IV). (Note: 
Patients enrolled at Dose Level 0 who experience dose-limiting thrombocytopenia 
after dose reduction of irinotecan should be removed from protocol therapy). If 
dose limiting thrombocytopenia recurs the patient should be removed from 
protocol therapy. 
 
6.1.2 
Patients who have dose-limiting neutropenia (Grade 4 neutropenia of > 7 days 
duration or delay in the start of the next cycle for > 14 days due to neutropenia) 
with no other dose-limiting toxicity should receive the same doses in the next cycle 
with myeloid growth factor support 24-48 hours after completion of irinotecan and 
AZD1775 (MK-1775).  [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 
treated with 65 mg/m2 irinotecan (or to 50 mg/m2 if original dose assignment was 
70 mg/m2) and the same dose of AZD1775 (MK-1775) for subsequent cycles. If 
the patient develops dose-limiting neutropenia at the dose reduced irinotecan, the 
patient should be treated at the next lowest dose of AZD1775 (MK-1775) indicated 


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in the dosing nomogram (See Appx. IV) or removed from protocol therapy if 
enrolled at Dose Level 0. If dose limiting neutropenia recurs the patient should be 
removed from protocol therapy.  
 
6.1.3 
Patients who experience dose-limiting thrombocytopenia after one dose reduction 
of irinotecan and one dose reduction of AZD1775 (MK-1775) or dose-limiting 
neutropenia after addition of myeloid growth factor and one dose reduction of 
AZD1775 (MK-1775) must be removed from protocol therapy. 
 
6.1.4 
Patients who have a dose-limiting hematological toxicity that does not resolve to 
eligibility criteria or baseline within 21 days after the planned start of the next 
treatment cycle must be removed from protocol therapy. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity 
 
6.2.1 
Patients who have any dose-limiting non-hematological toxicity (as defined in 
Section 5.5.1) may continue on protocol therapy upon meeting eligibility lab 
requirements or baseline but should receive subsequent doses at the next lower 
dose level. Note: Patients enrolled at Dose Level 0 who experience dose-limiting 
non-hematological toxicity should be removed from protocol therapy. 
 
6.2.2 
If the same non-hematological dose-limiting toxicity recurs after one dose 
reduction, the patient must be removed from protocol therapy. 
 
6.2.3 
Patients who have a dose-limiting non-hematological toxicity that does not resolve 
to eligibility criteria or baseline within 21 days after the planned start of the next 
treatment cycle must be removed from protocol therapy. 
 
6.2.4 
Dose modifications for diarrhea 
See Appendix VI for specific guidelines for supportive care measures for patients 
who develop therapy-associated diarrhea.  
• 
If dose-limiting Grade 3 (> 3 days) or Grade 4 therapy-associated diarrhea 
is experienced by a patient despite maximal use of anti-diarrheal medications 
and appropriate use of prophylactic antibiotics, the dose of irinotecan should 
be reduced to 65 mg/m2 if original dose assignment was 90 mg/m2, or to 50 
mg/m2 if original dose assignment was 70 mg/m2 for subsequent cycles.  
• 
If dose-limiting Grade 3 (> 3 days) or Grade 4 diarrhea recurs despite 
maximal use of anti-diarrheals, prophylactic antibiotics, after a single 
irinotecan dose reduction, the patient should come off protocol therapy. 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug(s). 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. 


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7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary (see Section 6.0). See Sections 7.5 and 9.1.5 for 
drugs that should not be used concomitantly due to potential interactions with irinotecan 
and/or AZD1775 (MK-1775).  Use of prophylactic antimicrobials to prevent irinotecan-
associated diarrhea (cefixime or available equivalent, i.e. cefpodoxime) is required.  See 
the COG Supportive Care Guidelines 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 6.1 or for culture proven bacteremia or invasive 
fungal infection. The Study Chair should be notified before growth factors are initiated. 
 
7.5 
Concomitant Medications 
Anticonvulsants should be used as clinically indicated and tapered as soon as possible. The 
use of enzyme inducing anticonvulsants is not permitted. See Appendix II for a list of 
unacceptable enzyme inducing and recommended non-enzyme inducing anticonvulsants.  
Irinotecan is metabolized by CYP3A4.   
 
Moderate and potent inhibitors or inducers of CYP3A4 and sensitive CYP3A4 substrates 
and CYP3A4 substrates with a narrow therapeutic range should not be used concomitantly 
with AZD1775 (MK-1775) (See Appendix III). Corticosteroids may induce CYP3A4 and 
are therefore not routinely recommended on study unless deemed absolutely necessary or 
when used in stable or decreasing doses from the time of study enrollment. The use of 
aprepitant as an antiemetic is prohibited due to early drug interaction data 
demonstrating increased exposure to AZD1775 (MK-1775).  
 
Caution should be exercised with concomitant administration of AZD1775 (MK-1775) and 
agents that are sensitive substrates of CYP2C8, 2C9 and 2C19, or substrates of this enzyme 
with narrow therapeutic ranges, as well as agents that are inhibitors or substrates of P-gp. 
 
Drugs that prolong the QTc may be used only if the drug is necessary and no alternatives 
are available. See Appendix XV for drugs that may prolong the QTc. 
 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) must be no older than seven (7) days at the start of chemotherapy. The 
start of chemotherapy is defined as the initiation of treatment with AZD1775 (MK-1775) 
and irinotecan. The start of protocol therapy is defined as the initiation of cefixime or an 
available equivalent antibiotic (i.e. cefpodoxime). Laboratory tests need not be repeated if 
chemotherapy 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 chemotherapy: CBC with differential, bilirubin, ALT (SGPT) and serum 
creatinine.  If the recheck is outside the limits of eligibility, the patient may not receive 
protocol-prescribed chemotherapy and will be considered off protocol therapy. Imaging 
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studies must be obtained within 14 days prior to start of chemotherapy (repeat the tumor 
imaging if necessary). For patients whose disease is evaluated with a bone marrow 
examination, the bone marrow aspirates and biopsies are required within 14 days prior to 
the start of chemotherapy. 


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Page 29 
 
 
STUDIES TO BE OBTAINED 
for PART A (Phase 1 Dose-Escalation): 
Pre-
Study 
During Cycle 1 
Prior to Subsequent 
Cycles^ 
End of Study 
Treatment 
History 
X 
Weekly 
X 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
X 
Height, weight, BSA 
X 
X 
X 
 
Performance Status 
X 
 
X 
 
CBC, differential, platelets 
X 
Twice Weekly 
(every 3 to 4 days)1 
Weekly2 
 
Urinalysis 
X 
 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
 
Albumin 
X 
 
X 
 
Pregnancy Test 
X3 
 
 
 
Tumor Disease Evaluation4 
X 
End of Cycle 1 
Every other cycle x 2 
then q 3 cycles 5 
X 
Bone Marrow Evaluation6 
X 
End of Cycle 1 
With Tumor Disease 
Evaluation 
 
Pharmacokinetics7 
 
X 
 
 
Pharmacodynamics8 
 
X 
 
 
Bone Marrow for Correlative Biology 
Studies9 
X 
End of Cycle 19 
With Tumor Disease 
Evaluation 9 
 
Tumor Tissue Submission10 
X 
 
 
 
Patient Diary11 
 
X 
X 
 
EKG12 
X 
 
 
 
^  Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery to Grade 
3 or until meeting the criteria for dose limiting toxicity. 
2 If patients develop Grade 4 neutropenia then CBCs should be checked every 3 to 4 days until recovery to Grade 3. 
If patient remains on study for > 4 cycles and ≥ Grade 3 cytopenias are not observed, CBCs may be checked prior 
to subsequent cycles and as clinically indicated. 
3 Women of childbearing potential require a negative pregnancy test prior to starting protocol therapy; sexually 
active patients may not participate unless they have agreed to use an effective double barrier contraceptive method.  
Abstinence is an acceptable method of birth control. 
4     Patients with neuroblastoma must have both CT/MRI and MIBG scintigraphy performed prior to enrollment if the 
patient was enrolled with or has a history of MIBG avid tumor. Otherwise, the NBL patient must have both CT/MRI 
and bone scan prior to enrollment. For patients with neuroblastoma and measurable disease by CT or MRI, lesions 
should be measured and followed using the same modality (CT or MRI) in addition to MIBG or bone scan. For 
patients with neuroblastoma with evaluable disease by MIBG scintigraphy or bone scan, use the same modality 
(MIBG scintigraphy or bone scan) to image patients; CT/MRI are not required but may be performed as clinically 
indicated. 
5 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation of either a 
PR or CR. Please note that for solid tumor patients, if the institutional investigator determines that the patient has 
progressed based on clinical or laboratory evidence, he/she may opt not to confirm this finding radiographically. 
6    Patients with neuroblastoma must have bilateral bone marrow aspirates and biopsies. These do not need to be 
repeated if negative at study enrollment and patient is responding to therapy.  
7 See Section 8.3 for timing and details regarding pharmacokinetic (PK) studies. 
8 See Section 8.4 for timing and details regarding pharmacodynamic studies. 
9 For patients with known or suspected marrow disease for whom consent for correlative studies has been obtained, 
collect bone marrow (5-10 mL) in preservative-free heparin when marrow evaluations are being performed for 
clinical indications.  See Section 8.5 for details. 
10 See Section 8.6 for details regarding tumor tissue submission. If tissue blocks or slides are unavailable, the study 
chair must be notified prior to study enrollment. 
11     Patient diary (see Appendix XIII) should be reviewed and uploaded into RAVE at the end of each cycle. 


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12 12-lead EKG to be obtained at baseline and as clinically indicated. 
 
STUDIES TO BE OBTAINED 
for PART B, PART C, and PART D 
(Phase 2 Expansion): 
Pre-
Study 
During 
Cycle 1  
Prior to Subsequent 
cycles^ 
End of Study 
Treatment 
History 
X 
 
X 
X 
Physical Exam with vital signs 
X 
 
X 
X 
Height, weight, BSA 
X 
  
X 
 
Performance Status 
X 
 
X 
 
CBC, differential, platelets1 
X 
Weekly 
Weekly 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
 
X 
 
Creatinine, ALT, bilirubin 
X 
 
X 
 
Albumin 
X 
 
 
 
Pregnancy Test 
X2 
 
 
 
Tumor Disease Evaluation3 
X 
End of Cycle 1 
Every other cycle x 2 
then q 3 cycles 4 
X 
Bone Marrow Evaluation5 
X 
End of Cycle 1 
With Tumor Disease 
Evaluation 
 
Bone Marrow for Correlative Biology 
Studies6 
X 
End of Cycle 
1 
With Tumor Disease 
Evaluation 
 
Tumor Tissue Submission7 
X 
 
 
 
Patient Diary8 
 
X 
X 
 
EKG9 
X 
 
 
 
^  Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 If patients develop Grade 4 neutropenia then CBCs should be checked every 3 to 4 days until recovery to Grade 3. 
If patient remains on study for > 4 cycles and ≥ Grade 3 cytopenias are not observed, CBCs may be checked prior 
to subsequent cycles and as clinically indicated. 
2 Women of childbearing potential require a negative pregnancy test prior to starting protocol therapy; sexually 
active patients may not participate unless they have agreed to use an effective double barrier contraceptive method.  
Abstinence is an acceptable method of birth control. 
3     Patients with neuroblastoma must have both CT/MRI and MIBG scintigraphy performed prior to enrollment if the 
patient was enrolled with or has a history of MIBG avid tumor. Otherwise, the NBL patient must have both CT/MRI 
and bone scan prior to enrollment. For patients with neuroblastoma and measurable disease by CT or MRI, lesions 
should be measured and followed using the same modality (CT or MRI) in addition to MIBG or bone scan. For 
patients with neuroblastoma with evaluable disease by MIBG scintigraphy or bone scan, use the same modality 
(MIBG scintigraphy or bone scan) to image patients; CT/MRI are not required but may be performed as clinically 
indicated. 
4 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation of either a 
PR or CR. Please note that for solid tumor patients, if the institutional investigator determines that the patient has 
progressed based on clinical or laboratory evidence, he/she may opt not to confirm this finding radiographically. 
5    Patients with neuroblastoma must have bilateral bone marrow aspirates and biopsies. These do not need to be 
repeated if negative at study enrollment and patient is responding to therapy.  
6 For patients with known or suspected marrow disease for whom consent for correlative studies has been obtained, 
collect 5-10 mL bone marrow in preservative-free heparin when marrow evaluations are being performed for 
clinical indications.  See Section 8.5 for details. 
7 
See Section 8.6 for details regarding tumor tissue submission. If tissue blocks or slides are unavailable, the study 
chair must be notified prior to study enrollment. 
8      Patient diary (see Appendix XIII) should be reviewed and uploaded into RAVE at the end of each cycle.   
9 12-lead EKG to be obtained at baseline and as clinically indicated. 
 
 
 
8.2 
Radiology Studies 


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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 hard copy film, CD ROM, USB flash drive or by FTP.  Submitted imaging 
studies should be clearly marked with the COG patient ID, study number 
(ADVL1312) and date and shipped to Syed Aamer at the address below: 
 
Syed Aamer, MBBS, CRP  
Administrator, Imaging Research Center 
Children’s Hospital Los Angeles  
4650 Sunset Boulevard, MS # 81 
Los Angeles, CA 90027 
Phone: (323) 361-3898 
Fax: 
(323) 361-3054 
E-mail: saamer@chla.usc.edu 
 
8.3 
Pharmacokinetics (Required for Part A only) 
 
8.3.1 
Description of Studies and Assay 
Plasma will be collected and AZD1775 (MK-1775) concentrations will be 
analyzed using an appropriate bioanalytic method. 
 
8.3.2 
Sampling Schedule 
Blood samples will be obtained during Cycle 1 at the time points listed in 
Appendix VIII. 
 
8.3.3 
Sample Collection and Handling Instructions 
Blood samples (2-3 mL) will be collected in lavender-top K2EDTA tubes, gently 
inverted 6 to 8 times, and immediately placed in an ice bath. Record the exact time 
that the sample is drawn along with the exact time that the drug is administered. 
 
8.3.4 
Sample Processing 
Blood must be processed within 30 minutes from the time it is drawn. Centrifuge 
the blood samples for 10 minutes at 1500xg in a refrigerated centrifuge at 4°C. 
Remove at least 1 mL plasma by transfer pipette and transfer the plasma into a 3.6 
ml nunc tube. Cap the tube tightly. Freeze immediately at -70 °C and store frozen 
until shipment.  
 
8.3.5 
Sample Labeling 
Each tube must be labeled with the patient’s I.D., patient’s accession number, the 
study I.D. (ADVL1312), and the date and time the sample was drawn. Complete 
the Pharmacokinetic Study Form (see Appendix VIII), recording the date and time 
of collection for each sample. A copy of this form must accompany the sample(s) 
at time of shipment. 
 


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8.3.6 
Sample Shipping Instructions 
Samples may be batched for shipment, in freezer boxes containing at least 10 kg 
of DRY ICE. The samples must be securely packed in boxes to avoid breakage 
during transit, double-bagged to contain leaks, and where applicable, packed with 
a sufficient quantity of dry ice to ensure they remain frozen for at least 72 hours. 
 
Shipments should be sent Monday or Tuesday only for priority overnight 
delivery to the following address: 
 
Mark Hoffmann 
Principal Investigator, Bioanalytical Services Covance Laboratories, Inc. 
3301 Kinsman Blvd. 
Madison, Wisconsin 53704 
USA 
Phone: 608-230-1762 
Fax: 608-242-2735 
Email: mark.hoffmann@covance.com  
 
A notification email should be sent to Mark Hoffmann with courier name, airway 
bill number, expected delivery date/time and shipment contact. 
 
8.4 
Pharmacodynamics (for Part A only) 
Preclinical studies showed that inhibition of p-CDK1 correlated with AZD1775 (MK-
1775) exposures that resulted in tumor regression and immunohistochemical evidence of 
Wee1 inhibition in both tumor tissues and skin punch biopsies.  While this trial is designed 
to define a maximally tolerated dose, the two correlative and exploratory studies below 
will aid in determining at which dose(s) p-CDK1 and -H2AX target engagement are 
occurring.  Both studies will be done from the same collection (with the p-CDK1 being the 
priority if sample is limited). 
 
8.4.1 
Description of Studies  
 
8.4.1.1 p-CDK1 inhibition:  Whole blood will be collected for analysis of CDK1 
phosphorylation in peripheral blood mononuclear cells (PBMCs). 
 
8.4.1.2 -H2AX induction: Whole blood will be collected for analysis of  -
H2AX induction in peripheral blood mononuclear cells (PBMCs). 
 
8.4.2 
Sampling Schedule 
Samples will be collected in consenting patients at the following 4 time points:  
 
Day 1: prior to the irinotecan dose, prior to the AZD1775 (MK-1775) dose and 4 
hours after the dose of AZD1775 (MK-1775) is given. 
 
Day 2: prior to the irinotecan dose. 
 
8.4.3 
Sample Collection and Handling Instructions 
Blood samples (1 ml per time point) will be collected in heparinized (green-top) 
tubes transferred to a smart tube followed by a 30 minute incubation period in a 
37°C water bath. For each time point a separate smart tube will be used. After the 
37°C incubation period, the smart tubes will be activated and then incubated at 
room temperature for 8 minutes. Samples will be stored at -80°C until shipment. 
Record the exact time that the sample is drawn along with the exact time that the 
drug is administered. Transport of frozen vials, if necessary, should take place on 


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dry ice. Record the exact time that the sample is drawn along with the exact time 
that the drug is administered. Please see details of preparation in Appendix IX-B. 
 
 
8.4.4 
Sample Labeling 
Each tube must be labeled with the patient’s I.D., patient’s accession number, the 
study I.D. (ADVL1312), and the date and time the sample was drawn.  Data should 
be recorded on the Pharmacodynamic Study Form (Appendix IX-A), which must 
accompany the sample(s). 
 
8.4.5 
Sample Shipping Instructions 
Samples may be batched for shipment, in freezer boxes containing at least 10 kg 
of DRY ICE. 
 
Shipments should be sent Monday or Tuesday only for priority overnight 
delivery to the following address: 
 
Attn: Dr. Kristina Cole 
The Children’s Hospital of Philadelphia 
The Colket Translational Research Building 
Room 3300 
3501 Civic Center Boulevard 
Philadelphia, PA 19104 
 
Please notify Dr. Cole of a pending shipment along with the Federal Express 
tracking number by e-mail at colek@email.chop.edu. 
 
8.5 
Bone marrow Studies (for Parts A, B, or C, or D) 
Preclinical studies have shown that tumors with activated Wee1 (as measured by p-Wee1) 
or high levels of MYC / MYCN are more sensitive to Wee1 inhibition and are potential 
predictive biomarkers. 
 
8.5.1 
Description of Studies 
Bone marrow samples will be analyzed for expression of potential predictive 
biomarkers of Wee1 inhibition responsiveness in correlative and exploratory 
studies. 
 
8.5.2 
Sampling Schedule 
Samples will be collected at baseline and with disease re-evaluations in consenting 
patients with known or suspected marrow disease. 
 
8.5.3 
Sample Collection and Handling Instructions 
Bone marrow samples (5-10 mL) will be collected and placed in tubes containing 
preservative-free heparin.  
 
8.5.4 
Sample Processing 
Marrow samples in preservative-free heparin do not require additional on-site 
processing, but must be shipped to the Dr. Kristina Cole on the same day that they 
are obtained (see Appendix X).  
  
8.5.5 
Sample Labeling 
Each tube must be labeled with the patient’s I.D., patient’s accession number, the 
study I.D. (ADVL1312), and the date and time the sample was drawn.  Data should 


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be recorded on the Bone Marrow Study Form (see Appendix X), which must 
accompany the sample(s). 
 
 
8.5.6 
Sample Shipping Instructions 
See Appendix X for detailed shipping and contact information for Dr. Cole’s 
laboratory.  Samples should be shipped on the same day that they are obtained.  
Specimens should be packed using appropriate biohazard materials and shipped at 
room temperature using an overnight courier. 
 
8.6 
Tissue Studies (for Parts A, B,  C, or D) 
Preclinical studies have shown that tumors with activated Wee1 (as measured by p-Wee1), 
high levels of EZH2 or high levels of MYC / MYCN are more sensitive to Wee1 inhibition 
and are potential predictive biomarkers. Archival tumor tissue should be submitted for all 
patients.  If a patient does not have tissue available, the study chair must be notified prior 
to enrollment. 
 
8.6.1 
Description of Studies 
Tissue will be collected from original diagnosis, relapse or any subsequent 
resection or biopsy for correlative and exploratory studies.  
 
8.6.2 
Sample Collection, Handling, and Shipment  
Tissue blocks or slides will be shipped to Dr. Kristina Cole at the Children’s 
Hospital of Philadelphia as described in Appendix XI. Detailed instructions 
regarding collection, handling, and shipping of tissue samples are located in 
Appendix XI. 
 
9.0 
AGENT INFORMATION 
 
9.1 
AZD1775  (MK-1775) 
NSC#751084;  
 
9.1.1 
Structure and molecular weight  
 
Chemical name: 2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-
methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-
3-one 
 
Molecular formula: C27H32N8O2·0.5H2O 
 
Molecular weight: 500.6 
 
Chemical Structure of MK-1775: 
 
 
 
9.1.2 
Supplied by: Division of Cancer Treatment and Diagnosis (DCTD), NCI 
 
9.1.3 
Formulation 
The agent is supplied as dry filled capsules in 25 mg (yellow color) and 100 mg 
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(orange color) strengths in size 2 gelatin capsules. The dry-filled capsules consist 
of a roler-compacted granule of drug substance, lactose monohydrate, 
microcrystalline, cellulos, croscarmellose sodium, and magnesium stearate. Each 
high-density polyethylene (HDPE) bottle contains 20 capsules. 
 
The pharmaceutical collaborator does not have stability data to support 
repackaging AZD1775 (MK-1775) capsules in any container other than what is 
provided. 
 
9.1.4 
Storage and Stability 
AZD1775 (MK-1775) is to be stored at 2 to 30° C (36 to 86° F. Do not freeze. 
Shelf life studies of AZD1775 (MK-1775) are on-going. If a storage temperature 
excursion is identified, promptly return AZD1775 (MK-1775) to 2 - 30° C and 
quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
There is no stability data to support repackaging AZD1775 (MK-1775) capsules in 
any container other than the original bottle.  Do not repackage in the pharmacy; 
dispense in the original container.  
 
9.1.5 
Administration 
Patients will take AZD1775 (MK-1775) orally based on assigned dose, one hour 
after oral irinotecan. 
 
AZD1775 (MK-1775) should be taken on an empty stomach one hour prior or two 
hours after a meal. Capsules should be swallowed whole and not opened or 
manipulated.  If a dose is vomited it should not be repeated; resume administration 
with the next regularly scheduled dose. 
 
AZD1775 (MK-1775) is primarily metabolized by CYP3A4 and is a weak, time-
dependent inhibitor of CYP3A4; do not use in patients taking moderate and potent 
3A4 inhibitors and inducers. The use of enzyme inducing anticonvulsants is not 
permitted (Appendix II) 
Avoid concomitant CYP3A4 moderate or strong inhibitors/inducers, and sensitive 
substrates with a narrow therapeutic index.  AZD1775 (MK-1775) is also a weak 
inhibitor of CYP2C19.  Caution should be exercised with concomitant 
administration of sensitive substrates or substrates with a narrow therapeutic index. 
 
In vitro transporter studies have shown that AZD1775 (MK-1775) was an inhibitor 
of OATP1B1, OATP1B3, MATE1, MATE2K, P-glycoprotein (P-gp) and breast 
cancer resistance protein (BCRP), and a substrate for P-gp and BCRP. The PK 
parameters of AZD1775 (MK-1775) could be altered if AZD1775 (MK-1775) is 
coadministered with P-gp and BCRP inhibitors/inducers, and there is potential for 
drug-drug interactions when coadministered with OATP1B1, OATP1B3, MATE1, 
MATE2K, P-gp and BCRP substrates. This finding is particularly relevant for 
drugs administered orally where exposure is normally limited by BCRP-mediated 
efflux, in particular some statins. Modelling has predicted a substantial increase in 
the exposure of atorvastatin when coadministered with AZD1775 (MK-1775) and 
the use of atorvastatin is therefore prohibited. 
 
The use of aprepitant as an antiemetic is prohibited due to early drug interaction 
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data demonstrating increased exposure to AZD1775 (MK-1775). AZD1775 (MK-
1775) is a p-glycoprotein substrate, but has not been evaluated as an inhibitor of 
p-glycoprotein; caution should be used with p-glycoprotein substrates and 
inhibitors. 
 
Please see Appendix XIV for drug interactions associated with the drugs used in 
this study. 
 
9.1.6 
AZD1775 (MK-1775) Toxicities 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 323 patients. 
Below is the CAEPR for AZD1775 (adavosertib). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
 Version 2.7, April 27, 20201 
 
 Adverse Events with Possible  
 Relationship to AZD1775 (adavosertib) 
 (CTCAE 5.0 Term) 
[n= 323] 
 
 Specific Protocol Exceptions 
to Expedited Reporting  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
Anemia (Gr 3) 
Febrile neutropenia 
CARDIAC DISORDERS 
Atrial fibrillation 
Supraventricular tachycardia 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
Abdominal pain (Gr 2) 
Constipation 
Constipation (Gr 2) 
Diarrhea 
Diarrhea (Gr 3) 
Dyspepsia 
Gastrointestinal hemorrhage2 
Mucositis oral 
Mucositis oral (Gr 2) 
Nausea 
Nausea (Gr 3) 
Vomiting 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Edema limbs 
Edema limbs (Gr 2) 
Fatigue 
Fatigue (Gr 3) 
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 Adverse Events with Possible  
 Relationship to AZD1775 (adavosertib) 
 (CTCAE 5.0 Term) 
[n= 323] 
 
 Specific Protocol Exceptions 
to Expedited Reporting  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Fever 
Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
Hepatobiliary disorders - Other
(hepatitis) 
INFECTIONS AND INFESTATIONS 
Infection3 
Infection3 (Gr 3) 
INVESTIGATIONS 
Alanine aminotransferase increased 
Alanine aminotransferase increased 
(Gr 3) 
Electrocardiogram QT corrected 
interval prolonged 
Lymphocyte count decreased 
Neutrophil count decreased 
Neutrophil count decreased (Gr 4) 
Platelet count decreased 
Platelet count decreased (Gr 4) 
Weight loss 
White blood cell decreased 
White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
Anorexia (Gr 2) 
Dehydration 
Hypokalemia 
Hypokalemia (Gr 2) 
Hypomagnesemia 
Hypomagnesemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Back pain 
Back pain (Gr 2) 
Muscle cramp 
Myalgia 
Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
` 
Dizziness 
Dizziness (Gr 2) 
Headache 
Headache (Gr 2) 
Intracranial hemorrhage 
PSYCHIATRIC DISORDERS 
Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Cough 
Cough (Gr 2) 
Dyspnea 
Dyspnea (Gr 2) 
Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Rash4 
Rash4 (Gr 2) 
VASCULAR DISORDERS 
Phlebitis 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
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Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal 
hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS 
SOC. 
 
3Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
4Rash may include rash, erythema, eczema, and rash maculo-papular. 
 
5Peripheral neuropathy includes both peripheral motor neuropathy and peripheral sensory neuropathy. 
 
6Acute kidney injury includes renal impairment and acute renal insufficiency. 
 
 
Adverse events reported on AZD1775 (adavosertib) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that AZD1775 (adavosertib) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Blood and lymphatic system disorders - Other (thrombocytosis); Blood and lymphatic 
system disorders - Other (right leg deep vein thrombosis); Leukocytosis 
Cardiac disorders - Cardiac disorders - Other (cardiomegaly); Chest pain - cardiac; Myocardial infarction; 
Palpitations; Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain; Hearing impaired; Tinnitus 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (eye swelling); Eye pain; Keratitis; 
Photophobia; Scleral disorder; Vision decreased; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal pain; Ascites; Belching; Bloating; 
Cheilitis; Colitis; Colonic obstruction; Dry mouth; Duodenal ulcer; Dysphagia; Enterocolitis; Flatulence; 
Gastric ulcer; Gastritis; Hemorrhoids; Oral pain; Rectal pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; 
Edema trunk; Flu like symptoms; Gait disturbance; General disorders and administration site conditions - 
Other (catheter site pain); Infusion site extravasation; Malaise; Non-cardiac chest pain; Pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and 
procedural complications - Other (excoriation); Injury, poisoning and procedural complications - Other 
(ligament sprain) 
INVESTIGATIONS - Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood 
bilirubin increased; Creatinine increased; GGT increased; Investigations - Other (blood urea increased); 
Lymphocyte count increased 
METABOLISM AND NUTRITION DISORDERS - Alkalosis; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hyponatremia; Hypophosphatemia; 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Bone 
pain; Flank pain; Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and 
connective tissue disorder - Other (groin pain); Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (carcinoid tumor); Tumor 
pain 
NERVOUS SYSTEM DISORDERS - Central nervous system necrosis; Cognitive disturbance; Depressed 
level of consciousness; Dysesthesia; Dysgeusia; Encephalopathy; Lethargy; Nervous system disorders - 
Other (hemiparesis); Paresthesia; Peripheral neuropathy5; Presyncope; Somnolence; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression 
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RENAL AND URINARY DISORDERS - Acute kidney injury6; Hematuria; Urinary frequency; Urinary 
incontinence; Urinary retention; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema; Reproductive system and 
breast disorders - Other (female genital tract fistula) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Apnea; 
Bronchopulmonary hemorrhage; Epistaxis; Hiccups; Nasal congestion; Pleural effusion; Pneumonitis; 
Pulmonary hypertension; Respiratory, thoracic and mediastinal disorders - Other (diaphragmalgia); Voice 
alteration; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Bullous dermatitis; Dry skin; 
Hyperhidrosis; Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Purpura; Rash 
acneiform; Skin ulceration; Urticaria 
VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypertension; Hypotension; 
Thromboembolic event 
 
 
 
Note: AZD1775 (adavosertib) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
9.1.7 
Agent Ordering and Agent Accountability 
AZD1775 (MK-1775) will be supplied by the NCI. NCI-supplied agents may be 
requested by eligible participating Investigators (or their authorized designee) at 
each participating institution. The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents. The eligible participating 
investigators at each participating institution must be registered with CTEP, DCTD 
through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there 
are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
participating investigator at that institution. 
 
9.1.8 
Clinical Drug Request 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. The current versions of the IBs for the agents will also be accessible 
to site investigators and research staff through the PMB Online Agent Order 
Processing (OAOP) application. Access to OAOP requires the establishment of a 
CTEP Identity and Access Management (IAM) account and the maintenance of an 
“active” account status, “current” password, and active person registration status. 
For questions about drug orders, transfers, returns, or accountability call or email 
PMB anytime. Refer to the PMB’s website for specific policies and guidelines 
related to agent management. Questions about IB access may be directed to the 
PMB IB coordinator via email. 
 
9.1.9 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the receipt, dispensing and final disposition of all 
agents received from PMB using the appropriate NCI Investigational Agent (Drug) 
Accountability Record (DARF) available on the CTEP forms page. Store and 
maintain separate NCI Investigational Agent Accountability Records for each 
agent, strength, formulation and ordering investigator on this protocol. 
 


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9.1.10 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators 
and research staff through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status and a “current” password. Questions about IB access may be directed to the 
PMB IB coordinator via email. 
 
9.1.11 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  
• PMB policies and guidelines: 
 
 
http://ctep.cancer.gov/branches/pmb/agent_management.htm     
• PMB Online Agent Order Processing (OAOP) application:  
 
 
https://ctepcore.nci.nih.gov/OAOP  
• CTEP Identity and Access Management (IAM) account:  
     https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help: 
 
ctepreghelp@ctep.nci.nih.gov   
• PMB email: PMBAfterHours@mail.nih.gov  
• PMB phone and hours of service: (240) 276-6575  
Monday through Friday between 8:30 am and 4:30 pm (ET) 
• PMB IB Coordinator: IBcoordinator@mail.nih.gov  
• Registration and Credential Repository (RCR): 
https://ctepcore.nci.nih.gov/rcr/  
 
9.2 
Cefixime 
 
 
 
 
 
 
(11/17/17) 
(Suprax®) 
 
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  
 
 
 
 
 
 
 
 


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Incidence 
Toxicities 
Common 
(> 20% of patients) 
None known 
Occasional 
(4-20% of patients) 
 
Diarrhea, nausea, flatulence, loose or frequent stools. 
 
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 
Administration 
Given orally at 8 mg/kg/day (maximum dose 400 mg) divided every 12-24 hours. 
May be administered with or without food; administer with food to decrease GI 
distress. However, if administered with food ensure that sufficient time has elapsed 
prior to administering AZD1775 (MK-1775) (refer to section 9.1.5 for details) 
 
Shake the suspension prior to withdrawing dose or administration. 
 
Please see Appendix XIV for drug interactions associated with the drugs used in 
this study. 
 


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9.2.5 
Supplied by:  Commercially available from various manufacturers. See package 
insert for more detailed information. 
 
9.3 
IRINOTECAN 
 
 
 
 
 
 
(03/07/17) 
[CPT-11,Camptothecin-11,7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-
camptothecin), Camptosar®],   NSC #616348  
 
 
 
 
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. 
 
 
 
 
 
 
 
 
 


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9.3.2 
Toxicity 
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 


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• 
Renal failure (secondary to severe dehydration) 
• 
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 and (Appendix V). 
For oral use, the appropriate volume of irinotecan solution (20 mg/ml) should be 
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 
protocol for pre-medication and supportive care measures. 
 
For this protocol, irinotecan is administered orally, 1 hour prior to AZD1775 (MK-
1775). 
 
Please see Appendix XIV for drug interactions associated with the drugs used in 
this study. 
 
9.3.5 
Supplied by:  
Commercially available from various manufacturers. See package insert for more 
detailed information. 
 
 


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10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12.0). 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6.0). 
c) 
Refusal of further 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 18 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 AZD1775 (MK-1775) (and/or irinotecan, if applicable).  See Sections 4.0 and 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 attributed to protocol therapy 
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 further 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 
 
Strata: 
 
 
Part A:  Patients with relapsed or refractory solid tumors (Phase 1) 
 
Part B:  Patients with relapsed or refractory neuroblastoma (Phase 2) 
 
  
Part C:  Patients with relapsed or refractory medulloblastoma/CNS PNET (Phase 2) 
 
Part D: Patients with relapsed or refractory rhabdomyosarcoma (Phase 2) 


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A minimum of 3 evaluable patients with relapsed or refractory solid tumors including CNS 
tumors (Part A) will be entered at each dose level for determination of MTD. Once the 
MTD or recommended phase 2 dose has been defined, up to 6 additional patients with 
relapsed/refractory solid tumors may be enrolled to acquire PK data in a representative 
number of young patients (i.e. 6 patients in each group of < 12 years old and ≥ 12 years 
old).  Review of the enrollment rate into previous COG new agent studies indicates that 1-
2 patients per month are available, which will permit completion of this part of the study 
within 22-44 months.  Assuming an inevaluability rate of 20%, a maximum of 44 patients 
is anticipated in Part A.  In the unlikely scenario that all dose levels require expansion to 
12 evaluable patients (Section 11.2.2), a maximum of 80 patients is anticipated. 
 
Accrual to Parts B, C, and D will only open once the MTD or recommended phase 2 dose 
has been determined in Part A, and may open concurrently with the PK expansion 
described above. Review of patient accrual onto recent Phase 2 studies indicates the 
following entry rates for the various tumors under study can be achieved: 
 
Disease Group/Part 
 
Patients/Year 
Neuroblastoma 
  
36 
Medulloblastoma/CNS PNET  
15 
Rhabdomyosarcoma 
 
8 
 
A minimum of 29 patients and a maximum of 74 patients are expected to enroll in Parts B, 
C, and D, assuming an inevaluability rate of 20%.  We anticipate that the entire study will 
require 37-82 months for enrollment and evaluation of all parts.  
 
The MTD/RP2D of Part A was determined to be Dose Level 4 (85 mg/m2/dose AZD1775 
and 90 mg/m2/dose irinotecan on a 21-day cycle). Part A has been completed 37 patients 
were enrolled, no patients were ineligible.  
 
11.2 
Definitions 
 
11.2.1 Evaluable For Adverse Effects 
Any patient who experiences DLT at any time during protocol therapy is 
considered evaluable for Adverse Effects. Note: Patients who experience dose-
limiting diarrhea must have received at least 85% of the protocol-specified 
supportive care (e.g. cefixime or equivalent) in Cycle 1 to be considered evaluable 
for this Adverse Effect.  
 
Patients without DLT who receive all of the prescribed dose in Cycle 1 protocol 
guidelines and had the appropriate toxicity monitoring studies performed are also 
considered evaluable for Adverse Effects. Patients who are not evaluable for 
Adverse Effects at a given dose level will be replaced. 
 
11.2.2 Maximum Tolerated Dose 
The MTD or recommended phase 2 dose will be the maximum doses of AZD1775 
(MK-1775) and irinotecan at which fewer than one-third of patients experience 
DLT (See Section 5.5) when receiving AZD1775 (MK-1775) in combination with 
irinotecan in Part A. In the event that two DLTs observed out of 6 evaluable 
patients are different classes of Adverse Effects (e.g. hepatotoxicity and 
myelosuppression), expansion of the cohort to 12 patients will be considered if all 
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•  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 
 
Expansion will proceed according to the rules of the 3+3 design (Section 11.3): 
Three additional patients will be studied.  If none of the initial three additional 
patients experiences DLT, the dose will be escalated.  If one of the initial three 
additional patients experiences DLT, expansion to a total of 12 patients will 
continue.  If fewer than 1/3 of patients in the expanded cohort experience dose-
limiting toxicities, the dose escalation can proceed. 
 
11.2.3 Evaluability for Response 
Any patient who is enrolled and receives at least one dose of AZD1775 (MK-1775) 
in combination with irinotecan will be considered evaluable for response provided: 
(1) the patient demonstrates progressive disease or death while on protocol 
therapy; or (2) the patient is observed on protocol therapy for at least one cycle and 
the tumor is not removed surgically prior to the time complete response or partial 
response is confirmed, or (3) the patient demonstrates a complete or partial 
response as confirmed according to protocol criteria. Patients who demonstrate a 
complete or partial response confirmed by central review will be considered to 
have experienced a response for the application of the rule given in Section 11.4. 
Two objective status determinations are required to confirm best response (Section 
12.7). All other patients will be considered non-responders. All patients considered 
to have a response (CR or PR) must have imaging studies reviewed centrally at the 
COG. Centers will be notified by the COG about requests for scans of patients with 
stable disease. See Section 8.2 regarding shipping instructions. Preliminary 
assessment of activity using institutionally provided tumor measurements will be 
entered into CDUS quarterly. The central review by COG will be provided as the 
final reviewed assessment of response when such becomes available. 
 
11.3 
Dose Escalation and Determination of MTD (Part A) 
The 3+3 design will be used for dose-escalation in Part A for determination of MTD in 
each Part of the study 
 
11.3.1 Three patients are studied at the first dose level. 
 
11.3.2 If none of these three patients experience DLT, then the dose is escalated                                                                             
to the next higher level in the three subsequent patients. 
 
11.3.3 If one of three patients experiences DLT at the current dose, then up to three more 
patients are accrued at the same level. 
 
a)  If none of these three additional patients experience DLT, then the dose is 
escalated in subsequent patients. If there are no further dose escalations, then 
the RP2D has been confirmed. 
 
b)  If one or more of these three additional patients experiences DLT, then patient 
entry at that dose level is stopped.  (See Section 11.2.2 for exception to rule).  
Up to three more patients are treated at the next lower dose (unless six patients 
have already been treated at that prior dose). 
 
11.3.1 If two or more of a cohort of up to six patients experience DLT at a given dose 


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level, then the MTD has been exceeded and dose escalation will be stopped (see 
Section 11.2.2 for exception to rule).  Up to three more patients are treated at the 
next lower dose (unless six or more patients have already been treated at that 
prior dose). The highest dose with less than two DLTs out of six evaluable 
patients will be the estimated MTD. 
 
In addition to determination of the MTD, a descriptive summary of all toxicities 
will be reported. 
 
The MTD/RP2D of Part A was determined to be Dose Level 4 (85 mg/m2/dose 
AZD1775 and 90 mg/m2/dose irinotecan on a 21-day cycle). 
 
11.4 
Phase 2 Evaluation in Neuroblastoma (Part B), Medulloblastoma/CNS PNET (Part 
C) and Rhabdomyosarcoma (Part D) 
 
The best response of disease to AZD1775 (MK-1775) in combination with 
irinotecan will be examined separately in each of Parts B,  C, and D.   
 
11.4.1 Study Design for patients with Neuroblastoma (Part B)  
 
The following Simon’s optimal two stage design35 will be used in Part B. 
 
 
Cumulative Number 
of Responses 
Decision 
Stage 1: Enter 10 patients 
0 
Terminate the trial: agent ineffective 
1 or more 
Inconclusive result, continue trial 
(proceed to stage 2) 
 
Stage 2: Enter 10 additional 
patients 
2 or less      
Terminate the trial: agent ineffective 
3 or more 
Terminate the trial: agent effective 
 
AZD1775 (MK-1775) in combination with irinotecan will not be considered of 
sufficient interest for further evaluation in a disease category if the true response 
rate is 5% and of sufficient activity if the true response rate is 25%. If AZD1775 
(MK-1775) in combination with irinotecan has a true response rate of 5%, the rule 
described above will identify it of sufficient activity for further study with 
probability 0.07 (type I error), and the trial will have an expected sample size of 
14 with 60% probability of early termination.  If AZD1775 (MK-1775) in 
combination with irinotecan has a true response rate of 25%, the rule described 
above will identify it of sufficient activity for further study with probability 0.88 
(power against the alternative hypothesis P = 0.25). 
 
 


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11.4.2 Study Design for patients with Medulloblastoma/CNS PNET (Part C)  
The following Simon’s optimal two stage design35 will be used in Part C. 
 
 
Cumulative Number 
of Responses 
Decision 
Stage 1: Enter 9 patients 
1 or less 
Terminate the trial: agent ineffective 
2 or more 
Inconclusive result, continue trial 
(proceed to stage 2) 
 
Stage 2: Enter 10 additional 
patients 
5 or less      
Terminate the trial: agent ineffective 
6 or more 
Terminate the trial: agent effective 
 
AZD1775 (MK-1775) in combination with irinotecan will not be considered of 
sufficient interest for further evaluation in a disease category if the true response 
rate is 15% and of sufficient activity if the true response rate is 40%. If AZD1775 
(MK-1775) in combination with irinotecan has a true response rate of 15%, the 
rule described above will identify it of sufficient activity for further study with 
probability 0.05 (type I error), and the trial will have an expected sample size of 
13 with 60% probability of early termination.  If AZD1775 (MK-1775) in 
combination with irinotecan has a true response rate of 40%, the rule described 
above will identify it of sufficient activity for further study with probability 0.81 
(power against the alternative hypothesis P = 0.40). 
 
 
11.4.3 Study Design for patients with Rhabdomyosarcoma (Part D) 
The following Simon’s optimal two stage design35 will be used in Part D.  
 
 
Cumulative Number 
of Responses 
Decision 
Stage 1: Enter 10 patients 
0 
Terminate 
the 
stratum: 
agent 
ineffective 
1 or more 
Inconclusive result, continue stratum 
(proceed to stage 2) 
 
Stage 2: Enter 10 additional 
patients 
2 or less      
Terminate 
the 
stratum: 
agent 
ineffective 
3 or more 
Terminate the stratum: agent effective 
 
AZD1775 (MK-1775) in combination with irinotecan will not be considered of 
sufficient interest for further evaluation in a disease category if the true response 
rate is 5% and of sufficient activity if the true response rate is 25%. If AZD1775 
(MK-1775) in combination with irinotecan has a true response rate of 5%, the rule 
described above will identify it of sufficient activity for further study with 
probability 0.07 (type I error), and the trial will have an expected sample size of 
14 with 60% probability of early termination.  If AZD1775 (MK-1775) in 
combination with irinotecan has a true response rate of 25%, the rule described 
above will identify it of sufficient activity for further study with probability 0.88 
(power against the alternative hypothesis P = 0.25). 


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Response in all patients will be determined according to the evaluation criteria 
outlined in Section 12.0 as either complete response (CR), partial response (PR), 
stable disease (SD) or progressive disease (PD) and reported as final results.  A 
report on the efficacy assessment will be posted on the completed disease stratum 
as part of the semi-annual study committee meeting book report. 
 
Data collected from any patients enrolled at the MTD or recommended phase 2 
dose or enrolled onto Parts B, C, or D will be utilized in the Phase 2 study. 
 
 
11.4.4 Method of Analysis 
Response criteria are described in Section 12.0. Response rates will be calculated 
as the percent of patients whose best response is a CR or PR and confidence 
intervals will be constructed according to the method of Chang.36 A responder is 
defined as a patient who achieves a best confirmed response (as defined in Section 
12.7) of PR or CR on the study.  
 
11.5 
Inclusion of Children, Women and Minorities 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual 
to past COG studies of new agents demonstrates the accrual of both genders and all NIH-
identified ethnicities to such studies.  Efforts will be made to extend the accrual to a 
representative population, but in a Phase 1 trial which will accrue a limited number of 
patients, a balance must be struck between patient safety considerations and limitations on 
the number of individuals exposed to potentially toxic or ineffective treatments on the one 
hand and the need to explore gender, racial, and ethnic aspects of clinical research on the 
other. If differences in outcome that correlate to gender, racial, or ethnic identity are noted, 
accrual may be expanded or additional studies may be performed to investigate those 
differences more fully. 
 
11.6 
Pharmacokinetic and Correlative Studies and Response Analysis 
A descriptive analysis of pharmacokinetic (PK) parameters of AZD1775 (MK-1775) 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 AZD1775 (MK-1775), 
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. 
 
Decreased p-CDK1 indicating Wee1 inhibition by AZD1775 (MK-1775) and predictive 
biomarkers of AZD1775 (MK-1775) sensitivity will also be investigated.  All these 
analyses will be descriptive and exploratory and hypotheses generating in nature. 
 
 
 


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12.0 
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
12.2 
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 at least 21 days 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 
combination 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 
might or might not be considered measurable.  If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 
 
12.2.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 


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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 
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. 


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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 that may bias an investigator if it is not 
routinely or serially performed.   
 
12.2.3.5 Tumor markers: Tumor markers alone cannot be used to assess response.  
If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.  
 
12.2.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.2.3.7 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-


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up is a sign of PD based on a new lesion. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
 
12.2.4 Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
12.2.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to < 10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions 
is also considered progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
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 


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


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12.3.6 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7 from a sequence of overall response assessments. 
 
 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
Note:  Neuroblastoma patients who do not have MIBG positive lesions or bone 
marrow involvement should be assessed for response as solid tumor patients with 
measurable or evaluable disease. 
 
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 
scale as outlined below. Central review responses will be used to assess efficacy 
for study endpoint. See Section 8.2.1 for details on transferring images to the 
Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 


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The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
12.4.4 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Table 5 in Section 12.7. 
 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
Note:  Neuroblastoma patients who do not have MIBG positive lesions or bone 
marrow involvement should be assessed for response as solid tumor patients with 
measurable or evaluable disease. 
 
12.5.1 Bone Marrow Involvement  
Bone marrow obtained within 14 days prior to start of protocol therapy 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 


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catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there 
is a doubling in the amount of tumor in the marrow AND 
a minimum of 25% tumor in bone marrow by 
morphology. (For example, a patient entering with 5% 
tumor in marrow by morphology must increase to ≥ 25% 
tumor to have progressive disease; a patient entering with 
30% tumor must increase to > 60%). 
 
In patients who enroll without evidence of neuroblastoma 
in bone marrow will be defined as progressive disease if 
tumor is detected in 2 consecutive bone marrow biopsies 
or aspirations done at least 21 days apart. 
 
 
Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
12.5.2 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.7. 
 
12.6 
Response Criteria for Patients with CNS Tumors 
 
12.6.1 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
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. 
 


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12.6.4 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in 
other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions: 
 
• 
Complete Response (CR): Disappearance of all target lesions. 
 
• 
Partial response (PR): ≥50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements. 
 
• 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of 
the two perpendicular diameters of all target lesions to qualify for PR, nor 
sufficient increase in a single target lesion to qualify for PD. 
 
• 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
12.6.5 Response Criteria for Non-Target Lesions: 
 
• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
• 
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
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 


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PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7 from a sequence of overall response assessments. 
 
 
12.7 
Best Response 
 
12.7.1 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥21 days Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
≥21 days Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once 
≥21 days from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
 
 


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Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Table 3.  Sequences of overall response assessments with corresponding best response. 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
Table 4: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
Table 5: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly identified lesion by 
CT/MRI that occurs during therapy would be considered progressive disease. 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
12.7.2 Duration of Response 


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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.  
 
 
 


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13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  Adverse events are reported in a routine manner at scheduled times 
during a trial.  (Please follow directions for routine reporting provided in the data collection packet 
for this protocol).  Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  The following sections provide information 
about expedited reporting. 
 
 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered serious; 
3) the grade (severity); and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source.  The NCI, rather than a commercial distributor, may on some occasions 
distribute commercial agents for a trial. 
 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the NCI CTCAE version 5.0. All 
appropriate treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Step 2:  Grade the adverse event using the NCI CTCAE version 5.0. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
Note:  This includes all events that occur within 30 days of the last dose of protocol 
treatment.  Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the 
agent(s) must also be reported according to the instructions in the table 
below. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
 


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Table A: Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
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 to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR below under the section titled 
“Additional Instructions or Exceptions”. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific 
expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 


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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 that 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 AND LYMPHATIC SYSTEM 
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 
Dyspepsia 
METABOLISM AND NUTRITION DISORDERS 
Dehydration 
NERVOUS SYSTEM DISORDERS 
Dysgeusia 
PSYCHIATRIC DISORDERS 
Insomnia 
  
• See also the Specific Protocol Exceptions to Expedited Reporting (SPEER) in Section 9.1.6 of the 
protocol. Additional protocol-specific exceptions to expedited reporting of serious adverse events 
are the toxicities in bold font listed under the drug information section of the protocol (Section 9.1). 
 
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 call CTEP at: 301-897-7497 within 24 hours of 
becoming aware of the event if the CTEP-AERS 24-Hour Notification web-based 
application is unavailable) and by telephone call to the Study Chair. Once internet 
connectivity is restored, a 24-hour notification phoned in must be entered electronically 
into CTEP-AERS by the original submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 


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• 
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited 
Reporting 
System), 
accessed 
via 
the 
CTEP 
home 
page 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
.  
 
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 
https://ctepcore.nci.nih.gov/ctepaers/pages/task. 
 
A CTEP-AERS report must be submitted electronically via the CTEP-AERS Web-
based application located at https://ctepcore.nci.nih.gov/ctepaers/pages/task. If 
prompted 
to 
enter 
a 
sponsor 
email 
address, 
please 
type 
in: 
PEPCTNAERS@childrensoncologygroup.org. 
 
Send supporting documentation to the NCI by fax (fax # 301-230-0159) and by 
email to the ADVL1312 Study-Assigned Research Coordinator.  ALWAYS 
include the ticket number on all faxed documents. 
 
13.4 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG data 
submission forms and do not alter the guidelines for CTEP-AERS reporting. 
 
13.4.1 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
13.4.2 If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported. 
 
13.4.3 The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects.  
 
13.4.4 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than Grade 1, whichever level is higher (note that the resolution 
date may therefore be different from the date at which the grade of the AE 
decreased from its highest grade).  If the AE does not return to baseline the 
resolution date should be recorded as "ongoing."   
 
13.4.5 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
 
 
 
13.5 
Other Recipients of Adverse Event Reports 
 
13.5.1 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 


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should be reported at the end of each cycle using the forms provided in the data 
form 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 on NCI-sponsored trials following their chemotherapy for cancer must be 
reported to the Investigational Drug Branch (IDB) of the NCI Cancer Therapy Evaluation 
Program (CTEP) via CTEP-AERS and included as part of the second malignant neoplasm 
reporting requirements for this protocol (see data submission packet).  Submit the 
completed CTEP-AERS report within 14 days of an AML/MDS diagnosis occurring after 
treatment for cancer on NCI-sponsored trials. 
 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
2) Myelodysplastic syndrome (MDS) 
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified. 
 
13.7 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and faxed along with any 
additional medical information to (301) 230-0159 and also emailed to the ADVL1312 
Study-Assigned Research Coordinator. 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 that may be teratogenic. For this reason, pregnancy 


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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 
“Pregnancy, puerperium and perinatal conditions - Other (Pregnancy) 
under the Pregnancy, puerperium and perinatal conditions System Organ 
Class (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 Pregnancy Loss (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. 
 
• 
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. 
 
• 
Do NOT report a neonatal death resulting from a patient pregnancy or 
pregnancy in partners of men as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death.  
 
Pregnancy should be followed up until the outcome of the pregnancy is known at intervals 
deemed appropriate by her physicians. The “Pregnancy Information Form” should be used 
for 
all 
necessary 
follow-ups. 
This 
form 
is 
available 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyRepo
rtForm.pdf.  
 
 
 


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14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
entered in RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the data form packet. 
 
See separate Data Form Packet, which includes submission schedule. 
 
14.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis.  Reports are due January 31, April 30, July 31 and October 31.  
This is not a responsibility of institutions participating in this trial. 
 
14.3 
CRADA/CTA/CSA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
 


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2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order 
as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected , used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting 


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or publication in the proceedings. Press releases and other media presentations 
must also be forwarded to CTEP prior to release. Copies of any manuscript, 
abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
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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therapeutics 8:2992-3000, 2009 
25. 
Hirai H, Arai T, Okada M, et al: MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor 
efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer biology & therapy 
9:514-22, 2010 
26. 
Bridges KA, Hirai H, Buser CA, et al: MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes 
p53-defective human tumor cells. Clinical cancer research : an official journal of the American 
Association for Cancer Research 17:5638-48, 2011 
27. 
Sarcar B, Kahali S, Prabhu AH, et al: Targeting radiation-induced G(2) checkpoint activation with 
the Wee-1 inhibitor MK-1775 in glioblastoma cell lines. Molecular cancer therapeutics 10:2405-
14, 2011 
28. 
Caretti V, Hiddingh L, Lagerweij T, et al: WEE1 Kinase Inhibition Enhances the Radiation 
Response of Diffuse Intrinsic Pontine Gliomas. Molecular cancer therapeutics, 2013 
29. 
Kreahling JM, Gemmer JY, Reed D, et al: MK1775, a selective Wee1 inhibitor, shows single-agent 
antitumor activity against sarcoma cells. Molecular cancer therapeutics 11:174-82, 2012 
30. 
Leijen S, van Geel RMJM, Pavlick AC, et al: Phase I Study Evaluating WEE1 Inhibitor AZD1775 
As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With 
Advanced Solid Tumors. Journal of Clinical Oncology 34:4371-4380, 2016 
31. 
Leijen S, van Geel RMJM, Sonke GS, et al: Phase II Study of WEE1 Inhibitor AZD1775 Plus 
Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line 
Therapy Within 3 Months. Journal of Clinical Oncology 34:4354-4361, 2016 
32. 
Cole KA, Reid JM, Liu X, et al: Abstract CT144: Pediatric phase I trial of the WEE1 inhibitor 
AZD1775 and irinotecan in patients with refractory solid and CNS malignancies; A Children’s 
Oncology Group Study (ADVL1312). Cancer Research 77:CT144-CT144, 2017 
33. 
Kahen E, Yu D, Harrison DJ, et al: Identification of clinically achievable combination therapies in 
childhood rhabdomyosarcoma. Cancer Chemotherapy and Pharmacology 78:313-323, 2016 
34. 
Stewart E, Honnell V, Ocarz M et al: Targeting the cell cycle for cancer therapy in 
rhabdomyosarcoma. Proc Am Soc Clin Oncol 35:10535, 2017  
35. 
Simon R: Optimal two-stage designs for phase II clinical trials.Control Clin Trials. Controlled 
Clinical Trials 10(1):1-10, 1989 
36. 
Chang MN: Improved confidence intervals for a binomial parameter following a group sequential 
phase II clinical trial. Stat Med 23(18):2817-26, 2004 
37. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European journal of cancer (Oxford, England : 1990) 
45:228-247, 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:  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 III:  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 
 
 
 
Formatted: Highlight
Formatted: Highlight
Formatted: Highlight
Formatted: Highlight


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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 7.5 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) 
Formatted: Highlight


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APPENDIX IV: AZD1775 (MK-1775) DOSING NOMOGRAM 
 
 
AZD1775 (MK-1775) Dose Assignment Parts B, C, D  
(Recommended Phase 2 Dose  85 mg/m2) 
BSA (m2) 
Total Daily Dose (mg/day) 
0.49-0.73 
50 
0.74-1.03 
75 
1.04-1.32 
100 
1.33-1.62 
125 
1.63-1.91 
150 
1.92-2.2 
175 
2.21-2.5 
200 
≥ 2.51 
225 
 
 
AZD1775 (MK-1775) Dose Modification Parts  B, C, D 
(Dose Reduction for toxicity ≈ 65 mg/m2) 
BSA (m2) 
Total Daily Dose (mg/day) 
0.49-0.73 
25 
0.74-1.03 
50 
1.04-1.32 
75 
1.33-1.62 
100 
1.63-1.91 
100 
1.92-2.2 
125 
2.21-2.5 
150 
≥ 2.51 
175 
 
 
 


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APPENDIX V:  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 1 hour before the other study drug 
AZD1775 (MK-1775) 
 
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 at around the same time each 
day one (1) hour before the study drug AZD1775.   
• Take/Give irinotecan on an empty stomach, at least 
one (1) hour after food.  
• Wait one (1) hour after irinotecan before taking 
AZD1775. Wait at least one (1) hour after AZD1775 
before giving/eating any food. 
• 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 20 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 VI:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
 
Guidelines for the Treatment of Diarrhea 
 
Institutional practice may be used in place of these guidelines. 
 
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. Patients will also be instructed to contact their physician if any diarrhea 
occurs. Patients will be given loperamide based on body weight.  
 
Be aware of your child's bowel movements. At the first sign they become softer than usual or if your child 
has any notable increase in the number of bowel movements over what is normal for him/her, begin taking 
loperamide (Imodium). 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 2 hours until the diarrhea slows or the 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. 
 
Loperamide dosing recommendations for late diarrhea (maximum dose of Loperamide for adults is 16 
mg/day): 
 
 
 


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LOPERAMIDE DOSING RECOMMENDATIONS FOR LATE DIARRHEA 
(maximum dose of loperamide for adults is 16 mg/day) 
ALL patients: discontinue loperamide when the patient is no longer experiencing significant diarrhea. 
Weight (kg) 
ACTION 
<13 kg   
Take 0.5 mg (one-half teaspoonful of the 1 mg/5 mL oral solution) after the first 
loose bowel movement, followed by 0.5 mg (one-half teaspoonful of the 1 mg/5 
mL oral solution) every 3 hours.  During the night, the patient may take 0.5 mg 
(one-half teaspoonful of the 1 mg/5 mL oral solution) every 4 hours.  Do not 
exceed 4 mg per day (20 mL or 4 teaspoonfuls) per day. 
≥ 13 kg to < 20 kg 
Take 1 mg (1 teaspoonful of the 1 mg/5 mL oral solution or one-half tablet) after 
the first loose bowel movement, followed by 1 mg (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 (one teaspoonful of the 1 mg/5 mL oral solution or one-half tablet) 
every 4 hours.  Do not exceed 6 mg per day (30 mL or 6 teaspoonfuls) per day. 
≥ 20 kg to < 30 kg 
Take 2 mg (2 teaspoonfuls of the 1 mg/5 mL oral solution or 1 tablet) after the 
first loose bowel movement, followed by 1 mg (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 (2 teaspoonfuls of the 1 mg/5 mL oral solution or 1 tablet) every 4 hours. 
Do not exceed 8 mg per day (40 mL or 8 teaspoonfuls) per day. 
≥ 30 kg to < 43 kg 
Take 2 mg (2 teaspoonfuls of the 1 mg/5 mL oral solution or 1 tablet) after the 
first loose bowel movement, followed by 1 mg (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 (2 teaspoonfuls of the 1 mg/5 mL oral solution or 1 tablet) every 4 hours. 
Do not exceed 12 mg per day (60 mL or 12 teaspoonfuls) per day. 
Over 43 kg 
Take 4 mg (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 (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 (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 VII:  CORRELATIVE STUDIES GUIDE 
 
 
PART A 
 
Correlative Study 
 
Appendix 
Blood Volume 
 
 
Tube Type 
Volume 
per sample 
Total Volume 
> 30 kg 
Total Volume 
20-30 kg  
Total Volume 
<20 kg 
Pharmacokinetics 
VIII 
2-3 ml 
28-42 ml 
28-42 ml  
12-18 ml 
Lavender-top 
K2EDTA 
Pharmacodynamics 
IX 
5-8 ml* 
32 ml 
20 ml 
---- 
Heparinized 
 (green-top) 
Bone Marrow Studies 
X 
5-10 ml 
10-20 ml 
10-20 ml 
10-20 ml 
Preservative-
free heparin 
(green top) 
Tumor Tissue 
(Required)  
See Section 8.6 for 
details 
XI 
- 
- 
- 
- 
- 
Total Blood Volume 
60-74 ml 
48-62 ml 
12-18 ml 
 
Total Bone Marrow Volume 
10-20ml 
10-20ml 
10-20ml 
 
*Sample volume is 5 ml for patients 20-30 kg and 8 ml for patients > 30 kg. 
 
 
 
PART B, C, or D 
 
Correlative Study 
 
 
Appendix 
Sample Volume 
 
 
Tube Type 
Volume per 
sample 
Total  
Cycle 1 
Bone Marrow Studies 
X 
5-10ml 
10-20 ml 
Preservative-free heparin (green 
top) 
Tumor Tissue 
(Required) 
See Section 8.6 for details 
XI 
- 
- 
- 
Total Bone Marrow Volume 
10-20ml 
 
 
 


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APPENDIX VIII:  PHARMACOKINETIC STUDY FORM (PART A ONLY) 
 
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  
 
AZD1775 (MK-1775)  Dose Level: ______mg/m2    
AZD1775 (MK-1775) Total Daily Dose: ______mg 
 
Blood samples (2-3 mL) will be collected in K2 EDTA (lavender-top) tubes in patients ≥ 20 kg at the following 
time points (+/- 10 minutes): Day 1 (pre-dose, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr and 24 hours after dose), Day 4 (pre-
dose), Day 5 (pre-dose, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr after dose) of Cycle 1.  
 
For patients < 20 kg, samples will be collected at the following time points (+/- 10 minutes): Day 1 (pre-dose, 1 
hr and 8 hr after dose) and Day 5 (pre-dose, 1 hr and 8 hr after dose).  
 
Record the exact time the sample is drawn along with the exact time AZD1775 (MK-1775) is given on Day 1.  
 
 
 
 
 
 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time Sample 
Collected 
(24-hr clock) 
1* 
Day 1 
Prior to irinotecan dose 
___/___/___ 
|__|__| : |__|__| 
AZD1775 Dose on Day 1       Date:___/___/___       Time: |__|__| : |__|__| 
2* 
Day 1 
1 hr after AZD1775 dose 
___/___/___ 
|__|__| : |__|__| 
3 
Day 1 
2 hr after AZD1775 dose 
___/___/___ 
|__|__| : |__|__| 
4 
Day 1 
4 hr after AZD1775 dose 
___/___/___ 
|__|__| : |__|__| 
5 
Day 1 
6 hr after AZD1775 dose 
___/___/___ 
|__|__| : |__|__| 
6* 
Day 1 
8 hr after AZD1775 dose 
___/___/___ 
|__|__| : |__|__| 
7 
Day 2 
24 (±2) hrs after Day 1 AZD1775 dose 
(prior to irinotecan on Day 2) 
___/___/___ 
|__|__| : |__|__| 
AZD1775 Dose on Day 2       Date:___/___/___       Time: |__|__| : |__|__| 
8 
Day 4 
Prior to irinotecan dose 
___/___/___ 
|__|__| : |__|__| 
AZD1775 Dose on Day 4       Date:___/___/___       Time: |__|__| : |__|__| 
9* 
Day 5 
Prior to irinotecan dose 
___/___/___ 
|__|__| : |__|__| 
AZD1775 Dose on Day 5    Date:___/___/___       Time: |__|__| : |__|__| 
10* 
Day 5 
1 hr after AZD1775 dose 
___/___/___ 
|__|__| : |__|__| 
11 
Day 5 
2  hr after AZD1775 dose 
___/___/___ 
|__|__| : |__|__| 
12 
Day 5 
4 hr after AZD-1775 dose 
___/___/___ 
|__|__| : |__|__| 
13 
Day 5 
6 hr after AZD1775 dose 
___/___/___ 
|__|__| : |__|__| 
14* 
Day 5 
8 hr after AZD1775 dose 
___/___/___ 
|__|__| : |__|__| 
*  Patients < 20 kg should have only these samples collected. 
 
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should be sent with 
the samples to the address listed in Section 8.3.6.  See Section 8.3 for detailed guidelines for packaging and shipping 
PK samples.   
 
Signature: _________________________________________                    Date:___________________ 
 
(site personnel who collected samples) 
 


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APPENDIX IX-A:  PHARMACODYNAMIC STUDY FORM (PART A ONLY) 
 
COG Pt ID # _______________ 
 
 
 
Cycle 1, Day 1 Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Body Surface Area: ______m2  Dose Level: ______mg/m2 
 AZD1775 Total Daily Dose:  _____mg 
 
Blood samples (8 ml for patients > 30 kg and 5 ml for patients 20-30 kg) will be collected:  
 
Cycle 1 Day 1 prior to the irinotecan infusion, prior to the AZD1775 (MK-1775) dose, 4 hours after the 
dose of AZD1775 is given, and prior to the irinotecan dose on Day 2. 
 
 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time 
Actual Date 
Sample 
Collected  
Actual Time 
Collected  
(24-hr clock) 
1 
Cycle 1, Day 1 
prior to the irinotecan dose 
 
|__|__| : |__|__| 
Irinotecan Dose on Day 1       Date:___/___/___       Time: |__|__| : |__|__| 
2 
Cycle 1, Day 1 
prior to the AZD1775 dose  
 
|__|__| : |__|__| 
AZD1775 Dose on Day 1       Date:___/___/___       Time: |__|__| : |__|__| 
3 
Cycle 1, Day 1 
4 hours after the AZD1775 dose 
 
|__|__| : |__|__| 
4 
Cycle 1, Day 2 
24 (±2) hrs after Day 1 AZD1775 dose 
(prior to the irinotecan dose on Day 2) 
 
|__|__| : |__|__| 
 
 
One copy of this Pharmacodynamic Study Form should be uploaded into RAVE. A second copy should be 
sent with the samples to the address listed in Section 8.4.6.  See Section 8.4 for detailed guidelines for 
packaging and shipping PD samples.   
 
Record any notes for Sample Storage Conditions below. 
 
Notes:    ___________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
 
Signature: _________________________________________                    Date:___________________ 
 
 
(site personnel who collected samples) 
 
 
 
 


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APPENDIX IX-B: PD SAMPLE COLLECTION GUIDELINES 
 
Required Items: 
 
- 
Whole blood collection at required PD time points as outlined in Appendix IX-A 
- 
Smart Tubes at room temperature (one per incubation condition): will be provided by study team 
- 
Water bath pre-warmed to 37°C 
- 
-80°C freezer or dried ice 
- 
Complete RPMI (optional) 
 
Protocol: 
 
1. Use an approved tube containing sodium heparin (ie. green top Vacutainer) to collect PD sample.  
Ensure good mixing with the anticoagulant by inverting the securely capped tube at least 6 times.  
Begin incubation of the blood with the Smart Tube system as soon as possible, ideally within two 
hours of the blood draw.  Keep the blood at room temperature until it is assayed with the Smart 
Tube system. 
 
2. Add 1 milliliter (ml) of the whole blood sample to each Smart Tube.  Immediately cap the Smart 
Tube and vortex or invert six times to ensure good mixing with the agents added.   
 
3. Place the Smart Tubes in the 37°C water bath for 30 minutes. 
 
4. At the end of the 30 minutes incubation time remove the Smart Tubes from the water bath and 
activate the Smart Tubes manually.  To activate a Smart Tube manually, make sure the cap is 
screwed on securely and then bend the Smart Tube in the middle until you feel the ampoule 
inside break, then invert the Smart Tube 10 times to ensure good mixing (gently shaking the 
Smart Tube up and down 10 times is an acceptable alternative to inverting it 10 times). 
 
5. Incubate the activated Smart Tubes at room temperature for 8 minutes. 
 
6. Immediately transfer the Smart Tubes to a -80°C freezer or place in direct contact with dry ice.  
The Smart Tubes should be stored at -80°C until the sample is analyzed.  Samples frozen in 
Smart Tubes should not be stored at temperatures warmer than -80°C.  Smart Tubes have not 
been validated for storage in liquid nitrogen. Samples will be stored at -80°C and shipped when 
all PD time points have been collected. Tubes need to be shipped on dry ice. All samples should 
be shipped to address as outlined in section 8.4.3. Samples should NOT be shipped on a Friday or 
before a holiday. 
 
 


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APPENDIX X:  BONE MARROW STUDY FORM (PART A, B, C OR D) 
 
 
COG Pt ID # _______________ 
 
 
Cycle 1, Day 1 Date: _____________ 
 
Please do not write patient names on this form or on samples. 
 
Body Surface Area: ______m2  
Dose Level: ______mg/m2 
  Total Daily Dose: ________mg 
 
Bone marrow samples (5-10 ml) will be collected in preservative-free heparin (green-top) tubes at baseline 
and with disease re-evaluations in consenting patients with known or suspected marrow disease. 
 
Type of sample: 
bone marrow 
Check the box to indicate 
when sample was drawn: 
baseline 
other ________ 
Date Sample Collected: 
 
Time Sample Collected: 
 
Sample Volume 
______   mL 
Number of tubes 
 
 
Sample(s) should be shipped at room temperature to the address below the same day the samples are 
obtained, if possible. Samples should be shipped via overnight priority delivery for arrival on a Monday 
through Friday only. Weekend deliveries are not accepted at the laboratory. Bone marrow samples that 
cannot be delivered on a weekday should be stored refrigerated at 4°C until they are shipped that following 
Monday. Data should be recorded on this study form, and a copy of the form should be sent with the 
sample(s) at each shipment.  A copy of the form should also be uploaded into RAVE.   
 
Samples should be shipped to: 
 
Attn: Dr. Kristina Cole 
The Children’s Hospital of Philadelphia 
The Colket Translational Research Building 
Room 3300 
3501 Civic Center Boulevard 
Philadelphia, PA 19104 
 
Notes:    ___________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
 
Signature: ________________________________________            Date:________________________ 
 
 
(site personnel who collected samples) 
 
 


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APPENDIX XI:  TISSUE STUDY FORM (PART A, B, C, OR D) 
 
COG Pt ID # _______________ 
 
 
 
Cycle 1, Day 1 Date: _____________ 
 
Please do not write patient names on this form or on samples. 
 
Body Surface Area: ______m2  
Dose Level: ______mg/m2 
  Total Daily Dose: ________mg 
 
Tumor Sample Labeling: 
Samples should be labeled with the following information: 
 
Protocol number: ADVL1312 
Institution:        _________________ 
Patient ID #:     _________________ 
Accession #:     _________________ 
Sample Date:    _________________ 
Site of Acquired Tissue:  __________________ 
 
Tissue obtained at (check one option below): 
Diagnosis      Relapse 
 
Shipment of Tumor Tissue: 
Paraffin embedded tumor specimens must be packaged appropriately and shipped at room temperature to 
Dr. Kristina Cole (at the address below). If a tumor block is not available, please send as many scrolls from 
the tumor block and/or a minimum of 10 unstained slides may be shipped instead. Please indicate above 
the date of the sample, site of tissue acquisition and whether it was obtained at diagnosis or relapse. 
Shipments should be sent Monday through Thursday only for priority overnight delivery using the COG 
FedEx account (do not ship on Friday). One copy of this form should be uploaded into RAVE.  
 
A second copy should be sent with the tissue sample to lab address below. 
 
Attn: Dr. Kristina Cole 
The Children’s Hospital of Philadelphia 
The Colket Translational Research Building 
Room 3300 
3501 Civic Center Boulevard 
Philadelphia, PA 19104 
 
Notes:    ___________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
____________________________________________________________________________________________________________ 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
 
Signature: ___________________________________________             Date:______________________ 
 
 
(site personnel who collected samples) 
 


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APPENDIX XII: 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 XIII:  MEDICATION DIARY FOR AZD1775 (MK-1775) 
 
COG Patient ID:___________   Acc#_________________ 
 
 
 
 
  
 
Institution :________________________________  
Please do not write patient names on this form. 
 
Complete each day with the time and dose given for cefixime (CEF) or equivalent, irinotecan, and AZD1775 (MK-1775). If a 
dose is not due or is accidentally skipped leave that day blank. Make note of other drugs and supplements taken under the 
Comments section below. (NOTE: irinotecan should be taken 1 hour prior to AZD1775 (MK-1775); note the time taken in 
the comments column). Cefixime or an available equivalent antibiotic (i.e. cefpodoxime) will be used as diarrheal prophylaxis 
and administered at least 2 days prior to the first dose of irinotecan, during, and 3 days after the last dose of irinotecan. AZD1775 
(MK-1775) capsules should not be opened or crushed but should be swallowed whole. If capsule is broken and the powder of 
the capsules gets on skin, wash the exposed area with as much water as necessary.  Inform your study doctor or nurse if that 
occurs. AZD1775 (MK-1775) should be taken on an empty stomach 1 hour before or 2 hours after food. If you vomit after 
taking the medication, the dose will not be repeated. Add the dates to the calendar below and return the completed diary to your 
institution after each treatment cycle. Your institution will upload this document into RAVE after each treatment cycle.  
EXAMPLE 
 
 
Number of AZD1775 
(MK-1775) capsules 
Comments 
 
 
Date 
Time 
25 mg 
100 mg 
 
Day 1 
1/15/14 
8:30 AM 
2 
1 
He felt nauseated an hour after taking the drug 
but did not vomit. 
 
Cycle #: _____  AZD1775 (MK-1775)  Dose: ________   Start Date: |__/__|__/__|__/__|   End Date: |__/__|__/__|__/__| 
PRE 
Date 
Time 
 
Comments 
Day -2 
 
CEF:  ______________ 
 
 
Day -1 
 
CEF:  ______________ 
 
 
 
Date 
Time 
 
25 mg 
100 mg 
Comments 
Day 1 
 
CEF:  ______________ 
Irinotecan: __________ 
 
 
AZD1775:  __________ 
 
 
Day 2 
 
CEF:  _____________ 
Irinotecan: __________ 
 
 
AZD1775:  __________ 
 
 
Day 3 
 
CEF:  ______________ 
Irinotecan: __________ 
 
 
AZD1775:  __________ 
 
 
Day 4 
 
CEF:  ______________ 
Irinotecan: __________ 
 
 
AZD1775:  __________ 
 
 
Day 5 
 
CEF:  ______________ 
Irinotecan: __________ 
 
 
AZD1775:  __________ 
 
 
Day 6 
 
CEF:  ______________ 
 
 
Day 7 
 
CEF:  ______________ 
 
 
 


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COG Patient ID:___________   Acc#_________________ 
 
 
 
 
  
 
Institution :________________________________  
Please do not write patient names on this form. 
 
 
Date 
Time 
 
 
Comments 
Day 8 
 
CEF:  ______________ 
 
 
 
Day 9 
 
 
 
 
 
Day 10 
 
 
 
 
 
Day 11 
 
 
 
 
 
Day 12 
 
 
 
 
 
Day 13 
 
 
 
 
 
Day 14 
 
 
 
 
 
 
Date 
Time 
 
 
Comments 
Day 15 
 
 
 
 
 
Day 16 
 
 
 
 
 
Day 17 
 
 
 
 
 
Day 18 
 
 
 
 
 
Day 19 
 
 
 
 
 
Day 20 
 
CEF:  ______________ 
 
 
 
Day 21 
 
CEF:  ______________ 
 
 
 
 
 
 


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APPENDIX XIV:  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. 
 
AZD1775 (MK-1775)   
 
Drugs that may interact with AZD1775 (relevant drugs listed by generic name) 
• 
Some antibiotics (chloramphenicol, ciprofloxacin, clarithromycin, erythromycin, 
norfloxacin, rifabutin, rifampin, telithromycin) 
• 
Some antidepressants (fluoxetine, fluvoxamine, nefazodone) 
• 
Some antiepileptics (carbamazepine, oxcarbazepine, phenobarbital, phenytoin) 
• 
Some antifungals (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole) 
• 
Some antiretrovirals and antivirals (boceprevir, delaviridine, efavirenz, indinavir, nelfinavir, 
nevirapine, ritonavir, saquinavir) 
• 
Several other specific agents, including the following: 
o Aprepitant 
o Amiodarone 
o Barbiturates  
o Cimetidine 
o Diltiazem 
o Imatinib 
o Mifepristone  
o Modafinil 
o Pioglitazone 
o Verapamil 
Food and supplements* that may interact with AZD1775 
• 
Echinacea 
• 
St. John’s Wort 
• 
Some fruits and juices: grapefruit, grapefruit juice, Star fruit 
*Supplements may come in many forms such as teas, drinks, juices, liquids, drops, capsules, pills, and dried 
herbs. All forms should be avoided.   
 
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 
Formatted: Highlight
Formatted: Highlight
Formatted: Highlight
Formatted: Highlight
Formatted: Highlight


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Drugs that may interact with irinotecan 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
o Citalopram, clozapine, desipramine, nefazodone, sertraline 
• Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Anti-rejection medications 
o Cyclosporine, tacrolimus 
• Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, 
tipranavir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, dronedenarone, diltiazem, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Bosentan, sitaxentan, aprepitant, dexamethasone, ivacaftor, lomitapide, mifepristone, 
natalizumab, succinylcholine 
 
Food and supplements* that may interact with irinotecan 
• 
Echinacea 
• 
St. John’s Wort 
• 
Some fruits and juices: grapefruit, grapefruit juice, Star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.   
 
 
 


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


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APPENDIX XVI: CTEP AND CTSU REGISTRATION PROCEDURES  
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require 
all investigators participating in any NCI-sponsored clinical trial to register and to renew their 
registration annually. 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).  
 
Requirements For APEC1621I 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 ) 
• 
IROC Credentialing Status Inquiry (CSI) Form  
NOTE: For 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.   
 
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. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
 
 
Data Submission / Data Reporting 
 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to all 


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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) and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab 
Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum 
of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered 
as an NPIVR or IVR. Associates can hold read-only roles in Rave. If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on the 
DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on 
the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner of the 
iMedidata page. Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com.