Clinical trial NCT01922076
Conditions: Anaplastic Astrocytoma Anaplastic Oligoastrocytoma Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant Glioblastoma Gliosarcoma
Sponsor: National Cancer Institute (NCI)
Start date: 2013-09-03; Completion date: 2022-09-30
Enrollment: 46 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I trial studies the side effects and the best dose of adavosertib when given together with local radiation therapy in treating children with newly diagnosed diffuse intrinsic pontine gliomas. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays, gamma rays, neutrons, protons, or other sources to kill tumor cells and shrink tumors. Giving adavosertib with local radiation therapy may work better than local radiation therapy alone in treating diffuse intrinsic pontine gliomas.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) or recommended phase 2 dose and schedule of the adavosertib (Wee1 inhibitor AZD1775 \[MK-1775\]) administered concurrently with radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

II. To define and describe the toxicities of AZD1775 (MK-1775) given concurrently with radiation therapy in children with newly diagnosed DIPG.

III. To characterize the pharmacokinetics of AZD1775 (MK-1775) in children with newly diagnosed DIPG when given concurrently with radiation therapy.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of AZD1775 (MK-1775) within the confines of a phase 1 study, including response rate, progression free survival, and overall survival of treated patients.

II. To assess the biologic activity of AZD1775 (MK-1775) by measuring expression of phosphorylated-cell division cycle 2 G1 to S and G2 to M (p-CDC2) (cyclin-dependent kinase 1 \[CDK1\]) and phosphorylated-histone H3 (p-HH3) in peripheral blood mononuclear cells (PBMCs) before and after administration of AZD1775 (MK-1775) in children with newly diagnosed DIPG.

III. To assess the biologic activity of AZD1775 (MK-1775) by measuring expression of gamma-H2A histone family, member X (H2AX) in PBMCs, a marker of deoxyribonucleic acid (DNA) double-strand breaks (dsDNA), before and after administration of AZD1775 (MK-1775) in children with newly diagnosed DIPG.

OUTLINE: This is a dose-escalation study of adavosertib.

Patients undergo radiation therapy 5 days a week for 6 weeks (up to 30 fractions). Patients also receive adavosertib orally (PO) on days 1-5 of weeks 1, 3, and 5; days 1-5 of weeks 1, 3, and 5 AND days 1, 3, and 5 of weeks 2, 4, and 6; OR days 1-5 of weeks 1-6 depending on dose level assignment. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 2 months for 6 months, and then every 3 months thereafter.

Arms: arm 1: Patients undergo radiation therapy 5 days a week for 6 weeks (up to 30 fractions). Patients also receive adavosertib PO on days 1-5 of weeks 1, 3, and 5; days 1-5 of weeks 1, 3, and 5 AND days 1, 3, and 5 of weeks 2, 4, and 6; OR days 1-5 of weeks 1-6 depending on dose level assignment. Treatment continues in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Adavosertib intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study intervention 4: Radiation Therapy
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies intervention 4: Undergo radiation therapy

Protocol documents:
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. 
Adam
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version Date: 01/31/19 
 
i 
 
January 31, 2019 
 
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 #8 to ADVL1217, A Phase 1 Study of AZD1775 
(MK-1775) Concurrent with Local Radiation Therapy for the Treatment of Newly 
Diagnosed Children with Diffuse Intrinsic Pontine Gliomas.  
 
The protocol has been amended in response to the Request for Amendment from 
Dr. Malcolm Smith, dated December 20, 2018, in which COGC transitions to PEP-
CTN.  
 
Please contact us if you have any further questions. 
 
 
Sincerely, 
 
Alina Stout, Protocol Coordinator for 
Sabine Mueller, M.D., Ph.D., ADVL1217 Study Chair, and 
Brenda Weigel, M.D., PI, PEP-CTN 
 
 


                             
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SUMMARY OF CHANGES 
 
The following specific revisions have been made to the protocol and informed consent documents:  
 
I. 
Protocol Changes: 
# 
Section 
Comments 
1. 
Title Page 
The version date has been updated. 
 
 
The amendment number has been updated.  
 
The “Lead Organization” has been updated.  
 
The list of “Participating Organizations” has been removed.  
 
The following sentence has been revised:  
“For PEP-CTN Operations and Data/Statistics Contacts See: 
http://members.childrensoncologygroup.org For Group Operations and Statistics 
& Data Center Contacts See: http://members.childrensoncologygroup.org” 
2.  
TOC 
The Table of Contents has been updated. 
3. 
Study 
Committee 
The following sentence has been revised:  
 
"For Group Operations (GOC) andPEP-CTN Operations and Data/Statistics 
Statistics & Data Center (SDC) cContacts see: …”  
4. 
Certificate of 
Confidentiality 
The following sentence has been revised:  
“The Children’s Oncology Group has receivedhis trial is covered by a Certificate of 
Confidentiality…” 
5. 
13.3 
The 
CTEP-AERS 
sponsor 
email 
address 
has 
been 
updated 
from 
“COGCADEERS@childrensoncologygroup.org” 
to 
“PEPCTNAERS@childrensoncologygroup.org”. 
6.  
14.4 
References to “Developmental Therapeutics” have been replaced with references to 
“PEP-CTN”.  
 
 
II. 
Informed Consent Document Changes:  
# 
Section 
Comments 
7. 
General 
The version date has been updated.  
8. 
1st page  
References to the “Phase 1 Consortium” have been replaced with references to PEP-
CTN.  
9. 
“Will 
my 
medical 
The following sentence has been revised:  
 


                             
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information…
?” 
“The Children’s Oncology Group has receivedhis trial is covered by a Certificate of 
Confidentiality…” 
 
 


                             
ADVL1217 
                                     
 
Version Date: 01/31/19 
 
1 
 
Activated: 
August 19, 2013 
Version Date: 
01/31/19 
Closed: 
 
Amendment #: 
8 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
ADVL1217 
 
A PHASE 1 STUDY OF AZD1775 (MK-1775) CONCURRENT WITH LOCAL RADIATION 
THERAPY FOR THE TREATMENT OF NEWLY DIAGNOSED CHILDREN WITH 
DIFFUSE INTRINSIC PONTINE GLIOMAS 
 
Lead Organization: COG Pediatric Early Phase Clinical Trials Network (PEP-CTN) 
 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR 
USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS 
PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY 
PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH 
HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR 
HEALTHCARE INSTITUTION. 
 
STUDY CHAIR 
Sabine Mueller, MD, PhD 
UCSF Medical Center-Mission Bay 
Pediatric Hematology/Oncology, Box 0434 
550 16th Street, 4th Floor 
San Francisco, CA 94518 
Phone: (415) 476-3831 
Fax: 
(415) 353-2657 
E-mail: sabine.mueller@ucsf.edu 
 
 
For PEP-CTN Operations and Data/Statistics Contacts See: http://members.childrensoncologygroup 


                             
ADVL1217 
                                     
  
 
Version Date: 01/31/19 
 
2 
 
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 
8 
2.2 
Preclinical Studies 
10 
2.3 
Adult Studies 
15 
2.4 
Pediatric Studies 
17 
2.5 
Overview of Proposed Pediatric Study 
17 
2.6 
Amendment #4B Regarding Escalation of AZD1775 Dosing (2016) 
18 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
18 
3.1 
Current Study Status 
18 
3.2 
IRB Approval 
19 
3.3 
Patient Registration 
19 
3.4 
Reservation and Contact Requirements 
19 
3.5 
Informed Consent/Assent 
19 
3.6 
Screening Procedures 
20 
3.7 
Eligibility Checklist 
20 
3.8 
Institutional Pathology Report 
20 
3.9 
Study Enrollment 
20 
3.10 
Dose Assignment 
20 
4.0 
PATIENT ELIGIBILITY 
21 
4.1 
Inclusion Criteria 
21 
4.2 
Exclusion Criteria 
23 
5.0 
TREATMENT PROGRAM 
24 
5.1 
Overview of Treatment Plan 
24 
5.2 
Criteria for Starting Subsequent Cycles 
25 
5.3 
Dose Escalation Schema 
25 
5.4 
Grading of Adverse Events 
27 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
27 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
28 
6.1 
Dose Modifications for Hematological Toxicity During Radiation Therapy 
28 
6.2 
Dose Modifications for Non-Hematological Toxicity During Radiation Therapy 
28 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
29 
7.1 
Concurrent Anticancer Therapy 
29 
7.2 
Investigational Agents 
29 
7.3 
Supportive Care 
29 
7.4 
Growth Factors 
30 


                             
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7.5 
Concomitant Medications 
30 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
30 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
30 
8.2 
Required Observations Following Completion of Radiation Therapy 
31 
8.3 
Radiology Studies 
31 
8.4 
Pharmacology (Required) 
32 
8.5 
Pharmacodynamics (Required) 
33 
9.0 
AGENT INFORMATION 
35 
9.1 
AZD1775 (MK-1775) 
35 
9.2 
Agent Ordering and Agent Accountability 
38 
9.3 
Clinical Drug Request 
39 
9.4 
Agent Inventory Records 
39 
9.5 
Investigator Brochure Availability 
39 
9.6 
Useful Links and Contacts 
39 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
 
40 
10.1 
Criteria for Removal from Protocol Therapy 
40 
10.2 
Off Study Criteria 
40 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
41 
11.1 
Sample Size and Study Duration 
41 
11.2 
Definitions 
41 
11.3 
Dose Escalation and Determination of MTD 
41 
11.4 
Inclusion of Children, Women and Minorities 
43 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
43 
12.0 
EVALUATION CRITERIA 
43 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
43 
12.2 
Methodology to Determine Tumor Measurement 
44 
12.3 
Selection of Target and Non-Target Lesions 
45 
12.4 
Response Criteria for Target Lesions 
45 
12.5 
Overall Response Assessment 
46 
12.6 
Best Response 
46 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
47 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
47 
13.2 
When to Report an Event in an Expedited Manner 
49 
13.3 
Expedited Reporting Methods 
50 
13.4 
Definition of Onset and Resolution of Adverse Events 
50 
13.5 
Other Recipients of Adverse Event Reports 
51 
13.6 
Reporting Secondary AML/MDS 
51 
13.7 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
51 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
53 
14.1 
Categories of Research Records 
53 
14.2 
CDUS 
53 
14.3 
CRADA/CTA/CSA 
53 
14.4 
Data and Safety Monitoring Plan 
55 
15.0 
RADIATION THERAPY GUIDELINES 
56 


                             
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4 
 
15.1 
Indications for Radiation Therapy 
57 
15.2 
Timing 
57 
15.3 
Emergency Irradiation 
57 
15.4 
Equipment and Methods of Delivery and Verification 
57 
15.5 
Target Volumes 
58 
15.6 
Target Dose 
59 
15.7 
Treatment Technique 
60 
15.8 
Organs at Risk 
61 
15.9 
Dose Calculations and Reporting 
62 
15.10 
Quality Assurance Documentation 
62 
15.11 
Definitions of Deviations in Protocol Performance 
64 
REFERENCES 
 
65 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
67 
APPENDIX II:  UNACCEPTABLE ENZYME INDUCING AND RECOMMENDED NON-ENZYME 
INDUCING ANTICONVULSANTS 
68 
APPENDIX III:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
ERROR! BOOKMARK 
NOT DEFINED. 
APPENDIX IV:  PATIENT DIARY: RADIATION PHASE 
69 
APPENDIX V-A:  AZD1775 (MK-1775) DOSING NOMOGRAM 
71 
APPENDIX V-B:  GUIDELINES FOR AZD1775 (MK-1775) DOSING SCHEDULE 
75 
APPENDIX VI:  CORRELATIVE STUDIES GUIDE 
84 
APPENDIX VII:  PHARMACOKINETIC STUDY FORM 
85 
APPENDIX VIII:  PHARMACODYNAMIC STUDY FORM 
86 
APPENDIX IX:  PD SAMPLE COLLECTION GUIDELINES 
87 
APPENDIX X: TOXICITY SPECIFIC GRADING 
88 
APPENDIX XI: PREPARATION OF PLASMA SAMPLES FOR AZD1775 (MK-1775) PK 
ASSESSMENT  
89 
APPENDIX XII:  POTENTIAL DRUG INTERACTIONS WITH AZD1775 (MK-1775) 
90 
APPENDIX XIII: MEDICATIONS ASSOCIATED WITH PROLONGED QTC ERROR! BOOKMARK 
NOT DEFINED. 
APPENDIX XIV:  INSTRUCTIONS FOR TREATING DIARRHEA 
91 
APPENDIX XV: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
93 
APPENDIX XVI: EXAMPLES OF CLINCAL SUBSTRATE TRANSPORTERS AND INHIBITORS 
 
ERROR! BOOKMARK NOT DEFINED. 
 
 


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STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS  
Sabine Mueller, MD, PhD 
Brenda J. Weigel, MD 
UCSF Medical Center-Mission Bay 
Chair, Developmental Therapeutics  
Pediatric Hematology/Oncology, Box 0434 
Hematology/Oncology 
550 16th Street, 4th Floor 
University of Minnesota Medical Center - Fairview 
San Francisco, CA 94518 
Department of Pediatrics 
Phone: (415) 476-3831 
420 Delaware Street, SE  MMC 366 
Fax: (415) 353-2657 
Minneapolis, MN 55455 
E-mail: sabine.mueller@ucsf.edu  
Phone:   (612) 626-5501 
 
Fax:  
 (612) 624-3913 
STUDY VICE CHAIR, RADIATION ONCOLOGIST 
E-mail: weige007@umn.edu 
Daphne Haas-Kogan, MD 
 
Dana-Farber/Harvard Cancer Center 
Brigham and Women’s Hospital 
Elizabeth Fox, MD 
Boston Children’s Hospital  
Vice Chair, Developmental Therapeutics 
Radiation Oncology  
Children’s Hospital of Philadelphia 
450 Brookline Ave 
Pediatrics/Division of Oncology 
D1622 
3501 Civic Center Blvd. 
Boston, MA 02215 
CTRB-4016 
Phone: (617) 632-2291 
Philadelphia, PA 19104 
Fax: 
(617) 632-2290 
Phone:   (267) 425-3010  
E-mail: dhaas-kogan@lroc.harvard.edu 
Fax:  
 (267) 425-0113  
 
Email: foxe@email.chop.edu  
RADIATION ONCOLOGIST 
 
Ralph Ermoian, MD 
Amar Gajjar, MD 
Seattle Children’s Hospital 
Hematology/Oncology 
UWMC Radiation Oncology 
St. Jude Children's Research Hospital Memphis 
1959 NE Pacific Street 
Hematology/Oncology 
Box 356043 
262 Danny Thomas Place 
Seattle, WA 98195-6043 
MS 260 
Phone: (206) 598-4100 
Memphis, TN 38105-3678 
Fax: (206) 598-3786 
Phone: (901) 595-2615 
E-mail: ralphpe@uw.edu  
Fax: 
(901) 521-9005 
 
E-mail: amar.gajjar@stjude.org  
SENIOR STATISTICIAN  
 
Charles Minard, PhD 
STUDY PHARMACOLOGIST 
Baylor College of Medicine  
Joel M. Reid, PhD 
One Baylor Plaza, BCM 122 
Mayo Clinic 
Houston, TX 77030 
Guggenheim 17-42C 
Phone:   (713) 798-2353 
200 First St SW 
Fax:  
 (713) 798-2816 
Rochester, MN 55905 
E-mail: minard@bcm.edu 
Phone:  (507) 284-0822 
 
Fax: 
(507) 284-3906 
STATISTICIAN  
E-mail: reid.joel@mayo.edu  
Xiaowei Liu, MS 
 
Children's Oncology Group - Operations Center 
 
222 E. Huntington Drive, Suite 100 
 
Monrovia, CA  91016 
 
Phone: (626) 241-1535 
 
Fax: 
(626) 445-4334 
 


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E-mail: xwliu@childrensoncologygroup.org 
 
 
 
STUDY PHARMACIST 
 
Olga Militano, PharmD 
STUDY NURSE 
Pharmacy 
Elizabeth Gilger, MSN 
Children's Oncology Group - Operations Center 
Cincinnati Children’s Hospital Medical Center 
222 E. Huntington Drive, Suite 100 
Oncology Program 
Monrovia, CA  91016 
MLC 11013 
Phone: (626) 241-1517 
3333 Burnet Avenue 
E-mail: omilitano@childrensoncologygroup.org 
Cincinnati, OH 45229 
 
Phone: (513) 636-4266 
 
Fax: 
(513) 636-9653 
PROTOCOL COORDINATOR 
E-mail: elizabeth.gilger@cchmc.org   
Alina Stout, BS 
 
Children’s Oncology Group – Operations Center 
 
222 E. Huntington Drive, Suite 100 
 
Monrovia, CA  91016 
 
Phone: (626) 241-1566 
For PEP-CTN Operations and Data/Statistics 
Fax: 
(626) 445-4334 
Contacts see: 
E-mail: astout@childrensoncologygroup.org  
http:members.childrensoncologygroup.org  
 
 
 
AGENT NSC#  
 
 
 
NCI-Supplied Agent: 
AZD1775 (MK-1775) (NSC # 751084) 
 
 
 
SEE SECTION 8.4.6 AND 8.5.5 FOR SPECIMEN SHIPPING ADDRESSES 
 


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This trial is covered by a Certificate of Confidentiality from the federal government, which will 
help us protect the privacy of our research subjects.  The Certificate protects against the involuntary 
release of information about subjects collected during the course of our covered studies.  The 
researchers involved in the studies cannot be forced to disclose the identity or any information 
collected in the study in any legal proceedings at the federal, state, or local level, regardless of 
whether they are criminal, administrative, or legislative proceedings.  However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain 
circumstances.  For example, if the subject or his/her guardian requests the release of information 
in writing, the Certificate does not protect against that voluntary disclosure.  Furthermore, federal 
agencies may review our records under limited circumstances, such as a DHHS request for 
information for an audit or program evaluation or an FDA request under the Food, Drug and 
Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers 
of information on suspected child abuse, reportable communicable diseases, and/or possible threat 
of harm to self or others. 
 
ABSTRACT 
AZD1775 (formerly MK-1775) is an oral selective Wee1 kinase inhibitor. Wee1 kinase is a critical 
driver of G2-M cell cycle progression.  Activated Wee1 phosphorylates CDC2, inhibiting its 
function. In normal cells, increasing levels of inactivated, phosphorylated CDC2 prevents damaged 
cells from entering into mitosis before DNA is repaired.  Like normal cells, most cancer cells rely 
on this pathway to delay cell cycle progression and allow repair of DNA damage caused by rapid 
cell division or DNA-damaging agents. Without a proficient G2 checkpoint, cancer cells progress 
through the cell cycle with damaged DNA and ultimately succumb to fatal mitosis. Wee1 is highly 
expressed in pediatric high-grade gliomas, including diffuse intrinsic pontine gliomas (DIPG) and 
in vitro and in vivo studies have shown that the combination of Wee1 inhibitor AZD1775 (MK-
1775) radiosensitizes pediatric glioma cells.  
 
This is a dose escalation study of AZD1775 (MK-1775) in combination with radiation for newly 
diagnosed children with DIPG. We will evaluate the MTD and toxicity profile of AZD1775 (MK-
1775) in combination with a standard radiation therapy regimen used in the treatment of this 
disease. Pharmacokinetic and pharmacodynamics studies will be conducted to further define the 
exposure to and activity of AZD1775 (MK-1775) in combination with radiation in pediatric 
patients. 
 
 
EXPERIMENTAL DESIGN SCHEMA 
AZD1775 (MK-1775) will be administered orally after a predetermined number of radiation 
therapy fractions given on a Monday through Friday schedule for a total of 30 fractions over 6 
weeks.  The number or fractions followed by AZD1775 (MK-1775) will depend upon assigned 
dose level.   
 
Treatment 
Monday through Friday  
Saturday and Sunday 
Radiation therapy  
X 
 
AZD1775 (MK-1775) 
X^ 
 
Rest Period 
 
X 
^Frequency of AZD1775 (MK-1775) will vary depending on dose level. See Section 5.1 and Appendix V for 
specific dosing. 
 


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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
 
To estimate the maximum tolerated dose (MTD) or recommended phase 2 
dose and schedule of the Wee1 inhibitor AZD1775 (MK-1775) 
administered concurrently with radiation therapy in children with newly 
diagnosed diffuse intrinsic pontine glioma (DIPG). 
 
 
To define and describe the toxicities of AZD1775 (MK-1775) given 
concurrently with radiation therapy in children with newly diagnosed 
DIPG. 
 
 
To characterize the pharmacokinetics of AZD1775 (MK-1775) in children 
with newly diagnosed DIPG when given concurrently with radiation 
therapy. 
 
1.2 
Secondary Aims 
 
 
To preliminarily define the antitumor activity of AZD1775 (MK-1775) 
within the confines of a phase 1 study, including response rate, progression 
free survival, and overall survival of treated patients. 
 
 
To assess the biologic activity of AZD1775 (MK-1775) by measuring 
expression of p-CDC2 and p-HH3 in peripheral blood mononuclear cells 
(PBMCs) before and after administration of AZD1775 (MK-1775) in 
children with newly diagnosed DIPG. 
 
 
To assess the biologic activity of AZD1775 (MK-1775) by measuring 
expression of -H2AX in PBMCs, a marker of DNA double-strand breaks 
(dsDNA), before and after administration of AZD1775 (MK-1775) in 
children with newly diagnosed DIPG. 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
Pre-clinical studies provide the rationale for targeting Wee1 in combination with 
radiation for the treatment of children with DIPG. Wee1 is significantly over-
expressed in pediatric high-grade gliomas as well as DIPGs and the Wee1 inhibitor 
AZD1775 radiosensitizes a variety of cancer cells including pediatric high-grade 
gliomas. Therefore, we propose a phase 1 study of AZD1775 administered 
concurrently with focal radiation therapy. We know from prior experience that 
focal radiation therapy for children with DIPG is generally well tolerated and that 
radiation therapy by itself has no significant hematological toxicity. Other 
expected side effects from treatment with AZD1775, based on adult phase 1 
studies, include gastrointestinal related toxicity as well as constitutional symptoms 
such as fatigue.  
 
Diffuse Intrinsic Pontine Gliomas in Children: 


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The diagnosis of DIPG continues to carry a dismal prognosis with virtually no 
long-term survivors.1 Despite several lines of research, outcomes for these 
children have not significantly changed over many decades and most children 
die after a median survival of 9 months even when treated on recently conducted 
clinical trials. DIPGs continue to be diagnosed mainly by radiographic 
appearance. In children who undergo biopsies the most common histological 
diagnoses are high-grade gliomas.1 Radiation therapy is the only proven 
effective therapy in prolonging life for children with DIPGs. Therefore, 
demonstrating synergy of targeted agents with radiation is a key step towards 
producing novel drugs with potential to impact survival.  
 
Radiation causes DNA damage that activates a cascade of signaling events 
leading to cell cycle arrest that allows DNA repair, and should DNA damage fail 
to be repaired, cell death ensues. Disruption of normal cell-cycle check-points 
due to p53 mutation is common in cancer cells including pediatric HGGs as well 
as in DIPGs.2,3 Whereas normal cells with wild-type (wt) p53 have both the G1 
and G2 checkpoints at their disposal to protect against DNA damage, cancer cells 
with p53 mutations have a greater dependency on the G2 checkpoint to initiate 
repair mechanisms in order to prevent entry into fatal mitosis.4 Therefore, 
targeting the remaining G2 checkpoint in tumors may increase tumor specific 
toxicity of DNA-damaging therapies such as radiation.  
 
Cell cycle control 
 
Figure 1:  Schematic Overview of selective kinases, phosphatases 
and inhibitors involved in the G2 arrest. DNA damage activates cell 
cycle checkpoints to arrest cells in G1 or G2.  G2 checkpoint prevents 
inappropriate mitosis of unrepaired DNA.  Entry into mitosis requires 
the association of cyclin B with Cdc2 (also called CDK1). p21 is a 
universal CDK inhibitor with ability to bind to G1 and G2 cyclin CDK 
complexes supporting a role of p53 in G1 and G2 arrest.  In p53 proficient 
cells, p21 leads to G2 arrest independent of WEE1 that cannot be 
abrogated by AZD1775. 
 
Key signaling cascades involved in cell cycle arrest and DNA repair are the ataxia-


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telangiectasia 
(ATM)-Chk2, 
Rad3-related 
protein 
 
(ATR)/Chk1, 
and 
p38MAPK/MAPKAP KINASE 2 (MK2) stress kinase pathways.5 The ATR/Chk1 
pathway is activated by bulky DNA lesions whereas the ATM/Chk2 pathway 
responds to DNA double strand breaks. The p38MAPK/MK2 pathway is activated 
by several cellular stressors including radiation and chemotherapy.  The 
p38MAPK/MK2 pathway seems to play an important role in p53 deficient cells to 
maintain adequate checkpoint signaling.5,6 All three of these DNA repair cascades, 
ATM, ATR and p38MAPK/MK2, converge on Cdc25, a positive regulator of cell 
cycle progression. Cdc25 is inhibited by phosphorylation by either Chk1 or Chk2. 
Wee1, a critical regulator of this cascade, plays a key role in cell cycle progression, 
as discussed below.  
 
Role of Wee1 in Cell Cycle Control 
Wee1 kinase is a critical driver of G2-M cell cycle progression.  In response to 
DNA damage, several mediators, including ATM and ATR, activate Chk1 through 
specific phosphorylation events.  Chk1 activates Wee1 through phosphorylation of 
the Y15 residue and inactivates the inhibitory effects of Wee1 on Cdc25 
phosphatases. Cdc25 phosphatases remove inhibitory phosphate groups from 
cyclin dependent kinases (Cdk), and Wee1 kinase promoting cell cycle 
progression. Once activated, Wee1 is stabilized by the 14-3-3 complex.7-9 
Activated Wee1 phosphorylates CDC2, inhibiting its function (see Figure 1). In 
normal cells, increasing levels of inactivated, phosphorylated CDC2 prevent 
damaged cells from entering into mitosis before DNA is repaired.  Like normal 
cells, most cancer cells rely on this pathway to delay cell cycle progression and 
allow repair of DNA damage caused by rapid cell division (through growth factor 
activation) or DNA-damaging agents. Without a proficient G2 checkpoint cancer 
cells progress through the cell cycle with damaged DNA and ultimately succumb 
to fatal mitosis. 
 
2.2 
Preclinical Studies 
 
 
Antitumor Activity 
AZD1775 is a specific, ATP competitive and highly selective inhibitor 
of the Wee1 kinase (IC50 = 5.18 nM). AZD;-1775 was first described in 
2009 by Hirai et al. as a selective and potent Wee1 inhibitor. The initial 
studies showed that AZD1775 (MK-1775) inhibits the phosphorylation 
of CDC2 on Tyr15 at nanomolar concentrations compared to the 
inhibitory activities against a panel of 223 tested kinases. Furthermore, 
these 
studies 
showed 
that 
AZD1775 
(MK-1775) 
abrogates 
chemotherapy (cisplatin, gemcitabine, carboplatin) induced G2 arrest in 
p53 deficient cell lines.10 Since the initial publication, several preclinical 
studies have successfully tested AZD1775 (MK-1775) in combination 
with conventional chemotherapy or radiation in a variety of cancer 
models as outlined below.  
 
Effects of Wee1 kinase inhibition in combination with conventional 
chemotherapy 
Wee1 inhibition acts synergistically with conventional chemotherapy.11-
13 In vitro studies reveal that the Wee1 inhibitor AZD1775 (MK-1775) 
increases 
cytotoxic 
effects 
of 
conventional 
DNA 
damaging 
chemotherapy agents such as gemcitabine, carboplatin, cisplatin and 5-


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fluorouracil in a variety of cancer types including colorectal, non-small-
cell-lung, and pancreatic cancers in vitro and in vivo.10,11,13 The central 
mechanism by which Wee1 inhibition increases cytotoxicity is 
abrogation of the chemotherapy induced G2/M arrest, which in turn 
propels cells into premature mitosis. Interestingly, a recent study 
evaluating Wee 1 inhibition in combination with cytarabine for the 
treatment of acute myeloid anemia (AML)14 used a genome wide short-
hairpin RNA screen to demonstrate that Wee1 is a critical mediator of 
AML cell survival after cytarabine exposure. In these preclinical studies 
inhibition of CDC2 phosphorylation (Y15) and induction of histone H3 
phosphorylation (p-HH3) were observed upon treatment with AZD1775 
(MK-1775).14  
 
Effects of Wee1 kinase inhibition in combination with radiation  
Inhibition of Wee1 in combination with radiation reduces tumor growth 
in orthotopic models of adult glioblastoma (GBM) and propels cells into 
premature mitosis.15 Treatment with AZD1775 (MK-1775) in 
combination with radiation also delays tumor growth in human lung 
cancer Calu-6 xenografts.16 Although all groups describe similar 
radiosensitizing functions of Wee1 inhibition, conflicting results have 
been reported regarding the p53-dependence of such radiosensitization. 
Specifically, Drs. Mueller and Haas-Kogan at UCSF and others15 have 
found that the radiosensitization effects of Wee1 inhibition are 
independent of p53 status whereas others have reported that Wee1 
inhibition is only effective in p53 deficient cells.10,16,17 This controversy 
notwithstanding, Mir et al. demonstrated that the radiosensitizing effects 
of Wee1 inhibition are dependent on Wee1 expression levels and not on 
p53 status.15 Thus, two rationales exist for selective cytotoxicity of 
AZD1775 (MK-1775) against cancer cells compared to normal cells: 
p53 mutations and elevated Wee1 expression levels, both particularly 
relevant to pediatric gliomas (as described below). 
 
The role of Wee1 in human brain tumors 
Limited data are available describing the role of Wee1 in brain tumors. 
Wee1 kinase is overexpressed in adult GBMs and higher levels of 
overexpression correlate with worse clinical outcome. Using orthotopic 
models of adult GBMs, Mir et al. demonstrated that combining radiation 
therapy with Wee1 inhibition, using either small interference RNA or a 
small molecule inhibitor (PD0166285) improved survival in U251 and 
E98-FM orthotopic in vivo models of adult GBM.15 We have extended 
these preclinical studies to establish a role for Wee1 inhibition in the 
treatment of pediatric HGGs. The preclinical evidence for using AZD1775 
(MK-1775) in combination with radiation for pediatric gliomas has been 
generated by Drs. Mueller and Haas-Kogan at UCSF as detailed below and 
presented at the Annual Meeting of the Society of Neuro-Oncology 
2011.18 Further support of combining AZD1775 (MK-1775) in 
combination with radiation therapy for children with DIPG is presented in 
Caretti et al. 19 
 
Based on published results in adult HGGs, Drs. Mueller and Haas-Kogan 
assessed expression profiles of Wee1 in a cohort of pediatric gliomas. In 


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collaboration with Drs. Gupta and Smirnov (Department of Neurosurgery, 
UCSF) this group performed expression analyses with the Agilent 4x44k 
human array platform on all grade pediatric gliomas as well as on normal 
brain samples as controls. As shown in Figure 2, Wee1 is over-expressed 
in pediatric gliomas of all grades, with grade 4 tumors displaying highest 
expression levels. Of particular interest, this analysis included a pediatric 
DIPG primary cell line [modified with the human telomerase reverse 
transcriptase (htert)] that demonstrated the highest Wee1 expression 
levels. Statistical analyses showed that Wee1 was significantly over-
expressed in HGGs (grades 3+4) compared to low-grade gliomas (grades 
1+2) (p=0.007). Wee1 expression has also been evaluated in a published 
gene expression dataset (27 DIPGs, 6 low-grade gliomas and 2 normal 
brain specimens) by Dr. Blaney. As shown in Figure 3, Wee1 is 
significantly up-regulated in DIPGs compared to low-grade gliomas 
(LGG) and normal brain (two sided t-test p=0.005) reinforcing Wee1 as a 
promising target for the treatment of DIPGs. In another independent cohort 
of pediatric gliomas using a gene expression dataset published by Paugh 
et al.,20 Wee1 was expressed 4-fold higher in HGGs (including AA and 
GBM) compared to anaplastic oligo-astrocytomas (p=0.01).  
 
Gene Expression Analysis of Wee1 in a panel of pediatric gliomas 
              
 
Figure 2:  Expression analysis of Wee1 in pediatric gliomas 
based on grade; Y-scale is a log2 transformation of expression 
measure and each unit corresponds to a 2-fold change in 
expression. DIPG-t: DIPG derived primary cell line, h-tert 
modified. 
          
Gene Expression Analysis of Wee1 in a panel of pediatric DIPGS 


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Figure 3:  Expression analysis of Wee1 in DIPGs, low-grade 
gliomas (LGG) and normal brain.  Y-scale is a log2 
transformation of expression measure and each unit 
corresponds to a 2-fold change in expression 
 
Immunohistochemical analyses of Wee1 on a panel of pediatric gliomas 
of all grades (n= 43) confirmed up-regulation of Wee1 protein. Figure 4 
shows representative immunohistochemistry (IHC) stained samples. 
Similar to results found based on mRNA expression, Wee1 expression on 
the protein level is higher in high-grade versus low-grade pediatric 
gliomas. 
 
Expression of Wee1 protein in a panel of pediatric high-grade gliomas 
based on immunohistochemistry analysis 
             
 
Figure 4:  Immunohistochemical analysis of Wee1 
expression in a panel of pediatric gliomas.  IHC Score: 1 = 
<10%; 2= 10-15%; 3 = 25-75%; 4= >75% of total cells stained 
positive for Wee1 expression. 
Preclinical experience of AZD1775 (MK-1775) in combination with 
radiation therapy in models of pediatric high-grade gliomas  
In in vitro clonogenic survival assays, AZD1775 (MK-1775) exhibits 
dose-dependent anti-proliferative effects in multiple pediatric and adult 
high-grade glioma cell lines including a pediatric DIPG derived cell line 
(SF8628) and this effect is enhanced by radiation (Figure 5).  
 


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Figure 5:  Clonogenic survival of several pediatric (SF7269, 
SF188, KNS-42, SF8628) and adult (U87, GBM36) high-
grade glioma cell lines. 
 
A newly established DIPG xenograft model allowed AZD1775 (MK-
1775) to be evaluated together with radiation in vivo. Tumor cells derived 
from a biopsy of a child with DIPG were directly injected into mice, 
propagated and subsequently modified with the luciferase gene to monitor 
in vivo tumor burden as previously described.21 When tumors were 
visualized by bioluminescence, mice were treated with AZD1775 (MK-
1775) alone (60 mg/kg twice daily for a total of 10 days), radiation alone 
(0.5 Gy x 3 fractions), or a combination thereof. Each treatment group 
contained 10 mice. As shown in Figure 6, combination of AZD1775 (MK-
1775) and radiation led to statistically significant prolonged survival 
compared to each treatment modality alone.   
 
Figure 6:  In vivo efficacy of AZD1775 (MK-1775) in 
combination with XRT in an orthotopic model of pediatric 
DIPG. Kaplan Meier estimator was used to generate survival 
curves and differences in survival were calculated using a log-
rank test. 
 
Based on the underlying mechanism of action the clinical development of 
AZD1775 (MK-1775) should focus on combination treatment strategies. 


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Accumulated evidence reveals AZD1775 (MK-1775) as a new therapeutic 
agent for the treatment of pediatric HGGs, specifically DIPGs, in 
combination with radiation therapy.  
 
 
Animal Toxicology 
.     
 
 
Preclinical Pharmacokinetic Studies 
 
 
2.3 
Adult Studies 
 
Phase 1 Studies 
AZD1775 (MK-1775) was evaluated in a first in human study as 
monotherapy as well as in combination with gemcitabine, cisplatin, or 
carboplatin in adult patients with advanced solid tumors (PN001). This 
study is ongoing as of February, 2013. In this study, the specified 
maximum dose of 1300 mg as single oral dose was well tolerated and no 
MTD has been established for monotherapy. The MTD for the single dose 
combination treatment with either gemcitabine (1000 mg/m2) or cisplatin 
(75 mg/m2) was 200 mg and for the combination of AZD1775 (MK-1775) 
with carboplatin  (AUC5) was 325 mg. In this PN001 trial AZD1775 (MK-
1775) was given 24 hours after gemcitabine or cisplatin. The MTDs for 
BID dosing x 5 doses of AZD1775 (MK-1775) with similar chemotherapy 
regimens were 200 mg with cisplatin and 225 mg with carboplatin. 
AZD1775 (MK-1775) in combination with gemcitabine is currently being 
evaluated on a QD x2 schedule. 
 
 
The completed or terminated early studies include: 
 
• 
PN001 (NCT00648648) (except for Part 3): a first-time-in-
patients (FTIP), Phase I, dose-escalation study evaluating 
AZD1775 both as monotherapy and combination therapy with 
gemcitabine, cisplatin, or carboplatin in adult patients with 
advanced solid tumors 
 
• 
PN004 (NCT01357161): a Phase II study evaluating AZD1775 
combined with carboplatin and Paclitaxel in patients with 
platinum-sensitive p53-mutant ovarian cancer 
 
• 
PN005 (NCT01047007):: a Phase I, dose-escalation study 
evaluating AZD1775 as monotherapy (Part 1), combination 
therapy with 5-FU (Part 2), and combination therapy with 5 FU 
plus cisplatin (Part 3) in adult Japanese patients with advanced 
solid tumors. 
 
• 
PN008 (NCT01076400): a Phase I/IIa, dose-escalation study evaluating 
AZD1775 in combination with topotecan plus cisplatin in adult patients 


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with cervical cancer  
• 
PN011: a Phase I study of single-agent AZD1775, in patients with 
refractory solid tumors, sponsored by the National Cancer 
Institute (NCI) Cancer Therapy Evaluation Program in 
collaboration with AstraZeneca and Merck. This study reported 
AZD1775 monotherapy activity in patients carrying BRCA 
mutations for the first time. 
 
• 
D6011C00001 (NCT02087176; SCRI LUN 262): a lead-in Phase 
II multicentre, randomized, double-blind study comparing 
AZD1775 plus docetaxel with placebo plus docetaxel in 
previously treated patients with non-small-cell lung cancer 
(NSCLC) 
 
• 
D6011C00002 (NCT02087241; SCRI LUN 261): a Phase II study 
of AZD1775 plus pemetrexed and carboplatin followed by a 
randomized comparison of pemetrexed and carboplatin with or 
without AZD1775 in patients with previously untreated stage IV 
non-squamous NSCLC 
 
Ongoing: 
 
• 
D6010C00004 (NCT02272790; SCRI GYN 49): a multicentre 
Phase II study of AZD1775 plus either Paclitaxel, gemcitabine, 
carboplatin, or pegylated liposomal doxorubicin in patients with 
platinum-resistant epithlial ovarian, fallopian tube, or primary 
peritoneal cancer 
 
• 
D6010C00005 (NCT02511795; SCRI REFMAL 384): a Phase I 
study evaluating AZD1775 in combination with olaparib in 
refractory solid tumors. 
 
• 
D6011C00003 (NCT02341456): a Phase Ib dose-finding study 
evaluating AZD1775 as monotherapy and in combination with 
carboplatin and Paclitaxel in adult Asian patients with advanced 
solid tumors 
 
• 
D6015C00001 (NCT02482311; SCRI REFMAL 383): a Phase I, 
dose escalation, safety and pharmacokinetic study of AZD1775 
monotherapy (Schedule 1) in patients with advanced or metastatic 
solid tumors 
 
• 
D6015C00002 (NCT02617277; SCRI REFMAL 412): a Phase I 
study assessing the safety, tolerability, and pharmacokinetics of 
AZD1775 in combination with MEDI4736 in patients with 
advanced solid tumors 
 
• 
D6015C00003 (NCT02610075; SCRI REFMAL 398): a Phase Ib 
study to determine the maximum-tolerated dose (MTD) of 


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AZD1775 monotherapy (Schedule 2) in patients with locally 
advanced or metastatic solid tumors. 
 
To date, AZD1775 (MK-1775) has not been tested in combination with 
radiation therapy in children. An ongoing study in adults patients with 
glioblastoma is testing the safety and early efficacy of the combination of 
AZD1775, temozolomide and radiation therapy followed by a 
maintenance phase of temzolomide and AZD1775 in newly diagnosed 
adult subjects with glioblastoma. 
  
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
 
Work by Drs. Mueller and Haas-Kogan have demonstrated that tumors 
from mice treated with AZD1775 (MK-1775) and radiation have increased 
expression of -H2AX, a marker of double strand DNA breaks, as well as 
pHH3 compared to single modality treatment. As expected, glioma cells 
treated with AZD1775 (MK-1775) showed dose dependent reduction in p-
CDC2 expression.  
 
2.4 
Pediatric Studies 
 
Prior Experience in Children  
The phase 1 study of AZD1775 in combination with irinotecan has found the 
combination is well tolerated in pediatric relapse or refractory solid tumor patients. 
The pediatric recommended phase 2 dose was defined as AZD1775 85 mg/m2/dose 
PO + IRIN 90 mg/m2/dose PO; Cefixime 8 mg/kg PO or Cefpodoxime 5 mg/kg 
PO BID. Phase 2 expansions in medulloblastoma and neuroblastoma are currently 
accruing. (ADVL1312 Fall 2016 study progress report) 
 
2.5 
Overview of Proposed Pediatric Study 
As outlined above, there are compelling pre-clinical studies that provide the 
rationale for targeting Wee1 in combination with radiation for the treatment of 
children with DIPG. Therefore, we propose a phase 1 study of AZD1775 (MK-
1775) administered concurrently with focal radiation therapy. We know from prior 
experience that focal radiation therapy for children with DIPG is generally well 
tolerated and that radiation therapy by itself has no significant hematological 
toxicity. In the current phase 1 study we plan to first increase the number of days 
children are treated with specific Wee1 inhibitor AZD1775 (MK-1775) 
concurrently with radiation and then dose escalate depending on how well 
AZD1775 (MK-1775) is tolerated (see the treatment plan in Section 5.1 for 
details). Due to the unknown pharmacokinetics of AZD1775 (MK-1775) after 
prolonged administration, the age requirement of the first patient enrolled will be 
≥ 7 years. After considering toxicity and results of PK analysis for this patient, we 
will open the study to children less than 7 years of age.  
 
Radiation therapy is given at the current standard dose of 5400 cGy in 30 fractions 
of 180 cGy Monday through Friday for a total of 30 fractions over 6 weeks. 
AZD1775 (MK-1775) will be administered according to the schedule in Section 
5.1 after radiation therapy. Dose escalation will occur as outlined in Section 5.2.1.  
The starting dose of AZD1775 (MK-1775) for this trial was based on 40% of the 


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adult MTD in the multi-dose schedule of AZD1775 (MK-1775) in combination 
with chemotherapy in adult patients with solid tumors.    
 
 
2.6 
Amendment #4B Regarding Escalation of AZD1775 Dosing (2016) 
As of April 2015, 26 patients have been treated on ADVL1217: 6 on Dose Level 
1, 6 on dose level 2, 7 on dose level 3 and 7 on dose level 4. To date, the medication 
has been very well tolerated with minimal side effects. None of the patients treated 
at dose levels 1-3 experienced dose-limiting toxicity. One patient treated at dose 
level 4 (AZD1775 95 mg/m2 daily Mon-Fri during Weeks 1-6) had a dose-limiting 
toxicity of grade 3 ALT increase. 
 
Since the inception of the trial new information about PD as well as additional 
safety data from an ongoing adult glioblastoma (GBM) trial has become available.  
PD data from ongoing adult studies demonstrate that a minimum of 200-225 mg 
PO BID is required to see compelling modulation of p-CDC2 as the downstream 
effector molecule of Wee1 kinase. Also, PK analysis from one pediatric patient 
enrolled in ADVL1217 supports that pediatric patients will have a similar PK 
profile of AZD1775 compared to the adult population; however, that needs to be 
viewed with caution given that we only have data available from one patient.  
 
Further, additional safety information is available from the ongoing adult 
glioblastoma trial. Patients enrolled in this trial receive AZD1775 during radiation 
therapy (on days of radiation therapy) concurrent with the adult standard of care 
temozolomide dose of 75 mg/m2. In addition AZD1775 is given as adjuvant 
therapy on day 1-5 concurrently with temozolomide at 200 mg/m2 (day 1-5) on a 
28-day cycle. This trial determined the MTD of AZD1775 in combination with 
temzolomide and radiation therapy to be 200 mg/day (~ 115 mg/m2) (during 
radiation therapy) and 425 mg/day (~ 245 mg/m2) (Level 5) for the adjuvant arm. 
 
Because toxicity in patients treated on ADVL1217 has been relatively modest to 
date, the dose of AZD1775 will now be escalated stepwise to the dose of 200 
mg/m2 /dose daily Mon-Fri during Weeks 1-6 (Dose Level 7). 
 
Recent results from a phase 0 study of AZD1775 in adult subjects with recurrent 
adult GBM demonstrate that AZD1775 crosses the blood brain barrier and 
therefore strengthens the use of this agent in children with DIPG.22 Tumors with 
such elevated replication stress are expected to be sensitive to AZD1775 based on 
the underlying mechanisms of action. We have investigated the expression of these 
checkpoint inhibitors in pediatric gliomas and have found that these are also 
upregulated in pediatric high-grade gliomas. 
 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
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 


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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 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling 
patients. Sites must submit IRB/REB approvals to the NCI’s Cancer Trials Support 
Unit (CTSU) Regulatory Office and allow 3 business days for processing. The 
submission must include a fax coversheet (or optional CTSU IRB Transmittal 
Sheet) and the IRB approval document(s). The CTSU IRB Certification Form may 
be submitted in lieu of the signed IRB approval letter.  All CTSU forms can be 
located on the CTSU web page (www.ctsu.org). Any other regulatory documents 
needed for access to the study enrollment screens will be listed for the study on the 
CTSU Member’s Website under the RSS Tab.   
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office, where they 
will be entered and tracked in the CTSU RSS. 
ONLINE: www.ctsu.org (members’ section)  Regulatory Submission Portal 
EMAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document submission 
only) 
FAX: 215-569-0206 
MAIL: CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
When a site has a pending patient enrollment within the next 24 hours, this is 
considered a “Time of Need” registration. For Time of Need registrations, in 
addition to marking your submissions as ‘URGENT’ and faxing the regulatory 
documents, call the CTSU Regulatory Helpdesk at: 1-866-651-CTSU. For general 
(non-regulatory) questions, call the CTSU General Helpdesk at: 1-888-823-5923. 
 
3.3 
Patient Registration 
Prior to enrollment on study, all patients must be assigned a COG patient ID 
number. This number is obtained via the COG Registry system once authorization 
for the release of protected health information (PHI) has been obtained. 
 
3.4 
Reservation and Contact Requirements 
Before enrolling a patient on study, a reservation must be made through the OPEN 
website and the Study Chair or Vice Chair should be notified. (The patient will 
need a COG patient ID number in order to obtain a reservation.) Patients must be 
enrolled within 7 calendar days of making a reservation.  
 
Reservations may be obtained 24-hours a day through the OPEN website. 
 
3.5 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative 


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therapies will be carefully explained to the patient or the patient’s parents or 
guardian if the patient is a child, and a signed informed consent and assent will be 
obtained according to institutional guidelines. 
 
3.6 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for 
this trial must only be done after obtaining written informed consent.  This can be 
accomplished through one of the following mechanisms: a) the COG screening 
protocol, b) an IRB-approved institutional screening protocol or c) the study-
specific protocol.  Documentation of the informed consent for screening will be 
maintained in the patient’s research chart. Studies or procedures that were 
performed for clinical indications (not exclusively to determine eligibility) may be 
used for baseline values even if the studies were done before informed consent was 
obtained. 
 
3.7 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must 
sign and date the completed eligibility checklist.  A signed copy of the checklist 
will be uploaded into RAVE immediately following enrollment. 
 
3.8 
Institutional Pathology Report 
Because DIPGs are often not biopsied, enrollment of patients with typical-
appearing DIPG (see Section 4.1.2) without an institutional pathology report is 
allowed.  For patients with brainstem tumors not considered typical DIPG as 
defined in Section 4.1.2, they will only be eligible if their tumors are biopsied and 
meet the eligibility criteria as defined in Section 4.1.2.  Immediately following 
enrollment, the institutional pathology report for the diagnosis under which the 
patient is being enrolled must be uploaded into RAVE. The report must include 
the associated study number and COG patient registration and accession numbers. 
Personal identifiers, including the patient’s name and initials must be removed 
from the institutional pathology report prior to submission. 
 
3.9 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study 
have been met. Patients who give informed consent for the protocol in order to 
undergo screening for eligibility are not considered enrolled and should not be 
enrolled until the screening is completed and they are determined to meet all 
eligibility criteria. Study enrollment is accomplished by going to the CTSU OPEN 
(Oncology Patient Enrollment Network) https://open.ctsu.org/open/. For 
questions, please contact the COG Study Research Coordinator, or the CTSU 
OPEN helpdesk at https://www.ctsu.org/CTSUContact.aspx.  Patients must be 
enrolled before treatment begins.  The date protocol therapy is projected to start 
must be no later than five (5) calendar days after the date of study enrollment. 
Patients must not receive any protocol therapy prior to enrollment. 
 
3.10 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
 


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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). The 
start of protocol therapy is defined as the initiation of radiation therapy. 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 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).  
 
 
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 
 
 
Age:  Patients must be > than 36 months and  21 years of age at the time 
of study enrollment. The first patient enrolled on study must be ≥ 7 years 
of age.  Pending results of PK analysis, the study will open to children of 
ages 3-21 years of age. 
 
 
Diagnosis: Patients with newly diagnosed DIPGs, defined as tumors with a 
pontine epicenter and diffuse involvement of the pons, are eligible without 
histologic confirmation.  
 
Patients with brainstem tumors that do not meet these criteria or are not 
considered to be typical intrinsic pontine gliomas will only be eligible if 
the tumors are biopsied and proven to be an anaplastic astrocytoma, 
glioblastoma, gliosarcoma, diffuse midline glioma with histone H3 K27M 
mutation, or anaplastic mixed glioma. Patients with pilocytic astrocytoma, 
fibrillary astrocytoma, gangliogliomas, or other mixed gliomas without 
anaplasia are not eligible.  
 
Patients with disseminated disease are not eligible, and MRI of spine must 
be performed if disseminated disease is suspected by the treating 
physician. 
 
Enrollment must be no later than 28 days after the date of radiographic 
diagnosis or surgery, whichever is the later date. 
 
 
Body Surface Area: Patients must have a body surface area  0.35 m2 at 
the time of study enrollment. 


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Performance Level:  Karnofsky  50% for patients > 16 years of age and 
Lansky  50 for patients  16 years of age (See Appendix I). Patients who 
are unable to walk because of paralysis, but who are up in a wheelchair, 
will be considered ambulatory for the purpose of assessing the performance 
score. 
 
 
Prior Therapy 
Patients must not have received any prior anti-cancer therapy such as 
chemotherapy, radiation therapy, immunotherapy or bone marrow 
transplant for the treatment of DIPG. Prior dexamethasone and/or surgery 
are allowed. 
 
 
Organ Function Requirements 
 
 Adequate Bone Marrow Function Defined as: 
- 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). 
 
 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 
3 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 utilizing child 
length and stature data published by the CDC.23 
 
 Adequate Liver Function Defined as: 
- Bilirubin (sum of conjugated + unconjugated)  1.5 × upper 
limit of normal (ULN) for age.  
- SGPT (ALT)  3 × ULN = 135 U/L.  For the purpose of this 
study, the ULN for SGPT is 45 U/L.  
- SGOT (AST)  3 × ULN = 150 U/L. For the purpose of this 
study, the ULN for SGOT is 50 U/L. 
- Serum albumin  2 g/dL. 
 
 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 


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- Nervous system disorders (CTCAE v5) resulting from prior 
therapy must be  Grade 2 with the exception of tendon reflex 
(DTR). Any grade of DTR is eligible.  
 
 Adequate Cardiac Function Defined as: 
-  QTc≤ 480 msec 
 
 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. 
 
4.2 
Exclusion Criteria 
 
 
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.  Negative serum or urine pregnancy test within 3 
days prior to enrollment. 
 
b. Males or females of reproductive potential may not participate unless 
they have agreed to use an effective contraceptive methods as follows: 
fertile females of childbearing potential who agree to use adequate 
contraceptive measures from 2 weeks prior to the study and until 1 
month after study treatment discontinuation. Male patients willing to 
abstain or use barrier contraception (i.e. condoms) for the duration of 
the study and for 3 months after treatment stops. 
 
 
Concomitant Medications 
 
 Corticosteroids:  Patients receiving corticosteroids are eligible 
for this trial.  
 
 Investigational Drugs:  Patients who are currently receiving 
another investigational drug are not eligible. 
 
 
 Anti-cancer Agents:  Patients who are currently receiving other 
anti-cancer agents are not eligible. 
 
 Anticonvulsants: Patients must not currently be receiving 
enzyme inducing anticonvulsants (see Appendix II for a list of 
enzyme inducing and non-enzyme inducing anticonvulsants). 
 
 
 
 Herbal Preparations are not allowed throughout the study. These 
herbal medications include but are not limited to: St. John's 
wort, 
kava, 
ephedra 
(ma 
hung), 
gingko 
biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and 


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ginseng. Patients should stop using these herbal medications 7 
days prior to study enrollment. 
 
 Any known hypersensitivity or contraindication to the 
components of the study drug AZD1775. 
 
 
 
 
 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
Patients who have received a prior solid organ transplantation are not 
eligible. 
 
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.  
 
Major surgical procedures ≤ 28 days of beginning study treatment, or 
minor surgical procedures (including VP shunt placement or stereotactic 
biopsy of the tumor) ≤ 7 days. No waiting period required following port-
a-cath or other central venous access placement. 
 
Patients who in the opinion of the investigator may not be able to comply 
with the safety monitoring requirements of the study are not eligible 
                                           
 
5.0 
TREATMENT PROGRAM 
 
5.1 
Overview of Treatment Plan 
 
AZD1775 Administration During Radiation Therapy (Cycle 1) 
 
Treatment 
Monday through 
Friday  
Saturday and Sunday 
Radiation Therapy  
X 
 
AZD1775 (MK-1775) 
  X^ 
 
Rest Period 
 
X 
^Frequency of AZD1775 (MK-1775) will vary depending on dose level assignment. 
 
Radiation therapy (XRT) will be given at the current standard dose of 5400 cGy in 
30 fractions of 180 cGy Monday through Friday for a total of 30 fractions over 6 
weeks, with a rest period on Saturday and Sunday of each week. In the event a 
radiation fraction is not administered due to a holiday (per institutional schedule) 
or for another reason (e.g., adverse event, mask re-fitting, etc) it will be made up 
during week seven (or eight). See Section 15.0 for radiation therapy guidelines.   
 
During radiation, AZD1775 (MK-1775) will be administered orally based on the 
table above, once each day after that day’s radiation therapy fraction, for the 
duration of radiation treatment 
 
Drug doses should be adjusted based on the BSA calculated from height and 


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weight measured within 7 days prior to the beginning of chemoradiotherapy 
course, and according to the dosing nomogram (see Appendix V-A). See Appendix 
V-B for scheduling guidelines based on the day of the week that XRT is initiated. 
The original dose assignment should be maintained throughout the entire period of 
radiation therapy. 
 
. If a patient vomits after the dose of AZD1775 (MK-1775) the dose should NOT 
be repeated. 
 
Note:   It is recommended but not required that Day 1 of protocol therapy begin 
on a Monday. If a fraction of radiation is delayed because of holiday or other 
logistical reasons (e.g. equipment malfunction), patients should also hold 
AZD1775 (MK-1775) and only take AZD1775 (MK-1775) on days radiation is 
given. 
 
Patients should have AZD1775 (MK-1775) prescribed at the beginning of 
chemotherapy, with detailed instructions about the days of the week that drug 
is to be administered. 
 
5.2 
Criteria for Starting Subsequent Cycles  
 
5.2.1 
Chemoradiotherapy 
Radiation therapy should not be interrupted for AZD1775-related DLTs 
unless clinically indicated. 
 
 
5.3 
Dose Escalation Schema 
Inter-Patient Escalation The starting dose of AZD1775 (MK-1775) (50 
mg/m2; dose level 1) is 40% of the known MTD in adult studies of 
chemotherapy combination regimens (adult MTD 200 mg which 
corresponds to 115 mg/m2). If dose level 1 is well tolerated, we will 
escalate treatment first by increasing the number of days AZD1775 (MK-
1775) is given and then by escalating the dose of AZD1775 (MK-1775) 
stepwise to 95 mg/m2 as shown in the table below. If dose level 4 is well 
tolerated, further dose escalation will be considered after evaluation of the 
pharmacokinetics and toxicity profile. PK simulation predicts higher 
exposures in children ≤ 6 years of age compared to older children (7 years 
and above). Therefore the age requirement of the first patient enrolled on 
dose level 1 will be 7 years or older. PK analysis will be performed prior 
to opening the study to younger children. 
 
 
 
Day 1-5 
Week 1 
 Day 8-12 
Week 2 
Day 15-19 
Week 3 
Day 22-26 
Week 4 
Day 29-33 
Week 5 
Day 36-40 
Week 6 
Dose Level 1: AZD1775 (MK-1775) 50 mg/m2 daily Mon-Fri, alternating weeks 
 (See Appendix V-B if start date not on Monday) 
XRT 
x x x x x 
x x x x x x x x x x x x x x x 
x x 
x x x 
x x x x x 
AZD1775 
(MK-
x x x x 
x 
 
x x x x x 
 
x x x x 
x 
 


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1775)  
50 mg/m2 
Dose Level 2: AZD1775 (MK-1775) 50 mg/m2 daily Mon-Fri dosing, alternating with weeks of QOD dosing 
(See Appendix V-B if start date not on Monday) 
XRT 
x x x x x x x x x x x x x x x x x x x x 
x x 
x x x 
x x x x x 
AZD1775 
(MK-
1775)  
50 mg/m2 
x x x x x x - 
x 
- 
x x x x x x x 
- 
x - 
x 
x x x x 
x x - x - x 
Dose Level 3: AZD1775 (MK-1775) 50 mg/m2 daily Mon-Fri During Weeks 1-6 
(See Appendix V-B if start date not on Monday) 
XRT 
x x x x x x x x x x x x x x x x x x x x 
x x 
x x x 
x x x x x 
MK-1775  
50 mg/m2 
x x x x x x x x x x x x x x x x x x x x 
x x x x 
x x x x x x 
Dose Level 4: AZD1775 (MK-1775) 95 mg/m2 daily Mon-Fri During Weeks 1-6 
(See Appendix V-B if start date not on Monday) 
XRT 
x x x x x x x x x x x x x x x x 
x x x x x x 
x x x x x x x x 
AZD1775 
(MK-
1775)  
95 mg/m2 
x x x x x x x x x x x x x x x x x x x x x x 
x x x x x x x x 
Dose Level 5: AZD1775 (MK-1775) 130 mg/m2 daily Mon-Fri During Weeks 1-6 
(See Appendix V-B if start date not on Monday) 
XRT 
x x x x x x x x x x x x x x x x 
x x x x x x 
x x x x x x x x 
AZD1775 
(MK-
1775)  
130 
mg/m2 
x x x x x x x x x x x x x x x x x x x x x x 
x x x x x x x x 
Dose Level 6: AZD1775 (MK-1775) 160 mg/m2 daily Mon-Fri During Weeks 1-6 
(See Appendix V-B if start date not on Monday) 
XRT 
x x 
x x 
x x 
x 
x x 
x 
x x 
x 
x x 
x 
x x x x x x x x x x x x x 
x 
AZD177
5 (MK-
1775) 
160 
mg/m2 
x x 
x x 
x x 
x 
x x 
x 
x x 
x 
x x 
x x x x x x x x x x x x x x 
x 
Dose Level 7: AZD1775 (MK-1775) 200 mg/m2 daily Mon-Fri During Weeks 1-6 
(See Appendix V-B if start date not on Monday) 
XRT 
x x x x x x x x x x x x x x x x 
x x x x x x 
x x x x x x x x 
AZD1775 
(MK-
1775)  
200 
mg/m2 
x x x x x x x x x x x x x x x x x x x x x x 
x x x x x x x x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 “x” = treatment; “-” = no treatment 
* Further dose escalation will be considered after evaluation of the pharmacokinetics and toxicity profile. 
 
If the MTD has been exceeded at dose level 1, then the subsequent cohort of patients will be treated 


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at dose level -1 (see below): 
 
Treatment De-Escalation (Dose Level -1) 
 
Day 1-5 
Week 1 
Day 8-12 
Week 2 
Day 15-19 
Week 3 
Day 22-26 
Week 4 
Day 29-33 
Week 5 
Day 36-40 
Week 6 
 
Dose Level -1: AZD1775 (MK-1775) 50 mg/m2 QOD alternating weeks 
See Appendix V-B if start date is not on Monday 
XRT 
x x 
x 
x x 
x 
x 
x x 
x x 
x 
x x 
x x 
x 
x x x 
x x 
x 
x 
x 
x x 
x x x 
AZD1775 
(MK-
1775)  
50 mg/m2 
x - 
x 
- x 
- 
- 
- 
- 
- x 
- 
x - 
x - 
- 
- - 
- 
x - 
x 
- 
x 
- 
- 
- - - 
 
If dose level -1 is not is not well tolerated, further de-escalation will not occur. The study will be 
closed for accrual. 
 
 
Intra-Patient Escalation 
Intra-patient dose escalation is not allowed on this study. 
 
 
5.4 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0.  A copy 
of the CTCAE version 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/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 AZD1775 (MK-1775).  The DLT observation period for 
the purposes of dose-escalation will be the entire duration of radiation therapy.  
 
Dose limiting hematological and non-hematological toxicities are defined 
differently.   
 
Interruption of Radiation Therapy 
Interruption of planned radiation for 5 consecutive fractions or 10 fractions 
total due to AZD1775 (MK-1775)-attributable toxicity (and not due to 
technical issues).  
 
Non-Hematological Dose-Limiting Toxicity 
 Any Grade 3 or Grade 4 non-hematological toxicity attributable 
to AZD1775 (MK-1775) with the specific exclusion of: 
- 
Grade 3 nausea and vomiting of less < 3 days duration (Grade 3 
nausea or vomiting ≥ 3 days in the presence of antiemetics will be 
considered a DLT) 
- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that 
returns to levels that meet initial eligibility criteria or baseline 


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within 7 days. See Appendix X for values that represent thresholds 
between CTCAE grades. 
Note: For the purposes of this study the ULN for ALT is defined as 45 
U/L. 
- 
Grade 3 or 4 fever < 5 days duration. 
- 
Grade 3 infection < 5 days duration. 
- 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to oral supplementation 
• 
Any Grade 2 non-hematological toxicity attributable to AZD1775 
(MK-1775) that persists for ≥ 7 days and is considered sufficiently 
medically significant or sufficiently intolerable by patients that it 
requires interruption of AZD1775 (MK-1775) for 7 days. 
• 
Note: Allergic reactions that necessitate discontinuation of study drug 
will not be considered a dose-limiting toxicity. 
 
Hematological dose limiting toxicity  
• 
Grade 3 thrombocytopenia (platelet count < 50,000/mm3) 
• 
Grade 4 neutropenia 
 
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 During Radiation Therapy  
 
For AZD1775 (MK-1775)-related hematologic DLTs, AZD1775 (MK-1775) will 
be withheld until criteria in 6.1.1 and 6.1.2 are met, and AZD1775 (MK-1775) will 
be restarted at one dose level lower, if not already at Dose Level -1. If the same 
DLT is experienced at the lower dose level then AZD1775 (MK-1775) should be 
discontinued.  If a different DLT is encountered, then the patient may restart 
AZD1775 (MK-1775) at the next lower dose level, if not already at Dose Level -
1. Please contact the Study Chair and Operations Center if guidance is required 
with regard to the day/schedules for AZD1775 (MK-1775) administration in the 
event the dose is de-escalated. 
 
In the event of hematological DLT, a CBC should be checked at least every other 
day until recovery of ANC ≥ 1,000/mm3 and platelet ≥ 100,000/mm3.  
 
A patient who experiences any DLT despite being treated on Dose Level -1 will 
then complete radiation therapy without AZD1775 (MK-1775). Radiation is 
conventional therapy for diffuse intrinsic pontine gliomas and should be 
continued despite AZD1775 (MK-1775)-related DLT, unless there is a strong 
clinical contraindication.  
 
6.1.1 
Radiation should not be interrupted unless clinically indicated. 
 
6.1.2 
. Radiation should not be interrupted unless clinically indicated. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity During Radiation 
Therapy  


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If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.5.2, AZD1775 (MK-1775) will be withheld until the toxicity resolves to 
meet eligibility or baseline parameters. Patients may then resume treatment at the 
next lower dose level. For patients enrolled at Dose Level 1, the dose should be 
reduced to Dose Level -1. Doses reduced for toxicity will not be re-escalated, even 
if there is minimal or no toxicity with the reduced dose.   
 
A patient who experiences any DLT despite being treated on Dose Level -1 will 
then complete radiation therapy without AZD1775 (MK-1775). Radiation is the 
standard of care and should be continued despite AZD1775 (MK-1775)-
related DLT, unless there is a strong clinical contraindication.  
 
If toxicity does not resolve to meet eligibility or baseline parameters within 14 
days of drug discontinuation, the patient must be removed from protocol therapy. 
 
If the same dose-limiting toxicity recurs in a patient who has resumed treatment at 
the reduced dose level, the patient must be removed from protocol therapy.  
 
 
 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, immunotherapy, or biologic 
therapy may NOT be administered to patients receiving study drug except radiation 
therapy per study protocol. If these treatments are administered the patient will be 
removed from protocol therapy. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and 
general supportive care are to be used as necessary (see Section 6.0).   
 
Evaluation and management of diarrhea  
. 
 
 
. 
 
 
Promethazine, prochlorperazine, and benzodiazepine may still be used as 
additional adjunctive treatments during AZD1775 therapy.   
 
 
. 
 
Patients should be strongly encouraged to maintain liberal oral fluid intake. 
 
Suitable alternative medications may be used, with adequate justification, in 
those studies where the use of any of the above medications might interfere 
with other study procedures or are deemed insufficient.  
 


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7.4 
Growth Factors 
. 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). Prophylactic anticonvulsants are strongly discouraged.  
 
 
CYP3A4 
 
 
CYP2C19  
 
 
Transporters  
 
 
 
Herbal Preparations: 
Herbal Preparations are not allowed throughout the study. These herbal 
medications include but are not limited to: St. John's wort, kava, ephedra 
(ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto and ginseng. Patients should stop using these herbal medications 7 
days prior to first dose of study treatment. 
 
 
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). The start of protocol therapy is defined 
as the initiation of radiation therapy. 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 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). 
 
STUDIES TO BE OBTAINED 
Pre-Study 
During Radiation Therapy 
History 
X 
Weekly 
Physical exam with vital signs 
X 
Weekly 
Neurologic exam 
X 
End of radiation therapy 
Height, weight, BSA 
X 
 
Performance status 
X 
 


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CBC, differential, platelets 
X 
Twice weekly 
(every 3 to 4 days)2 
Urinalysis 
X 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
Creatinine, ALT, bilirubin 
X 
Weekly 
Albumin 
X 
Weekly 
Tumor disease evaluation 
X 
End of radiation therapy6 
Pregnancy test3 
X3 
 
Patient diary4 
 
Weekly 
Pharmacokinetics5 
                             See Section 8.4 
Pharmacodynamics 
                             See Section 8.5 
EKG7 
               X 
 
 
1 
See Table 8.2 for required observations during the follow-up period. 
2 
In the event of hematological DLT, a CBC should be checked at least every other day 
until recovery of ANC ≥ 1,000/mm3 and platelet ≥ 100,000/mm3 (See Section 6.1). 
3 
Women of childbearing potential require a negative pregnancy test negative 3 days prior  
to enrollment; sexually active patients must use an acceptable method of birth control.  
Abstinence is an acceptable method of birth control.  
4 
Patient diary (see Appendix IV) should be reviewed and uploaded into RAVE weekly 
and after completion of protocol therapy.   
5 
If patients undergo CSF collection anytime while being treated with AZD1775 (MK-
1775), patients can opt to send samples for PK evaluation. 
 
6 
Tumor disease evaluation should be obtained within 3-4 weeks after completion of 
radiation therapy (within 3-4 weeks after completion of radiation therapy and then 
according to Table 8.2)  
 
7        12-lead EKG to be obtained at baseline and as clinically indicated 
 
8.2 
Required Observations Following Completion of Radiation Therapy 
The following studies are required until the patient is off study as defined in 
Section 10.2.  
 
STUDIES TO BE 
OBTAINED 
30 Days After Last 
dose of AZD1775 
(AZD1775 (MK-1775)) 
Every 3 Months  
History 
  X 
X 
Physical exam with vital 
signs 
X 
X 
Neurologic exam 
X 
X 
CBC, differential, platelets 
X 
X 
Tumor disease evaluation1 
X1 
X 
                       1         Tumor disease evaluation should be obtained within 3-4 weeks after completion  
 
        of radiation therapy and then every 3 months + 14 days. 
 
8.3 
Radiology Studies 
 
Central Radiology Review for Response:  Patients who respond (CR, PR) to 
therapy or have long term stable disease (SD > 6 months from study entry) on study will 
be centrally reviewed. Further, central review of disease progression will also occur. COG 


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Operations Center will notify the Imaging Center of any patient requiring central review. 
The Imaging Center will then request that the treating institution forward the requested 
images for central review. The central image evaluation results will be entered into RAVE 
for review by the COG Operations Center and for data analysis.  
 
The images are to be forwarded electronically to the Imaging Research Center at 
Children’s Hospital Los Angeles via the ImageInBox.   
 
COG institutions that are not connected via the ImageInBox can send the images 
on CD ROM or USB flash drive.  Submitted imaging studies should be clearly 
marked with the COG patient ID, study number (ADVL1217) 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 
 
8.4 
Pharmacology (Required) 
 
 
Description of Studies and Assay 
To date there is no experience with AZD1775 (MK-1775) in the pediatric 
population. To better characterize the pharmacokinetic (PK) properties of 
AZD1775 (MK-1775) in children, we will perform PK analyses on children treated 
on this study.  
 
AZD1775 (MK-1775) will be measured in plasma using LC/MS/MS assay 
methodology and analyzed by Merck 
 
 
Sampling Schedule-See Appx. V-B and Appx. VII for details 
 Blood samples will be obtained at the time points outlined in Appendix 
VII. 
 
 
 
Sample Collection and Handling Instructions 
 Blood samples (2-3 mL) will be collected in 4 ml K2 EDTA (lavender-
top) tubes, gently inverted 6 to 8 times, and immediately processed (See 
Section 8.4.4). Record the exact time that the sample is drawn along with 
the exact time that the drug is administered on the Pharmacokinetic 
Study Form (see Appendix VII). 
 
If the blood samples cannot be centrifuged immediately, the tubes will be 
placed on ice. The total time from drawing blood to transferring the plasma 
to the freezer cannot exceed 30 minutes. 
 
 
Sample Processing 


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See Appendix XI for processing details. Freeze immediately at -20 °C and store 
frozen until shipment. Complete the Pharmacokinetic Study Form (see Appendix 
VII), recording the date and time of collection for each sample. A copy of this form 
must accompany the sample(s) at time of shipment. 
 
 
Sample Labeling 
Each tube must be labeled with the COG patient ID and accession number, the 
study I.D. (ADVL1217), and the date and time the sample was drawn.  Data 
should be recorded on the Pharmacokinetic Study Form (see Appendix VII), 
which must accompany the sample(s). 
 
 
Sample Shipping Instructions 
Samples should be batched and shipped on dry ice prepaid via overnight Federal 
Express, Monday through Wednesday to: 
 
Covance Central Laboratory Services 
Attn: Phyllis Sellars - Special Handling 
8211 SciCor Drive 
Indianapolis, Indiana 46214 
Phone:  317-271-1200 
Fax:  1-800-335-1462 
Emails: SMSpecialHandlingIndy@Covance.com, Phyllis.Sellars@Covance.com 
and Cheryl.Hinton@Covance.com 
 
The samples must be securely packed in boxes to avoid breakage during transit, 
double-bagged to contain leaks, and packed with a sufficient quantity of dry ice 
to ensure they remain frozen for at least 72 hours. A notification email should be 
sent to the emails above with courier name, airway bill number, expected 
delivery date/time and shipment contact. The PK Pre-Alert Form, available on 
the protocol homepage, should be completed and faxed to the number listed on 
the form.  
 
 
 
8.5 
Pharmacodynamics (Required) 
 
 
Description of Studies 
We will assess the expression of p-CDC2, p-HH3 and -H2AX in peripheral blood 
mononuclear cells (PBMC) collected within 7 days prior to treatment start as well 
as at the time points listed in Appendix VIII. Levels of -H2AX, p-CDC2 and p-
HH3 expression will be assessed using flow cytometry. 
 
-H2AX, p-CDC2 and p-HH3 measurement by flow cytometry: 
Samples will be collected at each site using the Smart Tube kit (see Appendix IX 
for details). Once received at the laboratory of Dr. Mueller, samples will be thawed 
at 37°C for 30 seconds, and then washed with PBS. All subsequent steps will take 
place on ice. Samples will be blocked for one hour in Block-9 staining buffer (1g/l 
BSA, 8% mouse serum, 0.1g/l RNaseA, phosphate inhibitors, 0.25 g/l herring 
sperm DNA, 0.1% Triton X-100, 5mM EDTA, 0.05% NaN3, filtered through 
0.22µm filter), and then incubated in 1:100 FITC-conjugated -H2AX/p-CDC2 


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and p-HH3 antibody. Additionally, the sample will be stained with 0.25ug/sample 
7-Amino-Actinomycin D (7-AAD) (559925, BD Pharmigen) for the visualization 
of DNA content. Sample analysis will be performed by FACS Calibur flow 
cytometer (BD Biosciences), where data for about 20,000 total events will be 
collected. -H2AX levels will be visualized in FL1-H, and the DNA content in the 
FL3-H channel respectively. 
 
Summary of assays to assess PD of AZD1775 (MK-1775) in PBMCs: 
 
Molecular Feature 
Assay (Reagent) 
p-CDC2 
R&D AF888 
p-HH3 
Cell Signaling #9701 
-H2AX 
Millipore 16-202A 
 
PD analyses will be carried out in the laboratory of Dr. Sabine Mueller upon 
validation of the p-CDC2 and p-HH3 assays. 
 
Baseline expression of -H2AX, p-CDC2 and p-HH3 prior to AZD1775 (MK-
1775) treatment will be established. We expect that expression of p-CDC2 will 
decrease and expression of -H2AX and p-HH3 increase after treatment with 
AZD1775 (MK-1775) and radiation. Since there might be physiologic variations 
in expression of these markers, we will obtain 2 baseline samples and calculate the 
intra-patient standard deviation of baseline levels. We will consider a change of 2 
standard deviations as significant.  
 
 
Sampling Schedule 
Two baseline samples will be collected before the first dose of AZD1775 (MK-
1775). Every effort should be made to obtain the baseline (pre-treatment) samples 
on two different days, if feasible. 
 
Blood samples will also be collected at the time points outlined in Appendix VIII. 
 
 
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 
dry ice. Please see details of preparation in Appendix IX. 
 
 
Sample Labeling 
Each tube must be labeled with the COG patient ID and accession number, the 
study I.D. (ADVL1217), and the date and time the sample was drawn.  Data should 
be recorded on the Correlative Study Form (see Appendix VIII), which must 
accompany the sample(s). 
 
 
Sample Shipping Instructions 
Samples should be batched and shipped on dry ice to the address below: 
 


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Mueller Laboratory 
Attn: Xiaodong Yang/Yuying Zhai 
Helen Diller Family Cancer Research Building 
1450 Third Street, Room 402 
San Francisco, CA 94158 
 
Prior to shipping, contact Xiaodong Yang at 415-476-0543 or 
emailxiaodong.yang@ucsf.edu, yuying.zhai@ucsf.edu and 
sabine.mueller@ucsf.edu with the tracking number. Samples should NOT be 
shipped on a Friday or before a holiday. 
 
 
 
9.0 
AGENT INFORMATION 
 
9.1 
AZD1775 (MK-1775) 
NSC#751084;  
 
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 AZD1775 (MK-1775): 
 
 
 
Supplied by: Division of Cancer Treatment and Diagnosis (DCTD), NCI 
 
 
Formulation 
 
 
Storage 
; dispense in the original container.  
 
 
Administration 
Patients will take AZD1775 (MK-1775) orally based on assigned dose. AZD1775 
(MK-1775) will be administered orally once each day it is assigned directly after 
that day’s radiation therapy fraction. 
 
  If a dose is vomited it should not be repeated; resume administration with the next 
regularly scheduled dose. 
 


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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/aeguideli
nes.pdf for further clarification. Frequency is provided based on 213 patients. Below 
is the CAEPR for AZD1775 (MK-1775). 
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 2.5, April 18, 20181 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  


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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. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
3Rash may include rash, erythema, eczema, and rash maculo-papular. 
 
4Peripheral neuropathy includes both peripheral motor neuropathy and peripheral sensory neuropathy. 
 
5Acute kidney injury includes renal impairment and acute renal insufficiency. 
 
 
Adverse events reported on AZD1775 (MK-1775) trials but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that AZD1775 (MK-1775) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Blood and lymphatic system disorders - Other (thrombocytosis); Febrile neutropenia; 
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; 


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Cheilitis; Colitis; Dry mouth; Duodenal ulcer; Dysphagia; Enterocolitis; Flatulence; Gastric ulcer; Gastritis; 
Hemorrhoids; Lower gastrointestinal hemorrhage; Oral pain; Rectal hemorrhage; 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; Electrocardiogram QT corrected interval prolonged; GGT 
increased; Investigations - Other (blood urea increased); Lymphocyte count increased; Weight loss 
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 cramp; 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; Dysesthesia; 
Encephalopathy; Lethargy; Nervous system disorders - Other (hemiparesis); Paresthesia; Peripheral 
neuropathy4; Presyncope; Somnolence; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression 
RENAL AND URINARY DISORDERS - Acute kidney injury5; 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; 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 (MK-1775) 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. 
 
 
9.2 
Agent Ordering and Agent Accountability 
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. 
 


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In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
9.3 
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.  
 
9.4 
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 
the 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. 
 
9.5 
Investigator Brochure Availability 
The current versions of the IB for the agent 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 IAM account and the maintenance 
of an “active” account status, a “current” password and active person registration status. 
Questions about IB access may be directed to the PMB IB coordinator via email. 
 
9.6 
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  
• 
Registration and Credential Repository (RCR): 
            https://ctepcore.nci.nih.gov/rcr/ 
• 
PMB email: 
PMBAfterHours@mail.nih.gov 
• 
IB Coordinator: 
IBCoordinator@mail.nih.gov 


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• 
PMB phone and hours of service: 
(240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) 
 
 
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 planned therapy on Day 42. 
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) (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
 
Patients who are removed from protocol therapy during radiation therapy should 
continue to have the required observations in Section 8.1 until the originally planned 
end of treatment 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 off protocol therapy are to be followed as described in Section 8.2 until 
they meet the criteria for Off Study (see below). Ongoing adverse events, or adverse events 
that emerge after the patient is removed from protocol therapy, but within 30 days of the 
last dose of investigational agent, must be followed and reported via RAVE and CTEP-
AERS (if applicable). Serious adverse events that occur during the follow-up period (more 
than 30 days after the last administration of investigational agent) and have an attribution 
of possible, probable, or definite require reporting per Footnote 1 of Table A. Follow-up 
data will be required unless consent is withdrawn. 
 
10.2 
Off Study Criteria 
 
a) 
Death 
b) 
Lost to follow-up 
c) 
Withdrawal of consent for any further required observations or data submission. 
d) 
Enrollment onto another COG therapeutic (anti-cancer) study  
 
 
 
 
 
 


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11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
A minimum of 2 evaluable patients will be entered at each dose level for determination of 
MTD. Once the MTD or recommended phase 2 dose has been defined, up to 6 additional 
patients with DIPG may be enrolled to acquire PK data in a representative number of young 
patients (i.e. patients < 12 years old).  Review of the enrollment rate into a recent COG 
study of DIPG, ACNS0927, indicates that 1-2 patients per month are available, which will 
permit completion of the study within 20-38 months if all dose levels are studied with 6 
evaluable patients. A maximum of 65 patients is anticipated, which accounts for potential 
expansion to 12 patients at each dose level (see Section 11.2) and an inevaluability rate of 
20%. 
 
As of Amendment #4, 26 patients have enrolled onto the study. An additional 24 evaluable 
patients may be required to evaluate Dose Levels 5-7, which will permit completion of the 
study within 12-24 months if these dose levels are studied with 6 evaluable patients each 
and an additional 6 patients are required for PK analysis. Up to 51 additional patients may 
be enrolled, which accounts for potential expansion to 12 patients at each dose level (see 
Section 11.2) and an inevaluability rate of 20%. This would be expected to be completed 
within 26-51 months. The maximum accrual for the study will increase from 65 to 77 
patients. 
 
11.2 
Definitions 
 
Evaluable For Adverse Effects 
Any patient who experiences DLT at any time during protocol therapy is 
considered evaluable for Adverse Effects. Patients without DLT who receive at 
least 85% of the prescribed dose of AZD1775 (MK-1775) and radiation therapy 
within 8 weeks of starting protocol therapy 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. 
 
Maximum Tolerated Dose 
The MTD will be the maximum dose at which fewer than one-third of patients 
experience DLT (See Section 5.4) during therapy. In the event that two DLTs 
observed out of 6 evaluable patients are different classes of Adverse Effects (e.g. 
hepatotoxicity and myelosuppression), expansion of the cohort to 12 patients will 
be considered if all of the following conditions are met:  
 
•  One of the DLTs does not appear to be dose-related. 
•  The Adverse Effects are readily reversible. 
•  The study chair, DVL statistician, DVL committee chair or vice chair, and 
IND sponsor all agree that expansion of the cohort is acceptable. 
 
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting 
toxicities, the dose escalation can proceed. 
 
11.3 
Dose Escalation and Determination of MTD 
The rolling six phase 1 trial design will be used for the conduct of this study.29 Due to the 


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unknown pharmacokinetics of AZD1775 (MK-1775) after prolonged administration, the 
age requirement of the first patient enrolled on dose level 1 will be ≥ 7 years. The study 
will be temporarily closed to accrual until PK analysis of this patient is completed. Pending 
results, the study will either open a slot to another patient 7 years of age or older, or to 
children greater than 3 years of age. Upon agreement from the study team, the rolling six 
design may then be utilized: Two to six patients can be concurrently enrolled onto a dose 
level, dependent upon (1) the number of patients enrolled at the current dose level, (2) the 
number of patients who have experienced DLT at the current dose level, and (3) the number 
of patients entered but with tolerability data pending at the current dose level.  Accrual is 
suspended when a cohort of six has enrolled or when the study endpoints have been met.  
 
 
Dose level assignment is based on the number of participants currently enrolled in the 
cohort, the number of DLTs observed, and the number of participants at risk for developing 
a DLT (i.e., participants enrolled but who are not yet assessable for toxicity). For example, 
when three participants are enrolled onto a dose cohort, if toxicity data is available for all 
three when the fourth participant entered and there are no DLTs, the dose is escalated and 
the fourth participant is enrolled to the subsequent dose level. If data is not yet available 
for one or more of the first three participants and no DLT has been observed, or if one DLT 
has been observed, the new participant is entered at the same dose level. Lastly, if two or 
more DLTs have been observed, the dose level is de-escalated. This process is repeated for 
participants five and six. In place of suspending accrual after every three participants, 
accrual is only suspended when a cohort of six is filled. When participants are inevaluable 
for toxicity, they are replaced with the next available participant if escalation or de-
escalation rules have not been fulfilled at the time the next available participant is enrolled 
onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the current dose 
level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the study 
is suspended to accrual: 
 
 
# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
3 
0 
3 
0 
Escalate** 
 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
 
4 
0 
4 
0 
Escalate** 
 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
 
5 
0 
5 
0 
Escalate** 
 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 


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6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
* If six patients already entered at next lower dose level, the MTD has been defined. 
**If final dose level has been reached, the recommended dose has been reached. 
 
If two or more of a cohort of up to six patients experience DLT at a given dose level, then 
the MTD has been exceeded and dose escalation will be stopped (see Section 11.2.2 for 
exception to rule). 
 
In addition to determination of the MTD, a descriptive summary of all toxicities will be 
reported. 
 
11.4 
Inclusion of Children, Women and Minorities 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual 
to past COG studies of new agents demonstrates the accrual of both genders and all NIH-
identified ethnicities to such studies.  Efforts will be made to extend the accrual to a 
representative population, but in a Phase 1 trial which will accrue a limited number of 
patients, a balance must be struck between patient safety considerations and limitations on 
the number of individuals exposed to potentially toxic or ineffective treatments on the one 
hand and the need to explore gender, racial, and ethnic aspects of clinical research on the 
other. If differences in outcome that correlate to gender, racial, or ethnic identity are noted, 
accrual may be expanded or additional studies may be performed to investigate those 
differences more fully. 
 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
A descriptive analysis of pharmacokinetic (PK) parameters of AZD1775 (MK-1775) will 
be performed to define systemic exposure 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).   
 
Biologic activity of AZD1775 (MK-1775) will be explored using expression of p-CDC2, 
p-HH3 and -H2AX in PBMCs before and after administration of AZD1775 (MK-1775) 
using paired analysis methods. 
 
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 criteria outlined in Section 12.0, and will be reported 
descriptively. Progression-free survival and overall survival will also be summarized using 
the Kaplan-Meier method and including 95% confidence intervals.  Both measurements of 
survival will be measured from the time of study entry. 
 
All these analyses will be descriptive and exploratory and hypotheses generating in 
nature. 
 
 
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 


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appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
12.2 
Methodology to Determine Tumor Measurement 
In order to completely document the assessment of response, the two-dimensional tumor 
measurements for all target lesions upon which the assessments of tumor response are 
based should be explicitly noted in the radiology report for the baseline and all subsequent 
follow-up exams. Reports for the follow-up exams should reiterate the measurements 
obtained at baseline for each target lesion. Newly occurring lesions should also be 
enumerated in these reports, and changes in lesions should be described. 
 
Tumor response criteria for this study are to be determined by changes in size using the 
maximal 2-dimensional cross-sectional tumor measurements, T x W (product of the longest 
diameter of the tumor [width (W)] and its longest perpendicular diameter [transverse (T)], 
using either T1 or T2 weighted images (which ever gives the best estimate of tumor 
size).  This will allow comparison with historical studies as outlined in the statistical design 
section, such as CCG-9941, ACNS0126, and ACNS0927 which used cross-sectional 
measurements in their determination of response status. 
 
Tumor length (L), perpendicular to the T x W plane should also be measured and 
recorded, since this will provide historical data for future studies that will rely 
exclusively on volumetric response determinations.  However, for the current study, 
3-dimensional tumor volume change will not be used to determine response status. 
  
The following section describes the methodology. 
  
(See drawing below for illustration) 
1.   For MRI imaging, the longest diameter can be measured from the axial plane or the 
plane in which the tumor is best seen or measured, provided the same plane is used in 
follow ups. 
2.   The longest measurement of the tumor (or width, W) should be determined.  
3.   The 2 perpendicular measurements should be determined (transverse (T) measurement-
perpendicular to the width in the selected plane, and the length (L) tumor extent in the 
plane perpendicular to the selected plane). 
4.   Leptomeningeal tumor spread is not a target lesion, as its presence at diagnosis would 
make the patient ineligible for this brainstem glioma study.  The presence and location 
of leptomeningeal tumor spread at relapse should be noted. 
 


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12.3 
Selection of Target and Non-Target Lesions 
For intrinsic pontine brainstem gliomas, only one lesion/mass is present at diagnosis, and 
therefore is considered a “target” for measurement/follow up to assess for tumor 
progression/response. (Patients with multiple target lesions at diagnosis are considered to 
have disseminated disease and would be ineligible for this study). 
 
If other non-target lesions develop at relapse (including CSF positive for tumor cells), their 
location should be noted, although they do not need to be measured. 
 
12.4 
Response Criteria for Target Lesions 
For this study, comparison of maximal 2-dimensional measurements, T x W (product of 
the longest diameter [width (W)] and its longest perpendicular diameter [transverse (T)] 
will be used for Response Criteria for Target Lesions. 
 
Complete Response (CR): The disappearance of all abnormal signal within the brainstem 
and return to normal size of the brainstem. 
 
Partial response (PR): ≥50% decrease in the sum of the products of the two perpendicular 
diameters of the target lesion, taking as reference the initial baseline measurements. 
 
Stable Disease (SD): Neither sufficient decrease in the products of the two perpendicular 
diameters of the target lesion to qualify for PR (taking as reference the initial baseline 


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measurements), nor sufficient increase in the target lesion to qualify for PD, (taking as 
reference the smallest disease measurement since the treatment started). 
 
Progressive Disease (PD):  Progressive disease is defined as 25% or more increase in the 
sum of the product of the perpendicular diameters of the target lesions, taking as reference 
the smallest sum of products observed since the start of treatment, or the appearance of one 
or more new lesions. 
 
12.5 
Overall Response Assessment 
The overall response assessment takes into account response in the target lesion, and the 
appearance of new lesions, 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, and new lesions in the preceding columns. 
 
 
 
12.6 
Best Response 
Two objective status determinations of disease status, by MRI, obtained on two 
consecutive determinations, separated by at least a 4 week time period, are required to 
determine the patient’s overall best response.  Two objective status determinations of CR 
before progression are required for best response of CR.  Two determinations of PR or 
better before progression, but not qualifying for a CR, are required for a best response of 
PR. Two determinations of stable/no response or better before progression, but not 
qualifying as CR or PR, are required for a best response of stable/no response; if the first 
objective status is unknown, only one such determination is required.  Patients with an 
objective status of progression on or before the second evaluations (the first evaluation is 
the first radiographic evaluation after treatment has been administered) will have a best 
response of progressive disease.  Best response is unknown if the patient does not qualify 
for a best response of progressive disease and if all objective statuses after the first 
determination and before progression are unknown. 
 
1st Status 
2nd Status 
3rd Status 
Best Response 
Progression 
 
 
Progressive disease 
Stable, PR, CR 
Progression 
 
Progressive disease 
Unknown 
Progression 
 
Progressive disease 
Stable 
Stable 
Progression 
Stable 
Stable, Unknown 
PR, CR 
Progression 
Stable 


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Stable, Unknown 
Unknown 
Progression 
Unknown 
PR 
PR 
Progression 
PR 
PR 
CR 
Progression 
PR 
PR, CR 
Unknown 
Progression 
Unknown 
CR 
CR 
Progression 
CR 
Unknown 
Stable 
Progression 
Stable 
 
 
 
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.  The 
descriptions and grading scales found in the revised CTCAE version 5.0 will be 
used for AE reporting. All appropriate treatment areas should have access to a copy 
of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded 
from 
the 
CTEP 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
Note:  This includes all events that occur within 30 days of the last dose of protocol 


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treatment.  Any event that occurs during the follow-up period (see Section 
10.2) more than 30 days after the last dose of treatment and is attributed 
(possibly, probably, or definitely) to the agent(s) must also be reported 
according to the instructions in the table below. Attribution categories are 
as follows: Unrelated, Unlikely, Possible, Probable, and Definite. 
 
Table A: Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (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. 
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 


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prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific 
expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 
birth defects must be reported via CTEP-AERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 1 
Trials Utilizing an Agent under a CTEP-IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not clearly due 
to progressive disease must be reported via CTEP-AERS for an agent under a CTEP or non-CTEP 
IND agent per the timelines outlined in the table above. 
 
• Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), does 
not require expedited reporting, unless it is associated with hospitalization. 
Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD 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.  
 
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 http://ctep.cancer.gov (telephone CTEP at: 301-897-7497 within 24 hours of 
becoming aware of the event if the CTEP-AERS 24-Hour Notification web-based 
application is unavailable) and by telephone call to the Study Chair. Once internet 


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connectivity is restored, a 24-hour notification phoned in must be entered electronically 
into CTEP-AERS by the original submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 
• 
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page https://eapps-
ctep.nci.nih.gov/ctepaers. 
 
 
13.3 
Expedited Reporting Methods  
 
 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 ADVL1217 COG 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 case report 
forms and do not alter the guidelines for CTEP-AERS reporting. 
 
If an adverse event occurs more than once in a course (cycle) of therapy only the most 
severe grade of the event should be reported. 
 
 
If an adverse event progresses through several grades during one course of therapy, only 
the most severe grade should be reported. 
 
The duration of the AE is defined as the duration of the highest (most severe) grade of the 
Adverse Effects.  
 
The resolution date of the AE is defined as the date at which the AE returns to baseline or 
less than Grade 1, whichever level is higher (note that the resolution date may therefore be 
different from the date at which the grade of the AE decreased from its highest grade).  If 
the AE does not return to baseline the resolution date should be recorded as "ongoing."   
 
An adverse event that persists from one course to another should only be reported once 
unless the grade becomes more severe in a subsequent course. An adverse event which 
resolves and then recurs during a different course, must be reported each course it recurs.  


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13.5 
Other Recipients of Adverse Event Reports 
 
Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) should be 
reported at the end of each cycle using the forms provided in the CRF packet (See Section 
14.1). 
 
COG will forward reports and supporting documentation to the Study Chair, to the FDA 
(when COG holds the IND) and to the pharmaceutical company (for industry sponsored 
trials). 
 
Adverse events determined to be reportable must also be reported according to the local 
policy and procedures to the Institutional Review Board responsible for oversight of the 
patient. 
 
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. 
 
Note: The AML/MDS Secondary Reporting form is no longer available on the CTEP 
website.  In lieu of this form, AML/MDS events are now to be reported via CTEP-AERS 
(in addition to your routine AE reporting mechanisms).  In CTCAE v4.0, the event(s) may 
be reported as either:  
1) Leukemia secondary to oncology chemotherapy,  
2) Myelodysplastic syndrome, or  
3) Treatment-related secondary malignancy.  
 
Non-treatment related cases of AML/MDS for CTCAE v4.0 should be reported using 
“Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify”. 
 
To grade a non life-threatening event for “Myelodysplastic syndrome”, use “Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other, specify” where the 
specified term is MDS. 
 
Note:  If a patient has been enrolled in more than one NCI-sponsored study, the CTEP-
AERS report must be submitted for the most recent trial. 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
 
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. The potential risk of exposure of the 
fetus to the investigational agent should be documented in the “Description of Event” 


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section of the CTEP-AERS report. 
 
 Pregnancy  
• 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic. For this reason, pregnancy 
occurring on study or within 6 months following the last dose of study 
therapy should be reported in an expedited manner via CTEP-AERS as 
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other 
(Pregnancy)” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. 
 
• 
There is a possibility that the sperm of male patients treated on studies 
involving possible teratogenic agents may have been damaged. For this 
reason, pregnancy in partners of men on study should also be reported and 
followed as described in this section. 
 
• 
Pregnancy should be followed until the outcome is known. If the baby is 
born with a birth defect or anomaly, then a second CTEP-AERS report is 
required.  
 
 
 Pregnancy Loss (Fetal Death) 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
 
• 
 Any pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 
since CTEP-AERS recognizes any Grade 5 event as a patient death.   
 
 
 Death Neonatal 
• 
Neonatal death, defined in CTCAE as “Newborn deaths occurring during 
the first 28 days after birth” that is felt by the investigator to be at least 
possibly due to the investigational agent/intervention, should be reported 
expeditiously. 
 
• 
A neonatal death should be reported expeditiously as Grade 4 “Death 
neonatal” under the “General disorders and administration” SOC when 
the death is the result of a patient pregnancy or pregnancy in partners 
of men on study. 
 
• 
Do NOT report a neonatal death resulting from a patient pregnancy or 
pregnancy in partners of men as a Grade 5 event as CTEP-AERS 
recognizes any Grade 5 event as a patient death.  
 
 
Pregnancy should be followed up until the outcome of the pregnancy is known at intervals 
deemed appropriate by her physicians. The “Pregnancy Information Form” should be used 
for 
all 
necessary 
follow-ups. 
This 
form 
is 
available 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyRepo
rtForm.pdf. 


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14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN  
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
entered in RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the case report form (CRF) 
packet. 
 
See separate CRF Packet, which includes submission schedule. 
 
14.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports 
are due January 31, April 30, July 31 and October 31.  Note: If this study has been assigned 
to CDUS-Complete reporting, all adverse events (both routine and expedited) that have 
occurred on the study and meet the mandatory CDUS reporting guidelines must be reported 
via the monitoring method identified above. If this study has been assigned to CDUS-
Abbreviated reporting, no adverse event reporting (routine or expedited) is required to be 
reported via CDUS. 
 
             This is not a responsibility of institutions participating in this trial. 
 
14.3 
CRADA/CTA/CSA 
Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by 
a Clinical Trials Agreement (CTA) or a Cooperative Research and Development 
Agreement. 
 
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 


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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. 
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 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 


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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 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. 
 
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 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. 
 
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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15.0 
RADIATION THERAPY GUIDELINES 
 
Radiation Therapy for patients on COG protocols can only be delivered at approved COG RT facilities.  
 
 
 
 
 
 
 
 
 
 
15.0.1 General Guidelines 
This is a dose escalation, Phase 1 study of the selective Wee1 kinase inhibitor AZD1775 (MK-
1775) in combination with radiation in patients with newly diagnosed diffuse intrinsic pontine 
glioma (DIPG). All patients will receive radiation therapy on this protocol with the targeted volume 
based on the extent of disease defined by neuroimaging prior to radiation therapy. This study 
specifies a 1 cm clinical target volume margin and mandates the use of CT-MR registration to 
define the target volume. The allowed treatment methods are restricted to conformal or intensity-
modulated radiation therapy using photons and electronic data submission is required. Proton 
therapy is not allowed. 
 
15.0.2 Treatment Planning Specifics 
The guidelines for this study were developed based on the performance of COG investigators when 
executing the guidelines in prior COG trials. The goal of the treatment planning process is to 
develop a plan to deliver a uniform dose to the planning target volume that includes all known 
tumor plus the specified clinical target volume margin. The protocol-specified total dose is 54 Gy 
using conventional fractionation. Because the total dose does not exceed the recommended dose 
limits for the spinal cord and optic chiasm, volume reductions are not required nor recommended.  
 
15.0.3 Required Benchmark and Questionnaires 
Radiation therapy will be administered using photons. Required photon methods include 3D-
conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT). Centers 
participating in this protocol using 3D-CRT are required to complete the 3D benchmark; sites using 
IMRT and not previously credentialed for use of IMRT in COG trials must irradiate the IMRT 
Head and Neck Phantom available from the IROC Houston QA Center (RPC) and update their 
Facility Questionnaire on the IROC Houston website (http://rpc.mdanderson.org/rpc). All centers 
participating in this protocol must complete the CT/MR image fusion benchmark. Benchmark 
materials and questionnaires may be obtained from IROC Rhode Island (www.irocri.qarc.org) and 
must be submitted before patients on this protocol can be evaluated.  
 
15.0.4 Guidelines and Requirements for the Use of IMRT 
Investigators using IMRT will be required to comply with the guidelines developed for the use of 
IMRT in National Cancer Institute sponsored cooperative group trials. These guidelines are 
available through www.irocri.qarc.org. These guidelines require that the protocol explicitly state 
their requirements and methods for localization and immobilization; the use of volumetric imaging; 
target and organ motion management; nomenclature, definitions and rationale for targets and 
organs at risk; target volume coverage and normal tissue dose constraints; effects of heterogeneity 
in tissues; and quality assurance. 
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility,  procedure and/or 
anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 (except where 
explicitly prohibited within the protocol).  


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15.1 
Indications for Radiation Therapy  
 
All patients enrolled on this protocol will receive concurrent AZD1775 (MK-1775) and 
radiation therapy. 
 
15.2 
Timing 
 
15.2.1 All patients should be seen in consultation by a radiation oncologist at the time of 
study enrollment. The purpose of the consultation is to participate in the initial 
evaluation and to review the adequacy of the initial diagnostic imaging studies that 
will be used for subsequent RT planning. If additional imaging studies are pursued, 
thin section MR (T2-weighted and FLAIR) sequences should be obtained for 
registration to the CT data set to assist in treatment planning. 
 
15.2.2 All patients must begin therapy no later than 7 days after study enrollment. 
Enrollment must be no later than 28 days after the date of radiographic diagnosis 
or surgery, whichever is the later date. 
 
15.2.3 There are no contraindications to radiation therapy.  There are, however, some 
restrictions with regard to concomitant medications and eligibility as detailed in 
Section 4.2.2. Patients must not be receiving enzyme-inducing anticonvulsants 
(see Appendix II for a list of enzyme inducing and non-inducing anticonvulsants). 
Within these constraints, corticosteroids and anticonvulsants should be used as 
clinically indicated and tapered as soon as possible. Prophylactic anticonvulsants 
are strongly discouraged.  
 
15.2.4 Please see Section 5.1 and Section 5.2 for details of timing of AZD1775 (MK-
1775) administration. AZD1775 (MK-1775) will be administered orally once each 
day it is assigned directly after each day’s radiation therapy fraction. 
 
15.3 
Emergency Irradiation 
 
Patients are not allowed to have received radiation therapy prior to enrollment on this 
protocol and urgent irradiation is not envisioned under any circumstance.  
 
15.4 
Equipment and Methods of Delivery and Verification  
 
Equipment 
Photons 
(any energy) 
IMRT 
(4-10MV) 
Linear Accelerator 
X 
X 
 
15.4.1 Treatment planning 
CT (volumetric) based planning is required to optimize dose to the PTV while 
protecting normal tissues. Organs at risk within the irradiated volume should be 
contoured. A dose-volume histogram (DVH) is necessary to determine target 
coverage and evaluate dose to normal tissues. CT section thickness should be ≤ 
5mm although 2-3mm is preferred. 
 
15.4.2 In-room verification of spatial positioning  
15.4.2.1 
Portal imaging is the most common system used to verify patient 
position, in particular when the target volume is believed to 
possess a fixed spatial relationship with visualized bony anatomy. 
Orthogonal paired (AP and lateral) portal images (MV or kV) are 


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required for IMRT and 3-D CRT to verify that the isocenter is in 
correct alignment relative to the patient position. 
 
15.4.2.2 
Volumetric imaging is allowed in this study. This includes in-
room kV or MV cone beam or conventional CT imaging.  
 
15.5 
Target Volumes 
 
15.5.1 General comments 
International Commission on Radiation Units and Measurements (ICRU) Reports 
50 and 62 (www.icru.org) define prescription methods and nomenclature that will 
be utilized for this study where applicable. Although the MRI obtained 
immediately prior to radiation therapy should be used for treatment planning, the 
target volumes for this study will be determined by the collective information that 
delineates the extent of disease before and after surgical resection or CSF shunting 
procedure. The investigators recognize that resection and shunting are unlikely for 
these patients. The sequence that best defines the extent of disease and post-
operative tumor bed (when applicable) should be used to determine the GTV and 
registered to the treatment planning CT. Most patients with DIPG require a 
combination of MR sequences to delineate the extent of disease.  MR T2 and 
FLAIR sequences are most likely to be those chosen for registration to the 
treatment planning CT data set. The GTV, CTV, PTV and normal tissues must be 
outlined on all axial imaging slices on which the structures exist.  
 
15.5.2 Definitions for GTV, CTV and PTV 
• 
Gross tumor volume (GTV) is based on the most recent MRI and/or post-
operative MRI examination (if resection was done) and includes gross residual 
tumor and the tumor bed at the primary site. In defining the GTV, the 
investigator should consider all imaging studies that have defined the extent of 
tumor and the tissues involved anatomically. The GTV in most cases will be 
the T2 or FLAIR abnormality on the appropriate MR sequence. Tissue defects 
resulting from surgical approaches, when undertaken, will not be included as 
part of the GTV when not previously involved by tumor. Investigators should 
register the immediate pre-irradiation MR imaging sequences that 
demonstrated tumor and contour the GTV. 
• 
Clinical target volume (CTV) includes the GTV with an added margin of 1 
cm. This is meant to treat subclinical microscopic disease and is anatomically 
confined (i.e., the CTV is limited to the confines of the bony calvarium, falx 
and tentorium where applicable or extends up to but not beyond neuroanatomic 
structures through which tumor extension or invasion is certain not to have 
occurred). The CTV may be manually moved inward to the inner table of the 
bony calvarium. When the GTV approaches the boundary of an anatomic 
compartment, the CTV will extend up to and include the boundary. The CTV 
margin chosen for this study requires treatment planning MR and/or diagnostic 
MR imaging data with image section thickness ≤ 5mm. 
• 
Planning target volume (PTV) includes a margin which is added to the CTV 
in 3-dimensions. It is geometric and not anatomically defined. The PTV has 
two components, the internal margin (IM) and the set-up margin (SM). The 


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IM is meant to compensate for all movements and variations in size and shape 
of the tissues contained within the CTV. The SM is meant to account for set-
up, mechanical and dosimetric uncertainties related to daily patient 
positioning, treatment equipment and software. For this study, the PTV margin 
should be 3 or 5 mm. The use of a PTV margin of 3 mm requires written 
documentation that image-guided radiation therapy (IGRT) methods are used 
on a daily basis or alternatively that a head fixation system or verification 
system is used with weekly or more frequent imaging. For this study, IGRT is 
defined as 2- or 3-dimensional digital imaging positioning. Given that the CTV 
is generally confined to the intracranial space, the PTV may extend into or 
beyond bone but is unlikely to extend beyond the surface of the patient. The 
PTV margin chosen by the treating investigator requires treatment planning 
MR and/or diagnostic MR imaging data with imaging section thickness ≤ the 
chosen PTV margin. 
 
15.6 
Target Dose 
 
15.6.1 Dose Definition  
Photon dose is to be specified in centigray (cGy)-to-muscle. 
 
15.6.2 Prescribed dose and fractionation 
The total dose to the isodose surface encompasses the PTV will be 5400 cGy 
administered in 30 fractions of 180 cGy. The patient should be treated with one 
fraction per day.  All fields should be treated each day. 
 
Table 15.6.2 
Prescribed Doses and Fractionation 
 
Nominal Dose by Site 
Target Volume 
Dose/fraction 
Number of Fractions 
Primary Site 5400 cGy 
PTV1 
180 cGy 
30 
 
 
15.6.3 Dose uniformity 
At least 95% of the protocol-specified dose should encompass 100% of the PTV 
and no more than 10% of the PTV should receive greater than 110% of the protocol 
dose as evaluated by DVH. The 100% isodose should be equal to the protocol 
specified dose. Wedges, compensators and other methods of generating more 
uniform dose distributions are encouraged. 
 
15.6.4 Tissue heterogeneity 
 
Calculations must take into account tissue heterogeneity and should be performed 
with CT-based treatment planning to generate dose distributions and treatment 
calculations from CT densities.  
 
15.6.5 Interruptions, Delays and Dose Modifications 
 
There will be no planned rests or breaks from treatment, and once radiation 
therapy has been initiated, treatment will not be interrupted except for life 
threatening infection or severe hematological toxicity defined as ANC < 300/L 
or platelets less than 40,000/L during the course of treatment. Blood product 


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support should be instituted according to institutional/protocol guidelines. The 
reason for any interruptions greater than 3 treatment days should be recorded in 
the patient treatment chart and submitted with the QA documentation. There 
should be no modifications in dose fractionation due to age or field size. 
 
15.7 
Treatment Technique 
 
15.7.1 Beam Configuration 
Every attempt should be made to minimize dose to organs at risk without 
compromising coverage of the target volume. Three-dimensional conformal 
therapy (coplanar or non-coplanar) or IMRT are required to minimize dose to 
normal tissues.  
 
15.7.2 Field Shaping  
 
Field shaping will be done with either customized cerrobend blocking or multileaf 
collimation. 
 
 
15.7.3 Simulation including patient positioning and immobilization 
 
15.7.3.1   
Patient positioning  
 
Reproducible setups are critical.  The patient may be treated in any 
appropriate, stable position. Consideration should be given to 
implications for inter- and intra-fraction motion when using non-
standard position approaches. 
 
 
15.7.3.2 
Immobilization devices 
 
Standard immobilization devices for the brain or head and neck 
are to be used. For IMRT delivery approaches, the methods used 
for localization and immobilization of both patient and tumor are 
critical. The imaging studies should provide a clear assessment of 
the target volume with the patient in the treatment position.  
 
 
15.7.4 Special considerations  
 
Anesthesia or sedation may be required in certain patients, such as very young 
patients, to prevent movement during simulation and daily treatments.  
 
 
15.7.5 Motion Management and Margins to Account for Target Volume Changes During 
Treatment 
 
Considering motion of target volumes is important. Brain tumors susceptible to 
cyst expansion should be monitored closely.  Any change in clinical condition or 
anatomy related to hydrocephalus, VP shunt placement, subdural fluid, 
pseudomeningocele, or steroid use should be monitored carefully with repeat 
imaging when indicated.  
 
If motion management techniques are used, a description of the method used and 
evidence of the remaining tumor motion (i.e., observed motion during fluoroscopy, 
motion of surrogate markers using camera systems, or analysis of 4D CT) should 
be submitted on the Motion Management Reporting Form with the Quality 
Assurance Documentation materials as noted in Section 15.10.  
 


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15.8 
Organs at Risk 
The organ at risk guidelines in this section are recommendations. If the recommended 
doses to the organs at risk are exceeded because of target volume coverage requirements 
or other conditions, an explanation should be included in the quality assurance 
documentation. In some cases, photon IMRT may be the preferred treatment method to 
meet these recommendations and the required target volume coverage guidelines. 
 
Dose Constraints 
 
15.8.1 Cochleae  
• 
D50% ≤ 3500 cGy – Goal (each cochlea) 
• 
D50% ≤ 2000 cGy – Preferred (each cochlea) 
• 
Comment – There is no dose maximum for the cochleae. 
• 
Structure definition - Each cochlea will be contoured on the treatment planning 
CT as a circular structure within the petrous portion of the temporal bone. The 
contour should appear on at least two successive CT images. 
15.8.2 Optic Globes  
• 
D90% ≤  500 cGy, D50% ≤ 1000 cGy and D10% ≤  3500 cGy – Goal 
• 
D90% ≤ 1000 cGy, D50% ≤  2000 cGy and D10% ≤ 5400 cGy – Maximum 
• 
Comment – Effort should be made to avoid direct treatment of the anterior chamber 
of the eye and minimize dose to the entire eye without compromising target volume 
coverage. In the event that the recommended maximum dose constraints provided 
in this section would be exceeded, the treating radiation oncologist may use their 
discretion to reduce target volume coverage. 
• 
Structure definition - Each eye should be separately contoured on the treatment 
planning CT or MR as a circular structure from the most superior to inferior 
aspect. 
 
15.8.3 Right and Left Optic Nerves and Chiasm  
• 
D90% ≤ 1000 cGy, D50% ≤ 5400 cGy and D10% ≤ 5600 cGy – Goal 
• 
D90% ≤ 5400 cGy, D50% ≤ 5600 cGy and D10% ≤ 5800 cGy – Maximum 
• 
Comment – These parameters apply to each of the separate three structures, not 
the combined volume of the three structures. Effort should be made to avoid direct 
treatment of the optic nerves and chiasm without compromising target volume 
coverage. In the event that the recommended maximum dose constraints provided 
in this section would be exceeded, the treating radiation oncologist may use his/her 
discretion to reduce target volume coverage. 
• 
Structure definitions – The optic nerves and chiasm may be contoured on CT or 
MR.  The contours should appear on at least two successive CT or MR images. 
 


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15.8.4 Spinal Cord  
• 
D90% ≤ 300 cGy, D50% ≤  2600 cGy and D10% ≤ 5700 cGy - Goal 
• 
D90% ≤  900 cGy, D50% ≤  5000 cGy and D10% ≤ 5900 cGy – Maximum 
• 
Comment – Effort should be made to minimize dose to the spinal cord without 
compromising target volume coverage. 
• 
Structure Definition - For the purposes of this study, the upper aspect of the spinal 
cord begins at the inferior border of the foramen magnum and should be contoured 
on the treatment planning CT. For purposes of comparison and consistency with 
dose volume data, the spinal cord should be contoured on a number of images to 
be determined by the image section thickness (CT section thickness, n=number of 
images; 2mm, n=30; 2.5 mm, n=24; 3 mm, n=20). Using these guidelines, only the 
superior-most 6 cm of anatomic spinal cord is contoured. 
 
15.9 
Dose Calculations and Reporting 
 
 
 
15.9.1 Prescribed Dose 
The dose prescription and fractionation shall be reported on the RT-1 Dosimetry 
Summary Form. The total dose delivered shall be reported on the RT-2 
Radiotherapy Total Dose Record. If IMRT is used, the monitor units generated by 
the IMRT planning system must be independently checked prior to the patient’s 
first treatment. Measurements in a QA phantom can suffice for a check as long as 
the patient’s plan can be directly applied to a phantom geometry.  
 
15.9.2 Normal Tissue Dosimetry 
The dose to the critical organs indicated should be calculated whenever they are 
directly included in a radiation field. The total dose shall be calculated and reported 
on the RT-2 Radiotherapy Total Dose Record form. The appropriate dose-volume 
histograms should be submitted. If IMRT is used for the primary tumor, a DVH 
must be submitted for a category of tissue called “unspecified tissue,” which is 
defined as tissue contained within the skin, but which is not otherwise identified 
by containment within any other structure.  
 
Table 15.9a Required DVH data:   
 
Required DVH 
Total Brain 
Optic Nerves (L+R) 
Optic Chiasm 
Brainstem 
Spinal Cord 
Cochleae (L+R) 
Unspecified Tissue 
 
15.10 Quality Assurance Documentation 
On-treatment review is NOT required for this study.  Within one week of the completion 
of radiation therapy, detailed treatment data shall be submitted.  


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Digital Submission: Submission of treatment plans in digital format (DICOM RT) is 
required. Digital data must include CT scans, structures, plan and dose files. Submission 
may be either by SFTP or CD. Instructions for data submission are on the IROC RI Web 
site at www.irocri.qarc.org. Any items on the list below that are not part of the digital 
submission may be submitted as screen captures along with the digital data. 
 
Treatment Planning System Output 
• 
RT treatment plan including CT, structures, dose, and plan files.  These items are 
included in the digital plan. 
• 
Dose volume histograms (DVH) for all target volumes and required organs at risk. 
A DVH shall be submitted for the organs at risk specified in Section 15.8.  When 
using IMRT, a DVH shall be submitted for a category of tissue called “unspecified 
tissue.”  This is defined as tissue contained within the skin, but which is not 
otherwise identified by containment within any other structure.  DVH’s are included 
in the digital plan. 
• 
Digitally reconstructed radiographs (DRR) for each treatment field.  Please include 
two sets, one with and one without overlays of the target volumes and organs at risk. 
When using IMRT, orthogonal setup images are sufficient. 
• 
Treatment planning system summary report that includes the monitor unit 
calculations, beam parameters, calculation algorithm, and volume of interest dose 
statistics. 
 
Supportive Data 
• 
All diagnostic imaging used to plan the target volume. This includes CT or MRI 
PRIOR to attempted surgical resection of the primary tumor. Digital format is 
preferred. 
• 
Radiotherapy record (treatment chart) including prescription and daily and cumulative 
doses to all required areas and organs at risk. 
• 
If the recommended doses to the organs at risk are exceeded, an explanation should be 
included for review. 
• 
If a PTV margin of 3 mm is used, written documentation that image-guided radiation 
therapy (IGRT) methods are used on a daily basis or alternatively that a head fixation 
system or verification system was used with weekly or more frequent imaging.  See 
Section 15.5.2. 
• 
Motion Management Reporting Form (if applicable, see Section 15.7.5). 
Forms 
• 
RT-1 Dosimetry Summary Form. 
• 
RT-2 Radiotherapy Total Dose Record form. 
 
These data should be forwarded to: 
IROC Rhode Island QA Center 
640 George Washington Highway  


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Building B, Suite 201 
Lincoln, Rhode Island 02865-4207 
Phone: 
(401) 753-7600 
Fax: 
(401) 753-7601 
 
Questions regarding the dose calculations or documentation should be directed to: 
COG Protocol Dosimetrist 
IROC Rhode Island QA Center  
640 George Washington Highway 
Building B, Suite 201 
Lincoln, Rhode Island 02865-4207 
 
 
15.11 Definitions of Deviations in Protocol Performance 
 
 
DEVIATION 
 
Minor 
Major 
Prescription Dose 
 
Difference in prescribed or computed 
dose is 6-10% of protocol specified dose 
Difference in prescribed or computed 
dose is > 10% of protocol specified dose 
Dose Uniformity and Coverage 
 
>10% PTV received > 110% 
of the protocol dose or 
95% isodose covers < 100% of CTV 
> 20% of PTV received >110% of the 
protocol dose or 
90% isodose covers < 100% of CTV 
Volume 
 
CTV or PTV margins are less than the 
protocol specified margins in the 
absence of anatomic barriers to tumor 
invasion (CTV) or without written 
justification (PTV) 
GTV does not encompass MR-visible 
residual tumor 
Organs at Risk 
 
Dose to any OAR exceeds the goal dose 
stated in 15.8 
Dose to any OAR exceeds the maximum 
dose stated in 15.8 
 
 
 


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2011 
19. 
Caretti V, Hiddingh L, Lagerweij T, et al: WEE1 Kinase Inhibition Enhances the Radiation 
Response of Diffuse Intrinsic Pontine Gliomas. Mol Cancer Ther 12:141-50 
20. 
Paugh BS, Qu C, Jones C, et al: Integrated molecular genetic profiling of pediatric high-grade 


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66 
 
gliomas reveals key differences with the adult disease. J Clin Oncol 28:3061-8 
21. 
Nicolaides TP, Li H, Solomon DA, et al: Targeted therapy for BRAFV600E malignant 
astrocytoma. Clin Cancer Res 17:7595-604, 2011 
22. 
Sanai N, Li J, Boerner J, et al: Phase 0 trial of AZD1775 in patients with first-recurrence 
glioblastoma. J Clin Oncol 34 (suppl; abstr 2008), 2016 
23. 
Schwartz GJ, Gauthier B: A simple estimate of glomerular filtration rate in adolescent boys. . J 
Pediatr 106(3):522-6, 1985 
24. 
This 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.,  
25. 
Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.,  
26. 
Acute kidney injury includes renal impairment and acute renal insufficiency.,  
27. 
Rash may include rash, erythema, eczema, and rash maculo-papular.,  
28. 
Peripheral neuropathy includes both peripheral motor neuropathy and peripheral sensory 
neuropathy.,  
29. 
Skolnik JM, Barrett JS, Jayaraman B, et al: Shortening the timeline of pediatric phase I trials: the 
rolling six design. J Clin Oncol 26(2):190-5, 2008 
  
 


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


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APPENDIX II:  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 IV:  PATIENT DIARY: RADIATION PHASE 
 
COG Patient ID:___________  Institution :__________  Please do not write patient names on this form. 
Complete each day with the time and dose of AZD1775 (MK-1775) given, and circle AM or PM. 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. 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 each week.  Your 
institution will upload this document into RAVE weekly. Refer to Appendix V-B for scheduling guidelines 
based on the day of the week XRT is initiated. 
 
EXAMPLE 
 
 
Number of capsules 
Comments 
 
WEEK 1 
Date 
Time 
10 mg 
25 mg 
100 mg 
Day 1: MONDAY 
1/15/14 
8:30 
AM 
 
2 
1 
He felt nauseated an hour after 
taking the drug but did not vomit. 
Cycle #: _____        Dose: ________   Start Date: |__/__|__/__|__/__|   End Date: |__/__|__/__|__/__| 
WEEK 1 
Date 
Time 
10 mg 
25 mg 
100 mg 
Comments 
Day 1:___________ 
 
 
AM/ PM 
 
 
 
 
Day 2:___________ 
 
 
AM/ PM 
 
 
 
 
Day 3:___________ 
 
 
AM/ PM 
 
 
 
 
Day 4:___________ 
 
 
AM/ PM 
 
 
 
 
Day 5:___________ 
 
 
AM/ PM 
 
 
 
 
Day 6:___________ 
 
 
AM/ PM 
 
 
 
 
Day 7:___________ 
 
 
AM/ PM 
 
 
 
 
WEEK 2 
Date 
Time 
10 mg 
25 mg 
100 mg Comments 
Day 8:___________ 
 
 
AM/ PM 
 
 
 
 
Day 9:___________ 
 
 
AM/ PM 
 
 
 
 
Day 10:___________ 
 
 
AM/ PM 
 
 
 
 
Day 11:___________ 
 
 
AM/ PM 
 
 
 
 
Day 12:___________ 
 
 
AM/ PM 
 
 
 
 
Day 13:___________ 
 
 
AM/ PM 
 
 
 
 
Day 14:___________ 
 
 
AM/ PM 
 
 
 
 
WEEK 3 
Date 
Time 
10 mg 
25 mg 
100 mg Comments 
Day 15:___________ 
 
 
AM/ PM 
 
 
 
 
Day 16:___________ 
 
 
AM/ PM 
 
 
 
 
Day 17:___________ 
 
 
AM/ PM 
 
 
 
 
Day 18:___________ 
 
 
AM/ PM 
 
 
 
 
Day 19:___________ 
 
 
AM/ PM 
 
 
 
 
Day 20:___________ 
 
 
AM/ PM 
 
 
 
 
Day 21:___________ 
 
 
AM/ PM 
 
 
 
 
 
 
 
 
COG Patient ID:___________   
 
 
 
 
 
  
   
Institution :________________________________  
Please do not write patient names on this form. 


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WEEK 4 
Date 
Time 
10 mg 
25 mg 
100 mg Comments 
Day 22:___________ 
 
 
AM/ PM 
 
 
 
 
Day 23:___________ 
 
 
AM/ PM 
 
 
 
 
Day 24:___________ 
 
 
AM/ PM 
 
 
 
 
Day 25:___________ 
 
 
AM/ PM 
 
 
 
 
Day 26:___________ 
 
 
AM/ PM 
 
 
 
 
Day 27:___________ 
 
 
AM/ PM 
 
 
 
 
Day 28:___________ 
 
 
AM/ PM 
 
 
 
 
WEEK 5 
Date 
Time 
10 mg 
25 mg 
100 mg Comments 
Day 29:___________ 
 
 
AM/ PM 
 
 
 
 
Day 30:___________ 
 
 
AM/ PM 
 
 
 
 
Day 31:___________ 
 
 
AM/ PM 
 
 
 
 
Day 32:___________ 
 
 
AM/ PM 
 
 
 
 
Day 33:___________ 
 
 
AM/ PM 
 
 
 
 
Day 34:__________ 
 
 
AM/ PM 
 
 
 
 
Day 35:___________ 
 
 
AM/ PM 
 
 
 
 
WEEK 6 
Date 
Time 
10 mg 
25 mg 
100 mg Comments 
Day 36:___________ 
 
 
AM/ PM 
 
 
 
 
Day 37:___________ 
 
 
AM/ PM 
 
 
 
 
Day 38:___________ 
 
 
AM/ PM 
 
 
 
 
Day 39:___________ 
 
 
AM/ PM 
 
 
 
 
Day 40:___________ 
 
 
AM/ PM 
 
 
 
 
Day 41:___________ 
 
 
AM/ PM 
 
 
 
 
Day 42:___________ 
 
 
AM/ PM 
 
 
 
 
 
Notes:    ___________________________________________________________________________________________________ 
 
___________________________________________________________________________________________________ 
 
___________________________________________________________________________________________________ 
 
___________________________________________________________________________________________________ 
 
___________________________________________________________________________________________________ 
 


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APPENDIX V-A:  AZD1775 (MK-1775) DOSING NOMOGRAM 
 
AZD1775 (MK-1775) Dose Assignment: 50 mg/m2/day*  
(Dose Levels -1, 1, 2, and 3) 
BSA (m2) 
Total Daily Dose (mg/day) 
0.35-0.44 
20 
0.45-0.54 
25 
0.55-0.64 
30 
0.65-0.74 
35 
0.75-0.84 
40 
0.85-0.94 
45 
0.95-1.04 
50 
1.05-1.14 
55 
1.15-1.29 
60 
1.30-1.44 
70 
1.45-1.60 
75 
1.61-1.84 
85 
1.85-2.14 
100 
2.15- ≥ 2.30 
110 
    *Dose Level -1: Days 1, 3, 5,15,17,19,29,31,33 
Dose Level 1:  Days 1-5, 15-19, 29-33 
Dose Level 2:  Days 1-5, 8, 10, 12, 15-19, 22, 24, 26, 29-33, 36, 38, 40 
Dose Level 3:  Days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40 
Refer to Appendix V-B for scheduling guidelines based on the day of the week XRT is initiated. 
 
 
AZD1775 (MK-1775) Dose Assignment: 95 mg/m2/day* (Dose Level 4) 
BSA (m2) 
Total Daily Dose (mg/day) 
0.35-0.39 
35 
0.40-0.44 
40 
0.45-0.49 
45 
0.50-0.55 
50 
0.56-0.60 
55 
0.61-0.68 
60 
0.69-0.76 
70 
0.77-0.86 
75 
0.87-0.97 
85 
0.98-1.10 
100 
1.11-1.23 
110 
1.24-1.36 
125 
1.37-1.49 
135 
1.50-1.63 
150 
1.64-1.76 
160 
1.77-1.97 
175 
1.98-2.15 
200 
2.16-2.28 
210 
2.29- ≥ 2.30 
225 
*Days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40 
Refer to Appendix V-B for scheduling guidelines based on the day of the week XRT is initiated. 


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AZD1775 Dose Assignment: 130 mg/m2/dose (Dose Level 5) 
BSA (m2) 
AZD1775 Dose (mg/dose) 
0.30-0.32 
40 
0.33-0.36 
45 
0.37-0.40 
50 
0.41-0.44 
55 
0.45-0.51 
60 
0.52-0.55 
70 
0.56-0.59 
75 
0.60-0.63 
80 
0.64-0.69 
85 
0.70-0.80 
100 
0.81-0.88 
110 
0.89-0.94 
120 
0.95-1.01 
125 
1.02-1.09 
135 
1.10-1.13 
145 
1.14-1.21 
150 
1.22-1.26 
160 
1.27-1.32 
170 
1.33-1.38 
175 
1.39-1.48 
185 
1.49-1.57 
200 
1.58-1.65 
210 
1.66-1.71 
220 
1.72-1.84 
225 
1.85-2.05 
250 
2.06-2.21 
275 
2.22-2.30 
300 
• 
For dose reduction due to toxicity, please refer to dose assignment 100 mg/m2/dose below 
 
 
AZD1775 Dose Assignment: 100 mg/m2/dose  
BSA (m2) 
AZD1775 Dose (mg/dose) 
0.30-0.32 
30 
0.33-0.37 
35 
0.38-0.42 
40 
0.43-0.47 
45 
0.48-0.52 
50 
0.53-0.57 
55 
0.58-0.67 
60 
0.68-0.72 
70 
0.73-0.77 
75 
0.78-0.82 
80 
0.83-0.90 
85 
0.91-1.05 
100 
1.06-1.15 
110 


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1.16-1.22 
120 
1.23-1.32 
125 
1.33-1.42 
135 
1.43-1.47 
145 
1.48-1.57 
150 
1.58-1.65 
160 
1.66-1.72 
170 
1.73-1.79 
175 
1.80-1.92 
185 
1.93-2.05 
200 
2.06-2.15 
210 
2.16-2.22 
220 
2.23-2.30 
225 
Refer to Appendix V-B for scheduling guidelines based on the day of the week XRT is initiated. 
 
 
AZD1775 Dose Assignment: 160 mg/m2/dose (Dose Level 6) 
BSA (m2) 
AZD1775 Dose (mg/dose) 
0.30-0.34 
50 
0.35-0.44 
60 
0.45-0.52 
75 
0.53-0.57 
85 
0.58-0.66 
100 
0.67-0.73 
110 
0.74-0.81 
125 
0.82-0.85 
135 
0.86-0.91 
145 
0.92-0.97 
150 
0.98-1.04 
160 
1.05-1.17 
175 
1.18-1.28 
200 
1.29-1.36 
210 
1.37-1.51 
225 
1.52-1.64 
250 
1.65-1.79 
275 
1.80-1.95 
300 
1.96-2.14 
325 
2.15-2.29 
350 
2.30 
375 
Refer to Appendix V-B for scheduling guidelines based on the day of the week XRT is initiated. 
 
 
 
AZD1775 Dose Assignment: 200 mg/m2/dose (Dose Level 7) 
BSA (m2) 
AZD1775 Dose (mg/dose) 
0.30-0.34 
60 
0.35-0.39 
75 
0.40-0.44 
85 
0.45-0.52 
100 
0.53-0.57 
110 


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74 
 
0.58-0.65 
125 
0.66-0.71 
135 
0.72-0.81 
150 
0.82-0.91 
175 
0.92-1.04 
200 
1.05-1.17 
225 
1.18-1.28 
250 
1.29-1.41 
275 
1.42-1.58 
300 
1.59-1.64 
325 
1.65-1.79 
350 
1.80-1.93 
375 
1.94-2.04 
400 
2.05-2.14 
425 
2.15-2.29 
450 
2.30 
475 
Refer to Appendix V-B for scheduling guidelines based on the day of the week XRT is initiated. 
 
 


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APPENDIX V-B:  GUIDELINES FOR AZD1775 (MK-1775) DOSING SCHEDULE 
Please refer to the tables below for scheduling guidelines based on the day of the week XRT is initiated. 
Dose Level -1: AZD1775 50 mg/m2/dose daily Mon-Fri QOD, alternating weeks 
 
Week 1: Days 1-7 
Week 2: Days 8-14 
Week 3: Days 15-21 
Week 4: Days 22-28 
Week 5: Days 29-35 
Week 6: Days 36-42 
 Monday Start Date for XRT 
 
M 
T 
W Th 
F 
Sa 
S 
M 
T 
W Th 
F Sa 
S 
M 
T 
W  Th 
F 
Sa 
S 
M 
T 
W  Th 
F 
Sa 
S 
M 
T 
W Th 
F Sa 
S 
M 
T 
W Th 
F Sa 
S 
XRT 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
AZD1775 50mg/m2 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
PK 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Tuesday Start Date for XRT 
 
T 
W Th 
F Sa 
S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W  Th F 
Sa 
S 
M 
T 
W  Th F 
Sa 
S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
XRT 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
AZD1775 50mg/m2 
x 
- 
x 
- 
- 
- 
x 
- 
- 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
PK 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wednesday Start Date for XRT 
 
W Th 
F 
Sa 
S 
M 
T 
W Th 
F 
Sa 
S M 
T 
W  Th 
F Sa 
S 
M 
T 
W  Th 
F 
Sa 
S 
M 
T 
W Th 
F 
Sa 
S M 
T 
W Th 
F Sa 
S M 
T 
XRT 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
AZD1775 50mg/m2 
- 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
PK 
 
 
 
 
 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thursday Start Date for XRT 
 
Th 
F 
Sa 
S 
M 
T 
W Th 
F 
Sa 
S 
M   T 
W  Th F 
Sa S 
M 
T 
W  Th F 
Sa 
S 
M 
T 
W Th 
F 
Sa 
S 
M T 
W Th 
F 
Sa S 
M T 
W 
XRT 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
AZD1775 50mg/m2 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
PK 
 
 
 
 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Friday Start Date for XRT 
 
F 
Sa 
S 
M 
T 
W Th 
F 
Sa 
S 
M 
T W 
 Th F 
Sa 
S M 
T 
W  Th F 
Sa 
S 
M 
T 
W Th 
F 
Sa 
S 
M 
T W 
Th 
F 
Sa 
S M 
T W 
Th 
XRT 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
AZD1775 50mg/m2 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
x 
- 
x 
- 
- 
- 
- 
- 
- 
PK 
 
 
 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X = treatment; “-” = no treatment 
 


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Dose Level 1: AZD1775 (MK-1775) 50 mg/m2/dose daily Mon-Fri, alternating weeks 
 
Week 1: Days 1-7 
Week 2: Days 8-14 
Week 3: Days 15-21 
Week 4: Days 22-28 
Week 5: Days 29-35 
Week 6: Days 36-42 
 Monday Start Date for XRT 
 
M 
T 
W 
Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
XRT 
x 
x x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
AZD1775 50mg/m2 
x 
x x 
x 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
x 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
x 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
PK 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Tuesday Start Date for XRT 
 
T 
W Th F 
Sa 
S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
XRT 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
AZD1775 50mg/m2 
x 
x 
x x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
x 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
- 
- 
- 
- 
- 
- 
- 
PK 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wednesday Start Date for XRT 
 
W Th 
F 
Sa 
S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M T 
W 
Th F 
Sa S 
M T 
XRT 
x 
x 
x - 
- x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
AZD1775 50mg/m2 
- 
- 
- 
- 
- x 
x 
x 
x 
x 
- 
- 
- 
- 
- 
- 
- - 
- 
x 
x 
x 
x 
x - 
- 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
x 
x 
- 
- 
- 
- 
PK 
 
 
 
 
 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thursday Start Date for XRT 
 
Th F 
Sa 
S M 
T 
W Th 
F Sa S 
M 
  T W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T W 
XRT 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
AZD1775 50mg/m2 
- 
- 
- 
- 
x 
x 
x 
x 
x - 
- 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
x 
x - 
- 
- 
- 
- 
- 
- - 
- 
x 
x 
x 
x 
x - 
- 
- 
- 
- 
PK 
 
 
 
 
x 
x 
 
x 
x  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Friday Start Date for XRT 
 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
XRT 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
AZD1775 50mg/m2 
- 
- 
- 
x 
x 
x 
x 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
x 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
x 
x 
- 
- 
- 
- 
- 
- 
PK 
 
 
 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“x” = treatment; “-” = no treatment 
 


ADVL1217                
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 01/31/19 
 
77 
 
Dose Level 2: AZD1775 (MK-1775) 50 mg/m2 daily Mon-Fri every other week, alternating with weeks of QOD dosing 
 
Week 1: Days 1-7 
Week 2: Days 8-14 
Week 3: Days 15-21 
Week 4: Days 22-28 
Week 5: Days 29-35 
Week 6: Days 36-42 
 Monday Start Date for XRT 
 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
XRT 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
AZD1775 50mg/m2 
x 
x 
x 
x 
x 
- 
- 
x 
- 
x 
- 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
- 
x 
- 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
- 
x 
- 
x - 
- 
PK 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Tuesday Start Date for XRT 
 
T 
W Th F 
Sa 
S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa 
S 
M 
T 
W Th 
F Sa 
S 
M 
XRT 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
AZD1775 50mg/m2 
- 
x 
- 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
- 
x 
- 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
- 
x 
- 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
PK 
 
 
 
 
 
 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wednesday Start Date for XRT 
 
W 
Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
M T 
XRT 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
AZD1775 50mg/m2 
x 
- 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
- 
x 
- 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
- 
x 
- 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
- 
PK 
 
 
 
 
 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thursday Start Date for XRT 
 
Th F 
Sa S 
M 
T W Th F 
Sa S 
M 
  T W Th F 
Sa S 
M 
T W Th 
F Sa S 
M 
T 
W 
Th F Sa 
S M 
T 
W Th 
F Sa 
S 
M 
T 
W 
XRT 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- x 
x 
x 
x 
x - 
- x 
x 
x 
AZD1775 50mg/m2 
- 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
- 
x 
- 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
- 
x 
- 
x - 
- x 
x 
x 
x 
x - 
- x 
- 
x 
PK 
 
 
 
 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Friday Start Date for XRT 
 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W 
Th F 
Sa S M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
XRT 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x x 
x 
x 
- 
- x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
AZD1775 50mg/m2 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
- 
x 
- 
x 
- 
- 
x 
x 
x 
x 
x 
- - 
x 
- 
x 
- 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
- 
x 
- 
PK 
 
 
 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“x” = treatment; “-” = no treatment 


ADVL1217                
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 01/31/19 
 
78 
 
Dose Level 3: AZD1775 (MK-1775) 50 mg/m2 daily Mon-Fri During Weeks 1-6 
 
 
Week 1: Days 1-7 
Week 2: Days 8-14 
Week 3: Days 15-21 
Week 4: Days 22-28 
Week 5: Days 29-35 
Week 6: Days 36-42 
 Monday Start Date for XRT 
 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
XRT 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
AZD1775 50mg/m2 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
PK* 
x 
x 
 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Tuesday Start Date for XRT 
 
T 
W Th F 
Sa 
S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa 
S 
M 
T 
W Th 
F Sa 
S 
M 
XRT 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
AZD1775 50mg/m2 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
PK* 
B 
 
 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wednesday Start Date for XRT 
 
W 
Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
M T 
XRT 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
AZD1775 50mg/m2 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
PK* 
B 
 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thursday Start Date for XRT 
 
Th F 
Sa S 
M 
T W Th F 
Sa S 
M 
  T W Th F 
Sa S 
M 
T W Th 
F Sa S 
M 
T 
W 
Th F Sa 
S M 
T 
W Th 
F Sa 
S 
M 
T 
W 
XRT 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- x 
x 
x 
x 
x - 
- x 
x 
x 
AZD1775 50mg/m2 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x x x 
x - 
- x 
x 
x 
x 
x - 
- x 
x 
x 
PK* 
B 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Friday Start Date for XRT 
 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W 
Th F 
Sa S M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
XRT 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x x 
x 
x 
- 
- x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
AZD1775 50mg/m2 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x x x x 
x 
- 
- 
x 
x 
x 
x 
x 
- - 
x x 
x x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x x 
x x 
PK* 
B 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“x” = treatment; “-” = no treatment 
* B= The initial Baseline/Pre-study blood sample is drawn within 7 days prior to XRT start date. “PK/PD Day 1” is scheduled for the Monday of the first full week 
of dosing. 


ADVL1217                
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 01/31/19 
 
79 
 
 
Dose Level 4: AZD1775 (MK-1775) 95 mg/m2 daily Mon-Fri During Weeks 1-6 
 
Week 1: Days 1-7 
Week 2: Days 8-14 
Week 3: Days 15-21 
Week 4: Days 22-28 
Week 5: Days 29-35 
Week 6: Days 36-42 
 Monday Start Date for XRT 
 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
XRT 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
AZD1775 95mg/m2 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
PK* 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Tuesday Start Date for XRT 
 
T 
W Th F 
Sa 
S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa 
S 
M 
T 
W Th 
F Sa 
S 
M 
XRT 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
AZD1775 95mg/m2 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
PK* 
B 
 
 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wednesday Start Date for XRT 
 
W 
Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
M T 
XRT 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
AZD1775 95mg/m2 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
PK* 
B 
 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thursday Start Date for XRT 
 
Th F 
Sa S 
M 
T W Th F 
Sa S 
M 
  T W Th F 
Sa S 
M 
T W Th 
F Sa S 
M 
T 
W 
Th F Sa 
S M 
T 
W Th 
F Sa 
S 
M 
T 
W 
XRT 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- x 
x 
x 
x 
x - 
- x 
x 
x 
AZD1775 95mg/m2 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x x x 
x - 
- x 
x 
x 
x 
x - 
- x 
x 
x 
PK* 
B 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Friday Start Date for XRT 
 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W 
Th F 
Sa S M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
XRT 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x x 
x 
x 
- 
- x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
AZD1775 95mg/m2 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x x x x 
x 
- 
- 
x 
x 
x 
x 
x 
- - 
x x 
x x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x x 
x x 
PK* 
B 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“x” = treatment; “-” = no treatment 
* B= The initial Baseline/Pre-study blood sample is drawn within 7 days prior to XRT start date. “PK/PD Day 1” is scheduled for the Monday of the first full week 


ADVL1217                
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 01/31/19 
 
80 
 
of dosing. 


ADVL1217                
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 01/31/19 
 
81 
 
Dose Level 5: AZD1775 (MK-1775) 130 mg/m2 Mon-Fri During Weeks 1-6 
 
Week 1: Days 1-7 
Week 2: Days 8-14 
Week 3: Days 15-21 
Week 4: Days 22-28 
Week 5: Days 29-35 
Week 6: Days 36-42 
 Monday Start Date for XRT 
 
M T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
XRT 
x x 
x 
x 
x 
- 
- 
x 
x 
x 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
AZD1775 130mg/m2 
x x 
x 
x 
x 
- 
- 
x 
x 
x 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
PK* 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Tuesday Start Date for XRT 
 
T 
W Th F 
Sa 
S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa 
S 
M 
T 
W Th 
F Sa 
S 
M 
XRT 
x x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
AZD1775 130mg/m2 
x x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
PK* 
B 
 
 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wednesday Start Date for XRT 
 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
M T 
XRT 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
AZD1775 130mg/m2 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
PK* 
B 
 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thursday Start Date for XRT 
 
Th F 
Sa S 
M 
T W Th F 
Sa S 
M 
  T W Th F 
Sa S 
M 
T W Th 
F Sa S 
M 
T 
W 
Th F Sa 
S M 
T 
W Th 
F Sa 
S 
M 
T 
W 
XRT 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- x 
x 
x 
x 
x - 
- x 
x 
x 
AZD1775 130mg/m2 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x x x 
x - 
- x 
x 
x 
x 
x - 
- x 
x 
x 
PK* 
B 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Friday Start Date for XRT 
 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W 
Th F 
Sa S M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
XRT 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x x 
x 
x 
- 
- x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
AZD1775 130mg/m2 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x x x x 
x 
- 
- 
x 
x 
x 
x 
x 
- - 
x x 
x x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x x 
x x 
PK* 
B 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“x” = treatment; “-” = no treatment 
* B= The initial Baseline/Pre-study blood sample is drawn within 7 days prior to XRT start date. “PK/PD Day 1” is scheduled for the Monday of the first full week 
of dosing. 


ADVL1217                
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 01/31/19 
 
82 
 
Dose Level 6: AZD1775 (MK-1775) 160 mg/m2 daily Mon-Fri During Weeks 1-6 
 
Week 1: Days 1-7 
Week 2: Days 8-14 
Week 3: Days 15-21 
Week 4: Days 22-28 
Week 5: Days 29-35 
Week 6: Days 36-42 
 Monday Start Date for XRT 
 
M T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
XRT 
x x 
x 
x 
x 
- 
- 
x 
x 
x 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
AZD1775 160mg/m2 
x x 
x 
x 
x 
- 
- 
x 
x 
x 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
PK* 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Tuesday Start Date for XRT 
 
T 
W Th F 
Sa 
S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa 
S 
M 
T 
W Th 
F Sa 
S 
M 
XRT 
x x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
AZD1775 160mg/m2 
x x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
PK* 
B 
 
 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wednesday Start Date for XRT 
 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
M T 
XRT 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
AZD1775 160mg/m2 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
PK* 
B 
 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thursday Start Date for XRT 
 
Th F 
Sa S 
M 
T W Th F 
Sa S 
M 
  T W Th F 
Sa S 
M 
T W Th 
F Sa S 
M 
T 
W 
Th F Sa 
S M 
T 
W Th 
F Sa 
S 
M 
T 
W 
XRT 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- x 
x 
x 
x 
x - 
- x 
x 
x 
AZD1775 160mg/m2 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x x x 
x - 
- x 
x 
x 
x 
x - 
- x 
x 
x 
PK* 
B 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Friday Start Date for XRT 
 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W 
Th F 
Sa S M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
XRT 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x x 
x 
x 
- 
- x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
AZD1775 160mg/m2 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x x x x 
x 
- 
- 
x 
x 
x 
x 
x 
- - 
x x 
x x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x x 
x x 
PK* 
B 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“x” = treatment; “-” = no treatment 
* B= The initial Baseline/Pre-study blood sample is drawn within 7 days prior to XRT start date. “PK/PD Day 1” is scheduled for the Monday of the first full 
week of dosing 


ADVL1217                
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 01/31/19 
 
83 
 
Dose Level 7: AZD1775 (MK-1775) 200 mg/m2 daily Mon-Fri During Weeks 1-6 
 
Week 1: Days 1-7 
Week 2: Days 8-14 
Week 3: Days 15-21 
Week 4: Days 22-28 
Week 5: Days 29-35 
Week 6: Days 36-42 
 Monday Start Date for XRT 
 
M T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
XRT 
x x 
x 
x 
x 
- 
- 
x 
x 
x 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
AZD1775 200mg/m2 
x x 
x 
x 
x 
- 
- 
x 
x 
x 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
PK* 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Tuesday Start Date for XRT 
 
T 
W Th F 
Sa 
S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa 
S 
M 
T 
W Th 
F Sa 
S 
M 
XRT 
x x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
AZD1775 200mg/m2 
x x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
PK* 
B 
 
 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wednesday Start Date for XRT 
 
W Th 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th 
F 
Sa S 
M 
T 
W Th 
F Sa S 
M 
T 
W Th F 
Sa S 
M T 
XRT 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
AZD1775 200mg/m2 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
PK* 
B 
 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thursday Start Date for XRT 
 
Th F 
Sa S 
M 
T W Th F 
Sa S 
M 
  T W Th F 
Sa S 
M 
T W Th 
F Sa S 
M 
T 
W 
Th F Sa 
S M 
T 
W Th 
F Sa 
S 
M 
T 
W 
XRT 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- x 
x 
x 
x 
x - 
- x 
x 
x 
AZD1775 200mg/m2 
x x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x - 
- 
x 
x 
x 
x 
x - 
- 
x 
x x x 
x - 
- x 
x 
x 
x 
x - 
- x 
x 
x 
PK* 
B 
 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Friday Start Date for XRT 
 
F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W 
Th F 
Sa S M 
T 
W Th F 
Sa S 
M 
T 
W Th F 
Sa S 
M 
T 
W Th 
XRT 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x x 
x 
x 
- 
- x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x 
x 
x 
x 
AZD1775 200mg/m2 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x x x x 
x 
- 
- 
x 
x 
x 
x 
x 
- - 
x x 
x x 
x 
- 
- 
x 
x 
x 
x 
x 
- 
- 
x x 
x x 
PK* 
B 
 
 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD* 
B 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“x” = treatment; “-” = no treatment 
* B= The initial Baseline/Pre-study blood sample is drawn within 7 days prior to XRT start date. “PK/PD Day 1” is scheduled for the Monday of the first full 
week of dosing 


ADVL1217                
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 01/31/19 
 
84 
 
 
 
 
APPENDIX VI:  CORRELATIVE STUDIES GUIDE 
 
 
Correlative Study 
 
Appendix 
Blood Volume 
 
 
Tube Type 
Volume per 
sample 
Total Volume 
≥ 20 kg 
Total Volume 
<20 kg 
 
Pharmacokinetics 
VII; X 
2-3 ml 
30-45 ml 
16-24 ml 
K2 EDTA (lavender-top) 
Pharmacodynamics 
VIII 
1 ml 
5 ml 
5 ml 
Heparinized (green-top); 
Smart Tubes  
Total Blood Volume 
35-50 ml 
21-29 ml 
 
 
 


ADVL1217                
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 01/31/19 
 
85 
 
APPENDIX VII:  PHARMACOKINETIC STUDY FORM 
 
COG Pt ID # _________ACC # _______     Day 1 of Protocol Therapy (XRT Start Date): ___________ 
Please do not write patient names on this form or on samples. 
 
 
 
 
 
 
 
 
 
  Patient weight:     ________kg 
Body Surface Area: ______m2 
 
Dose Level: ______mg/m2 
  Total Daily Dose: ________mg 
 
**Refer to Appendix V-B for PK collection based on XRT start date. ** 
 
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): Baseline, PK Day 1 (pre-dose, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr and 24 hours after dose), PK Day 5 
(pre-dose, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr after dose), and PK Day 8 (pre-dose).  
 
For patients < 20 kg, samples will be collected at the following time points (+/- 10 minutes): Baseline, PK Day 5 (pre-
dose, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr after dose), and PK Day 8 (pre-dose). 
 
 
Blood 
Sample 
No. 
Time Point** 
Scheduled Collection Time**   
Actual Date 
Sample 
Collected 
Actual Time 
Sample Collected 
(24-hr clock) 
0$ 
Baseline/Pre-study 
Within 7 days prior to XRT start date 
___/___/___ 
|__|__| : |__|__| 
1$, ^ 
Baseline/PK Day 1 
Prior to Monday dose  
___/___/___ 
|__|__| : |__|__| 
AZD1775 (MK-1775) Dose on PK Day 1**       Date:___/___/___       Time: |__|__| : |__|__| 
2^ 
PK Day 1 
1 hr after Monday dose 
___/___/___ 
|__|__| : |__|__| 
3^ 
PK Day 1 
2 hr after Monday dose 
___/___/___ 
|__|__| : |__|__| 
4^ 
PK Day 1 
4 hr after Monday dose 
___/___/___ 
|__|__| : |__|__| 
5^ 
PK Day 1 
6 hr after Monday dose 
___/___/___ 
|__|__| : |__|__| 
6^ 
PK Day 1 
8 hr after Monday dose  
___/___/___ 
|__|__| : |__|__| 
7^ 
PK Day 2 
24 (±2) hrs after Monday dose@ 
___/___/___ 
|__|__| : |__|__| 
8 
PK Day 4 
Prior to Thursday dose  
No Longer Collected per AMD#3 
9 
PK Day 5 
Prior to Friday dose  
___/___/___ 
|__|__| : |__|__| 
AZD1775 (MK-1775) Dose on PK Day 5**     Date:___/___/___       Time: |__|__| : |__|__| 
 
Hematocrit Value on PK Day 5 (if available): ________________ 
 
10% 
PK Day 5 
1 hr after Friday dose 
___/___/___ 
|__|__| : |__|__| 
11 
PK Day 5 
2  hr after Friday dose 
___/___/___ 
|__|__| : |__|__| 
12 
PK Day 5 
4 hr after Friday dose 
___/___/___ 
|__|__| : |__|__| 
13 
PK Day 5 
6 hr after Friday dose 
___/___/___ 
|__|__| : |__|__| 
14 
PK Day 5 
8 hr after Friday dose  
___/___/___ 
|__|__| : |__|__| 
15 
PK Day 8 
Prior to Monday dose  
___/___/___ 
|__|__| : |__|__| 
AZD1775 (MK-1775) Dose on PK Day 8**     Date:___/___/___       Time: |__|__| : |__|__| 
$ Baseline samples should be taken at least 1 day apart, if feasible.  
 
^  Patients ≥ 20 kg only 
**Refer to Appendix V-B for PK collection based on XRT start date.  
 
@  Hold Dose until PK sample is 
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 8.4.6.  See Section 8.4 and Appendix XI for detailed guidelines for packaging and 
shipping PK samples.   
 
Signature: _________________________________________                    Date: ___________________ 
 
 
(site personnel who collected samples) 
 


ADVL1217                
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
Version Date: 01/31/19 
 
86 
 
APPENDIX VIII:  PHARMACODYNAMIC STUDY FORM 
 
COG Pt ID # ________ ACC # _______       Day 1 of Protocol Therapy (XRT Start 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 
 
Blood samples will be obtained from all patients (1 ml per time point) prior to treatment start (two baseline 
samples are required) as well as at the following time points. Every effort should be made to obtain the 
baseline (pre-treatment) samples on two different days, if feasible. A total of 5 time points for the PD 
analysis will be collected. 
 
Blood 
Sample 
No. 
Time Point** 
Scheduled Collection Time** 
Actual Date 
Sample 
Collected 
Actual Time 
Sample Collected 
(24-hr clock) 
1* 
Baseline/Pre-study 
Within 7 days prior to XRT start date ___/___/___ 
|__|__| : |__|__| 
2* 
Baseline/ PD Day 1 
Prior to Monday dose  
___/___/___ 
|__|__| : |__|__| 
AZD1775 (MK-1775) Dose on PD Day 1**      Date:___/___/___       Time: |__|__| : |__|__| 
3 
PD Day 1 
6-8 hr after Monday dose 
___/___/___ 
|__|__| : |__|__| 
AZD1775 (MK-1775) Dose on PD Day 5**      Date:___/___/___       Time: |__|__| : |__|__| 
4 
PD Day 5 
6-8 hr after Friday dose  
___/___/___ 
|__|__| : |__|__| 
5 
PD Day 8 
Prior to Monday dose 
___/___/___ 
|__|__| : |__|__| 
AZD1775 (MK-1775) Dose on PD Day 8**       Date:___/___/___       Time: |__|__| : |__|__| 
*Baseline samples should be taken at least 1 day apart, if feasible. 
**Refer to Appendix V-B for PD collection based on XRT start date. 
 
One copy of this Pharmacodynamic Study Form should be uploaded into RAVE. A second copy should be 
sent with the samples to the address listed in Section 8.5.5.  See Section 8.5 for detailed guidelines for 
packaging and shipping PD samples.   
 
Record any notes for Sample Storage Conditions below. 
 
Notes:    
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
 
Signature: _________________________________________                    Date:___________________ 
 
 
(site personnel who collected samples) 


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APPENDIX IX:  PD SAMPLE COLLECTION GUIDELINES 
 
 
Required Items: 
 
- 
Whole blood collection at required PD time points as outlined in Appendix VIII 
- 
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 (i.e. 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 8.5.5. Samples should NOT be shipped on a Friday or 
before a holiday. 
 
 


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


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APPENDIX XI: PREPARATION OF PLASMA SAMPLES FOR AZD1775 (MK-1775) PK 
ASSESSMENT 
 
I. 
Biosafety 
 
It is essential that universal precautions be taken while working with these specimens. However, 
you are encouraged to wear gloves and a lab coat/gown at all times to ensure safe handling of 
samples. If you should tear a glove, remove the torn one and replace it immediately.  
 
II. 
General Instructions 
 
Collect venous blood in a purple-topped vacutainer containing K2EDTA.   
 
III. Sample Preparation: 
 
Material Needed: 
1. 
Purple-topped vacutainer evacuated blood collection tubes (containing K2EDTA) 
2. 
3.6 mL NUNC internal thread round bottom cryotubes (NUNC Part #366524) for 
plasma  
 
Collection of Blood 
For specific time points of sample collection, please refer to Appendix VII and Appendix V-B. 
Procedure 
1. Samples in the blood collection tube will be centrifuged at between 1000-1300 RCF (x g) at 
between 4°C to 10°C for 10 minutes.  If the samples cannot be centrifuged immediately, the tubes 
should be kept on ice and centrifuged within 30 minutes of collection. 
Note:  RCF varies according to the centrifuge rotor radius.  The formula for computing RCF 
from rotation speed and centrifuge radius is RCF = 11.2r (RPM/1000)2, where r is rotor 
radius, in cm, and RPM is the rotations per minute setting of the centrifuge.   
2. Immediately after separation of the whole blood, carefully transfer the plasma (about 0.5 - 1.0 
mL) using a plastic pipette into a labeled 3.6 mL internally-threaded NUNC cryotube and store at 
-20°C until shipment on DRY ICE. 
Note:  In the event that the whole blood samples cannot be processed immediately the 
samples should be kept on ice.  No more than 60 minutes should elapse between blood draw 
and the freezing of plasma samples. 
 
IV. Laboratory Contact and Shipping Instructions 
It is the responsibility of the primary investigator to ensure that all staff personnel who will be handling, 
packaging, and/or shipping clinical specimens act in conformance with International Air Transport 
Association (IATA) regulations relating to the handling and shipping of hazardous goods. 
1.   AZD1775 (MK-1775) plasma shipments will be made in freezer boxes containing at least 10 kg 
DRY ICE. 
2.   Please include the PK Study Form (Appendix VII) with each shipment. 
3. Shipments should be sent via overnight Federal Express, Monday through Wednesday to assure 
receipt by Friday. All samples should be shipped to the address in Section 8.4.6. 
 
 


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APPENDIX XII:  POTENTIAL DRUG INTERACTIONS WITH AZD1775 (MK-1775) 
 
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) 
• 
Some heartburn medications (cimetidine, omeprazole, lansoprazole, rabeprazole) 
• 
Some cholesterol lowering medications (atorvastatin, pravastatin, rosuvastatin, simvastatin) 
• 
Several other specific agents, including the following: 
o Aprepitant/fosaprepitant 
o Amiodarone 
o Barbiturates 
o Diazepam 
o Diltiazem 
o Imatinib 
o Metformin 
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.   
 
 


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APPENDIX XIV:  INSTRUCTIONS FOR TREATING DIARRHEA 
 
Institutional practice may be used in place of these guidelines.   
 
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, initiate infectious evaluation including but not limited to bacterial 
culture, c. difficile toxin, viral infection (i.e. adenovirus, norovirus, rotavirus, enterovirus, CMV).   If studies 
are negative, initiate loperamide (dosing below).    
 
Any patient with diarrhea who is not already admitted to the hospital should be admitted for close 
monitoring for the occurrence of blood or black stools, symptoms of dehydration, fever, inability to take 
liquids by mouth, and inability to control diarrhea within 24 hours of using loperamide or other prescribed 
antidiarrheal medications. 
 
Patients will be given loperamide based on body weight. Loperamide may be discontinued when diarrhea 
has resolved for 12 hours. 
 
LOPERAMIDE DOSING RECOMMENDATIONS 
(NOTE: 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 (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral solution) after 
the first loose bowel movement, followed by 0.5 mg (2.5 mL [one-half 
teaspoonful] of the 1 mg/5 mL oral solution) every 3 hours.  During the night, the 
patient may take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral 
solution) every 4 hours.  Do not exceed 4 mg (20 mL or 4 teaspoonfuls) per day. 
 
≥ 13 kg to < 20 kg 
Take 1 mg (5 mL [1 teaspoonful] of the 1 mg/5 mL oral solution or one-half 
capsule or tablet) after the first loose bowel movement, followed by 1 mg (5 mL 
[one teaspoonful] of the 1 mg/5 mL oral solution) every 3 hours. During the night, 
the patient may take 1 mg (5 mL [one teaspoonful] of the 1 mg/5 mL oral solution) 
every 4 hours.  Do not exceed 6 mg (30 mL or 6 teaspoonfuls) per day. 
 
≥ 20 kg to < 30 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 capsule or 
tablet) after the first loose bowel movement, followed by 1 mg (5 mL [one 
teaspoonful] of the 1 mg/5 mL oral solution or one-half capsule or tablet) every 3 
hours.  During the night, the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 
1 mg/5 mL oral solution or 1 capsule or tablet) every 4 hours. Do not exceed 8 mg 
(40 mL or 8 teaspoonfuls) per day. 
 
≥ 30 kg to < 43 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 capsule or 
tablet) after the first loose bowel movement, followed by 1 mg (5 mL [one 
teaspoonful] of the 1 mg/5 mL oral solution or one-half capsule or tablet) every 2 
hours.  During the night, the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 
1 mg/5 mL oral solution or 1 capsule or tablet) every 4 hours. Do not exceed 12 mg 
(60 mL or 12 teaspoonfuls) per day. 
 
Over 43 kg 
Take 4 mg (20 mL [4 teaspoonfuls] of the 1 mg/5 mL oral solution or 2 capsules 
or tablets) after the first loose bowel movement, followed by 2 mg (10 mL 
[2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 capsule or tablet) every 


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2 hours.  During the night, the patient may take 4 mg (20 mL [4 teaspoonfuls] of 
the 1 mg/5 mL oral solution or 2 capsules or tablets) every 4 hours. Do not exceed 
16 mg (80 mL or 16 teaspoonfuls) per day. 
 
 
 
 


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APPENDIX XV: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions 
with Other Drugs and Herbal Supplements  
 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to the patient at the 
time of enrollment.  Use or modify the text as appropriate for the study agent, so that the patient is aware 
of the risks and can communicate with their regular prescriber(s) and pharmacist.  A convenient wallet-
sized information card is also included for the patient to clip out and retain at all times.  If you choose to 
use them, please note that the information sheet and wallet card will require IRB approval before 
distribution to patients.] 
 
 
The patient ____________________________ is enrolled on a clinical trial using the experimental study 
drug AZD1775 (MK-1775).  This clinical trial is sponsored by the National Cancer Institute.  This form is 
addressed to the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
 
 
 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
AZD1775 (MK-1775) may interact with other drugs which can cause side effects.  For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this clinical 
trial.  It is also very important to tell your doctors if you stop taking any regular medicines, or if you start 
taking a new medicine while you take part in this study.  When you talk about your current medications 
with your doctors, include medicine you buy without a prescription (over-the-counter remedy), or herbal 
supplements such as St. John’s Wort.  It is helpful to bring your medication bottles or an updated medication 
list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
 
 
•  Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
•  Your regular health care provider should check a frequently updated medical reference or call your 
study doctor before prescribing any new medicine or discontinuing any medicine. Your study 
doctor’s name is _____________________________________ and he or she can be contacted at 
_____________________________________.                                                                                                  May 2015 
 
 
 
 
➢ ” 
➢ Before prescribing new medicines, your regular prescribers 
should go to a frequently-updated medical reference for a list of 
drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is ________________________  
and can be contacted at _________________________.  
STUDY DRUG INFORMATION WALLET CARD   
 
You are enrolled on a clinical trial using the experimental study drug 
AZD1775 (MK-1775).  This clinical trial is sponsored by the NCI.  
Because of this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial.


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