Clinical trial NCT03213691
Conditions: Advanced Malignant Solid Neoplasm Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma Recurrent Childhood Central Nervous System Neoplasm Recurrent Childhood Non-Hodgkin Lymphoma Recurrent Malignant Solid Neoplasm Recurrent Neuroblastoma Refractory Malignant Solid Neoplasm Refractory Neuroblastoma Refractory Non-Hodgkin Lymphoma Refractory Primary Central Nervous System Neoplasm
Sponsor: National Cancer Institute (NCI)
Start date: 2017-10-30; Completion date: 2024-12-31
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II Pediatric MATCH trial studies how well selumetinib sulfate works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with MAPK pathway activation mutations that have spread to other places in the body and have come back or do not respond to treatment. Selumetinib sulfate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with selumetinib (AZD6244 hydrogen sulfate) with advanced solid tumors (including central nervous system \[CNS\] tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor activating genetic alterations in the MAPK pathway.

SECONDARY OBJECTIVES:

I. To estimate the progression free survival in pediatric patients treated with selumetinib (AZD6244 hydrogen sulfate) with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor MAPK activation mutations.

II. To obtain additional information about the tolerability of selumetinib (AZD6244 hydrogen sulfate) in children with relapsed or refractory cancer.

EXPLORATORY OBJECTIVES:

I. To evaluate other biomarkers as predictors of response to selumetinib (AZD6244 hydrogen sulfate) and specifically, whether tumors that harbor different mutations or fusions will demonstrate differential response to selumetinib (AZD6244 hydrogen sulfate) treatment.

II. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA).

OUTLINE:

Patients receive selumetinib sulfate 25 mg/m2/dose orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

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

Arms: arm 1: Patients receive selumetinib sulfate PO BID on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Selumetinib intervention 3: Selumetinib Sulfate
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
i 
 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, M.S. 
crabtreed@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 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
August 19, 2019 
 
Martha Kruhm, M.S., RAC 
Protocol and Information Office (PIO) Head 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
Attached for review is Amendment #3 to APEC1621E, NCI-COG Pediatric MATCH 
(Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of selumetinib (AZD6244 
hydrogen sulfate) in patients with tumors harboring activating MAPK pathway mutations. 
This amendment is being submitted in response to an RRA from Dr. Doyle 
(doylela@mail.nih.gov). In this amendment, the revised CAEPR for Selumetinib 
(AZD6244 hydrogen sulfate) (Version 2.8, June 13, 2019) has been inserted in the protocol, 
and the associated risk information in the informed consent document has been revised. 
 
 
 
 


                                                                     
 
 
APEC1621E 
 
 
 
ii 
 
SUMMARY OF CHANGES 
 The following specific revisions have been made to the protocol and informed consent document. 
Additions are in boldfaced font and deletions in strikethrough font. 
I. Changes made to the protocol by Principal Investigator:  
# 
Section 
Comments 
1. 
9.1.8 
The CAEPR has been updated in response to a rapid request for amendment:  
 
• 
The SPEER grades have been updated. 
 
• 
Added New Risk:  
• 
Rare but Serious: Eye disorders - Other (central serous retinopathy); Eye disorders - 
Other (retinal pigment epithelial detachment); Eye disorders - Other (retinal vein 
occlusion); Folliculitis; Nail infection; Papulopustular rash; Skin infection 
 
• 
Increase in Risk Attribution:  
• 
Changed to Rare but Serious from Also Reported on Selumetinib Trials But With 
Insufficient Evidence for Attribution: Ejection fraction decreased; Musculoskeletal and 
connective tissue disorder - Other (neck extensor muscle weakness) 
 
• 
Provided Further Clarification:  
• 
Footnote#4 is now deleted.  
II. Changes to the Informed Consent by Principal Investigator:  
 
# 
Section 
Comments 
1. 
ICD 
The Risk Profile has been updated. 
 
• 
Added New Risk: 
• 
Rare: Vision changes; Blood clot which may cause blurred vision or blindness 
 
• 
Increase in Risk Attribution: 
• 
Changed to Rare from Also Reported on Selumetinib Trials But With Insufficient 
Evidence for Attribution (i.e., added to the Risk Profile): Change in heart function; 
Muscle weakness 
 
• 
Provided Further Clarification:  
• 
Blurred vision (under Rare) is now reported as part of Blurred vision or blindness 
(under Rare). 
 
Sincerely, 
 
Rita Tawdros, Senior Protocol Coordinator, for 
Carl Allen, MD PhD, APEC1621E Study Chair 
Peter Adamson, M.D., Chair, Children’s Oncology Group
 


 
 
APEC1621E 
 
 
 
 
 
Page 1 
 
Activated: July 24th, 2017 
 
Version Date:  
08/19/2019 
Closed: 
 
Amendment# 
3 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
APEC1621E 
 
NCI-COG PEDIATRIC MATCH 
(MOLECULAR ANALYSIS FOR THERAPY CHOICE)- 
PHASE 2 SUBPROTOCOL OF SELUMETINIB (AZD6244 HYDROGEN SULFATE) IN 
PATIENTS WITH TUMORS HARBORING ACTIVATING MAPK PATHWAY MUTATIONS 
 
 
Open to COG Member Institutions in the USA  
 
 
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 
Carl E. Allen, MD, PhD 
Baylor College of Medicine/Dan L Duncan  
Comprehensive Cancer Center 
6621 Fannin St: CC1410.0 
Houston, TX 77054 
Phone: 832-824-4312 
Fax: 832-825-1453 
Email: ceallen@txch.org  


 
 
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TABLE OF CONTENTS 
SECTION 
PAGE 
 
 
CHILDREN’S ONCOLOGY GROUP 
1 
STUDY COMMITTEE, CONT. 
6 
COG OPERATIONS STAFF 
6 
ABSTRACT 
 
7 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Aims 
8 
1.2 
Secondary Aims 
8 
1.3 
Exploratory Aims 
8 
2.0 
BACKGROUND 
8 
2.1 
Introduction/Rationale for Development 
8 
2.2 
Preclinical Studies 
9 
2.3 
Adult Studies 
9 
2.4 
Pediatric Studies 
10 
2.5 
Overview of Proposed Pediatric Study 
11 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
12 
3.1 
Genetic Screening Procedures for Eligibility 
12 
3.2 
IRB Approval 
12 
3.3 
Informed Consent/Assent 
13 
3.4 
Screening Procedures 
13 
3.5 
Eligibility Checklist 
13 
3.6 
Study Enrollment 
13 
3.7 
Institutional Pathology Report 
14 
3.8 
Dose Assignment 
14 
4.0 
PATIENT ELIGIBILITY 
14 
4.1 
Inclusion Criteria 
14 
4.2 
Exclusion Criteria 
18 
5.0 
TREATMENT PROGRAM 
19 
5.1 
Overview of Treatment Plan 
19 
5.2 
Criteria for Starting Subsequent Cycles 
20 
5.3 
Grading of Adverse Events 
20 
5.4 
Definition of Dose-Limiting Toxicity (DLT) 
20 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
21 
6.1 
Dose Modifications for Hematological Toxicity 
21 
6.2 
Dose Modifications for Non-Hematological Toxicity 
21 
6.3 
Dose Modifications for Hepatic Adverse Events 
22 
6.4 
Dose Modifications for Dermatology/Skin Disorders 
22 
6.5 
Dose Modifications for Visual Disturbances 
22 
6.6 
Dose Modifications for Elevation of CPK 
22 
6.7 
Dose Modifications for Hypertension 
23 
6.8 
Dose Modification for Elevated Fasting Cholesterol 
27 


 
 
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7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
27 
7.1 
Concurrent Anticancer Therapy 
27 
7.2 
Investigational Agents 
27 
7.3 
Supportive Care 
27 
7.4 
Growth Factors 
28 
7.5 
Concomitant Medications 
28 
7.6 
Concurrent Anti-Hypertensive Therapy 
29 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
29 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
29 
8.2 
Monitoring for Specific Toxicities 
31 
8.3 
Radiology Studies 
31 
8.4 
Circulating Tumor DNA Study (optional) 
33 
9.0 
AGENT INFORMATION 
35 
9.1 
Selumetinib 
35 
9.2 
Agent Ordering and Agent Accountability 
39 
9.3 
Clinical Drug Request and Investigator Brochure Availability 
40 
9.4 
Agent Inventory Records 
40 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
41 
10.1 
Criteria for Removal from Protocol Therapy 
41 
10.2 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
41 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
41 
11.1 
Sample Size and Study Duration 
41 
11.2 
Dosing Considerations 
41 
11.3 
Study Design 
42 
11.4 
Methods of Analysis 
42 
11.5 
Evaluability for Response 
43 
11.6 
Evaluability for Toxicity 
43 
11.7 
Progression free survival (PFS) 
43 
11.8 
Correlative Studies 
43 
11.9 
Gender and Minority Accrual Estimates 
43 
12.0 
EVALUATION CRITERIA 
45 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
45 
12.2 
Progression-Free Survival 
45 
12.3 
Response Criteria for Patients with Solid Tumors 
45 
12.4 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
48 
12.5 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
50 
12.6 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
52 
12.7 
Response Criteria for Patients with CNS Tumors 
53 
12.8 
Response Criteria for Patients with non-Hodgkin Lymphoma/Histiocytosis 
55 
12.9 
Best Response 
57 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
58 
13.1 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
58 
13.2 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
59 
13.3 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements:
 
61 
13.4 
Definition of Onset and Resolution of Adverse Events 
62 
13.5 
Other Recipients of Adverse Event Reports 
62 


 
 
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13.6 
Specific Examples for Expedited Reporting 
63 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
65 
14.1 
Categories of Research Records 
65 
14.2 
CDUS 
65 
14.3 
CRADA/CTA/CSA 
65 
14.4 
Data and Safety Monitoring Plan 
67 
REFERENCES 
68 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
71 
APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
72 
APPENDIX III-A:  PATIENT DIARY FOR SELUMETINIB 
74 
APPENDIX III-B:  
PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
77 
APPENDIX IV:  SELUMETINIB (AZD6244 HYDROGEN SULFATE) DOSING NOMOGRAM 
79 
APPENDIX V: APEC1621E THERAPY DELIVERY MAP 
80 
APPENDIX VI: TARGET HISTOLOGIES FOR APEC1621E EXPANSION COHORTS 
86 
APPENDIX VII: APEC1621E ACTIONABLE MUTATIONS OF INTEREST 
87 
APPENDIX VIII:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
95 
APPENDIX IX: BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT 
PERCENTILE 96 
APPENDIX X: YOUTH INFORMATION SHEETS 
98 
APPENDIX XI CORRELATIVE STUDIES GUIDE 
100 
APPENDIX XII: CTEP AND CTSU REGISTRATION PROCEDURES 
101 
APPENDIX XIII: TOXICITY-SPECIFIC GRADING 
103 


 
 
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STUDY COMMITTEE 
STUDY CHAIR 
Nita Seibel, MD 
Carl E. Allen, MD, PhD 
National Cancer Institute 
Baylor College of Medicine/Dan L Duncan  
9609 Medical Center Drive, MSC 9739 
Comprehensive Cancer Center 
Rockville, MD 20892 
6621 Fannin St: CC730.06 
Phone:  (240) 276-6560 
Houston, TX 77030 
Fax:  (240) 276-7892 
Phone: 832-822-4200 
E-mail: seibelnl@mail.nih.gov  
Fax: 832-825-1453 
 
Email: ceallen@txch.org  
Olive S. Eckstein, MD 
 
STUDY VICE CHAIR 
Will Parsons, MD, PhD 
Baylor College of Medicine/Dan L Duncan 
Baylor College of Medicine 
1102 Bates, Suite 1025.21 
1102 Bates, Suite 1030.15 
Houston, TX 77030 
Houston, TX 77030 
Phone: (832) 824-1000 
Phone: (832) 824-4643 
Fax: 832 825-1503 
Email: dwparson@txch.org 
Email: eckstein@bcm.edu 
 
 
Todd Alonzo, PhD 
Peter C. Adamson, MD 
Study Statistician  
Children’s Hospital of Philadelphia 
COG Statistics and Data Center- Monrovia 
3501 Civic Center Blvd CTRB-10060 
222 East Huntington Dr., Suite 100 
Philadelphia, PA 19104 
Monrovia, CA 91016 
Phone:  (215) 590-6359 
Phone: (626) 241-1522 
Fax:  (215) 590-7544 
Fax: (626) 445-4334 
Email: adamson@email.chop.edu 
Email: talonzo@childrensoncologygroup.org 
 
 
Stacey Berg, MD 
Joel Reid, PhD. 
Study Design and Logistics 
Study Pharmacologist 
Baylor College of Medicine 
Mayo Clinic 
Pediatric Oncology  
Guggenheim 17-37 
6621 Fannin Street 
200 First St SW 
MC3-3320 
Rochester, MN 55905 
Houston, TX 77030 
Phone: (507) 284-0822 
Phone: (832) 824-4588 
Fax: (507) 284-3906 
Fax:  (832) 825-4039 
E-mail: reid.joel@mayo.edu  
Email: sberg@txch.org 
 
 
Jin Piao, PhD 
Elizabeth Fox, MD 
Study Statistician 
COG Statistics and Data Center- Monrovia 
Study Design and Logistics 
Children’s Hospital of Philadelphia 
222 East Huntington Dr., Suite 100 
Pediatrics/Division of Oncology 
Monrovia, CA 91016 
3501 Civic Center Blvd CTRB-4016 
Phone: (626) 241-1572 
Philadelphia, PA 19104 
Fax: (626) 445-4334 
Phone: (267) 425-3010 
Email: jpiao@childrensoncologygroup.org 
Fax:  (267) 425-0113 
 
Email: foxe@email.chop.edu 
 
 
 
 
 


 
 
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STUDY COMMITTEE, CONT. 
 
 
Study CRA 
TBD 
STUDY PHARMACIST  
Robbin Christensen, PharmD 
 
Saint Jude Children's Research Hospital 
 
262 Danny Thomas Place 
 
Memphis, TN 38105-3678 
 
Phone: (901) 595-3111 
Fax: (901) 595-3111 
 
E-mail: robbin.christensen@stjude.org 
 
 
 
 
COG OPERATIONS STAFF 
 
Wendy Martinez MPH CPH 
Lauren Saguilig, MS 
Research Coordinator 
Master Statistician  
Children’s Oncology Group – Operations Center  
222 East Huntington Dr. Suite 100  
Children’s Oncology Group – Operations Center 
222 E. Huntington Drive, Suite 100 
Monrovia, CA 91016 
Monrovia, CA  91016 
Phone (626) 241- 1733 
Phone: (626) 241-1547 
Fax (626) 445-4334 
Fax (626) 445-4334 
Email: wmartinez@childrensoncologygroup.org 
Email: lsaguilig@childrensoncologygroup.org 
 
 
Rita Tawdros, BS 
Scientific Writer/Protocol Coordinator 
 
Children’s Oncology Group – Operations Center 
 
222 E. Huntington Drive, Suite 100 
 
Monrovia, CA  91016 
 
Phone: (626) 241-1520 
 
Fax (626) 445-4334 
 
E-mail: rtawdros@childrensoncologygroup.org 
 
 
 
 
 
 
 
 
For Group Operations (GOC) and 
 
Statistics & Data Center (SDC) contacts see: 
 
https://members.childrensoncologygroup.org 
 
 
 
AGENT NSC# AND IND#’s 
 
NCI-Supplied Agents: 
Selumetinib (AZD6244 hydrogen sulfate) 
 
(NSC#748727) 
 
IND Sponsor: DCTD, NCI 
 
 
 
 
 
 
 


 
 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about subjects collected during the course of our covered studies.  The 
researchers involved in the studies cannot be forced to disclose the identity or any information collected in 
the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings.  However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances.  For example, if the subject or his/her 
guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
ABSTRACT 
This subprotocol is a component of the NCI-COG Pediatric MATCH trial APEC1621. The APEC1621SC 
screening protocol details the assay used for the integral genomic profiling which will determine eligibility 
for this subprotocol. Here we will conduct a phase 2 trial of selumetinib (AZD6244 hydrogen sulfate) in 
children with recurrent or refractory solid tumors (including non-Hodgkin lymphomas, histiocytoses and 
CNS tumors) harboring specified activating genetic alterations of the MAPK signaling pathway. 
Selumetinib (AZD6244 hydrogen sulfate) is a potent orally bioavailable small molecule inhibitor against 
ERK activation by activated MEK proteins. Selumetinib (AZD6244 hydrogen sulfate) will be given twice 
daily continuously for 28-day cycles. The primary endpoint will be objective response rate as determined 
by RECIST. Progression free survival (PFS) will be assessed as a secondary endpoint.  
 
EXPERIMENTAL DESIGN SCHEMA 
 
Day 1-28 
Day 28 
Selumetinib (AZD6244 hydrogen 
sulfate) (BID) 
Evaluation 
 
Patients will receive selumetinib (AZD6244 hydrogen sulfate) twice daily for 28-day cycles.  Evaluations 
will occur at the end of every other cycle x 3, then every 3 cycles. 
 
Therapy will be discontinued if there is evidence of progressive disease or drug related dose-limiting 
toxicity that requires removal from therapy (Section 6.0). Therapy may otherwise continue for up to 2 years 
provided the patient meets the criteria for starting subsequent cycles (Section 5.2) and does not meet any 
of the criteria for removal from protocol therapy criteria (Section 10.0).  
 
 
 
 
 
 
 
 
 
 


 
 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To determine the objective response rate (ORR; complete response + partial 
response) in pediatric patients treated with  selumetinib (AZD6244 hydrogen 
sulfate) with advanced solid tumors (including CNS tumors), non-Hodgkin 
lymphomas or histiocytic disorders that harbor activating genetic alterations in the 
MAPK pathway. 
 
1.2 
Secondary Aims 
 
1.2.1 
To estimate the progression free survival in pediatric patients treated with 
selumetinib (AZD6244 hydrogen sulfate) with advanced solid tumors (including 
CNS tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor MAPK 
activation mutations. 
 
1.2.2 
To obtain additional information about the tolerability of selumetinib (AZD6244 
hydrogen sulfate) in children with relapsed or refractory cancer. 
 
1.3 
Exploratory Aims 
 
1.3.1 
To evaluate other biomarkers as predictors of response to selumetinib (AZD6244 
hydrogen sulfate) and specifically, whether tumors that harbor different mutations 
or fusions will demonstrate differential response to selumetinib (AZD6244 
hydrogen sulfate) treatment. 
 
1.3.2 
To explore approaches to profiling changes in tumor genomics over time through 
evaluation of circulating tumor DNA. 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
The RAS–RAF–MEK1/2–ERK1/2 pathway, also known as the classical MAPK pathway, 
is responsible for controlling multiple key physiological processes.1 The MAPK pathway 
is one of the most frequently dysregulated signaling cascades in human cancer and the 
aberrant activation of this pathway commonly occurs through gain-of-function mutations 
in genes encoding RAS and RAF family members as well as by loss of NF1. Despite the 
low frequency of mutations in the MEK1/2 genes themselves2,3, MEK1 and MEK2 have 
emerged as an ideal targets for therapeutic development due to their narrow substrate 
specificities, distinctive structure and their place at the bottleneck in the MAPK signaling 
pathway. Among the malignances seen in pediatric and young adult population with known 
MAPK pathway aberrations include: hematological and lymphoid malignancies (activating 
N/K RAS mutations, 20%4), rhabdomyosarcoma (activating BRAF, NRAS and PTPN11 
mutations 20%5), low grade glioma (activating mutation or fusion in BRAF 70-100%), as 
well as in glioblastoma multiforme (loss of NF-1, 15%), neuroblastoma (activating 
mutations in NRAS, PTPN11, 2.9-3.6%6) malignant peripheral nerve sheath tumors (NF1 
loss 40-88%)7 and melanoma (activating mutation in BRAF, 86%). 8 
 
MEK inhibitors have shown clinical responses in patients with BRAF mutated melanoma 
refractory to BRAF inhibitors leading to FDA approval of trametinib for refractory 


 
 
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melanoma both as a single agent9 as well as in combination with BRAF inhibitor 
dabrafenib.10 Similarly, they have also shown clinical responses (20% with PR) in 
melanoma with NRAS mutated melanomas.11 In patients with KRAS mutant lung cancers 
MEK inhibitors combined with gemcitabine12 improves response rate and event-free 
survival. There is pre-clinical evidence for activity of MEK inhibitors in NF1 deficient 
neurofibromas and melanomas and a phase 1 trial of selumetinib (AZD6244 hydrogen 
sulfate) (AZD6244) demonstrated clinical responses in 17/24 (17%) pediatric patients with 
neurofibromatosis-1 (NF-1) with large plexiform neurofibroma.13-16 In uveal melanoma, 
which is characterized by mutations in GNAQ and GNA11, G-binding protein alpha 
subunits that signal via the MAPK pathway, selumetinib (AZD6244 hydrogen sulfate) 
results in a higher response rate and prolonged progression free survival when compared 
with chemotherapy.17 In summary, there is currently clinical evidence supporting diverse 
alterations in multiple MAPK genes as biomarkers for response, for example: activating 
RAS gene mutations (NRAS/KRAS/HRAS), activating BRAF mutations (V600E and 
others) and fusions, GNAQ and GNA11 activating mutations, inactivating mutations in 
PTPN11 and loss of NF1 through inactivating mutations or insertion/deletion. 14  
 
2.2 
Preclinical Studies 
 
2.2.1 
Antitumor Activity 
There are several pre-clinical studies demonstrating efficacy of MEK inhibitors in 
pediatric tumors with known RAS-ERK pathway aberrations. MEK/ERK inhibitor 
UO126 has shown to inhibit growth of rhabdomyosarcoma both as a single agent 
in vivo and in vitro18 as well as in combination with dual PI3K/mTOR inhibitor 
PI103. 19 In addition, in vitro and in vivo synergy has also been seen between 
inhibitors of TORC1/2 (AZD8055), and MEK (AZD6244) in embryonal 
rhabdomyosarcoma.20 Pre-clinical data also support potential activity for MEK 
inhibitors against neuroblastoma with MAPK gene mutations.21 Lastly, NF-1 
deficiency has shown to be predictive of sensitivity to MEK inhibitors in vitro in 
glioblastoma multiforme.22 In preclinical studies, some MAP2K1 mutations are 
sensitive to MEK inhibition.23,24 In view of the high frequency of aberrations seen 
in target biomarkers of MEK inhibitors within the pediatric oncology population, 
as well as the promising clinical activity in melanoma as well as in plexiform 
neurofibroma, TAP committee members were enthusiastic for including MEK 
inhibitors as a part of the Pediatric MATCH trial.  
 
2.2.2 
Animal Toxicology 
Mice and monkeys treated with selumetinib (AZD6244 hydrogen sulfate) were 
reported to develop diarrhea, dehydration and electrolyte imbalance in some 
animals.  Tissue mineralization was reported in mice that was not reversible with 
discontinuation of drug.  At the highest dose levels, skin lesions and/or scabs were 
observed in some mice as well as decreased cellularity of femoral bone marrow.  
Embryofetal development and survival in mice was impacted at levels that do not 
induce maternal toxicity (Selumetinib Investigators Brochure). 
 
2.3 
Adult Studies 
 
2.3.1 
Phase 1 Studies 
As of October 2015, selumetinib (AZD6244 hydrogen sulfate) has been used in 
approximately 2880 subjects, including two trials with pediatric subjects 8799 
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recommended Phase 2 dose for monotherapy has been established as 75 mg bid 
based on Phase 1 and PK data [D1532C00005; D1532C00066].  Early Phase 1 
studies reported the best overall response of stable disease in 18-40% of patients. 
25-28   
 
The most frequent AEs reported in Phase 1 studies with selumetinib (AZD6244 
hydrogen sulfate) dose 100 mg bid included rash (74%), diarrhea (58%), nausea 
(55%), fatigue (55%), and peripheral edema.  Grade 3 rash was reported in 14%, 
and 5.3% experienced Grade 3 fatigue. [D1532C0005].   
 
2.3.2 
Phase 2 Studies 
Phase 2 studies treating patients with malignant melanoma, pancreatic cancer, 
colorectal cancer, non-small-cell lung cancer, advanced hepatocellular carcinoma, 
metastatic biliary tract cancer, refractory papillary thyroid cancer, acute myeloid 
leukemia, multiple myeloma, and ovarian/peritoneal carcinoma, report that 11-
80% of subjects experienced stable disease with selumetinib (AZD6244 hydrogen 
sulfate) .29-43 The most common AEs reported in Phase 2 monotherapy studies 
included dermatitis (94%), diarrhea (54%), nausea (49%), peripheral edema 
(31%), vomiting (24%), and fatigue (21%) [DC1532C00003/8/11/12]. 
 
2.3.3 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
The PK of selumetinib (AZD6244 hydrogen sulfate) in the above studies was 
approximately dose proportional across the dose ranges studied for the Hyd-
Sulfate formulation (25-100 mg).  Drug exposure was reduced by CYP3A4 
induction with rifampicin, and increased by the CYP3A4 inhibitor itraconazole 
and the CYP2C19 inhibitor fluconazole.  Minimal effects on drug exposure were 
observed in subjects with end stage renal disease compared to healthy volunteers, 
and dialysis had minimal effect on removal of systemic selumetinib (AZD6244 
hydrogen sulfate). While there was no change in exposure in subjects with mild 
hepatic impairment, subjects with moderate or severe hepatic impairment showed 
higher selumetinib (AZD6244 hydrogen sulfate) AUC compared to healthy 
volunteers receiving the same dose.  Food was observed to decrease the rate of 
selumetinib (AZD6244 hydrogen sulfate) absorption, but with relatively small 
reduction in total exposure.  Therefore, pending further study, it is recommended 
to take the drug on an empty stomach (1 hour before or 2 hours after food). 
 
2.4 
Pediatric Studies 
 
2.4.1 
Prior Experience in Children  
Two pediatric studies including children with NF1-associated plexiform 
neurofibromas and low-grade gliomas report partial responses in 21% and 55% of 
patients, respectively.44,45  Early studies suggest that the adult RP2D (75 mg twice 
daily) equivalent may be toxic in children.  In a phase 1 study, Banerjee and 
colleagues report treating children with recurrent/refractory low-grade gliomas 
with 33 and 43 mg/m2/dose twice daily (patient numbers not noted in the abstract), 
and both levels were deemed intolerable due to DLTs of headache, rash and 
mucositis.  De-escalation to 25 mg/m2/dose twice daily (n=24) improved 
tolerability and resulted in plasma levels sufficient to inhibit ERK activation. The 
authors conclude that 25 mg/m2/dose twice daily is optimal for pediatric studies.  
Gross and colleagues describe a plan for a phase 2 study, for children with NF1 
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study, Widemann reported DLT in the first three cycles in 1/6 children and young 
adults with NF1 and inoperable neurofibromas treated with 25 mg/m2 twice daily 
(approximately 50% of the adult recommended phase 2 dose), which was 
reversible grade 3 rash. By comparison 4/6 children receiving 30 mg/m2 twice 
daily dosing experienced DLTs.  Throughout all treatment cycles, 3/6 patients in 
the 25 mg/m2 group and 4/6 in the 30 mg/m2 group experienced DLTs including 
creatine kinase elevation, gastrointestinal toxic effects, acneiform or 
maculopapular rash, and decreased left ventricular ejection fraction, all of which 
were reversible. The authors conclude that 25 mg/m2/dose twice daily is optimal 
for pediatric studies. 16  
 
2.4.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
Selumetinib (AZD6244 hydrogen sulfate) PK in children appear to be similar to 
adults.16,26 Selumetinib (AZD6244 hydrogen sulfate) was absorbed rapidly and the 
increase in drug exposures with increasing dose were less than dose-
proportional. The selumetinib (AZD6244 hydrogen sulfate) half-life in children 
was approximately 6 hours at the 25 mg/m2 dose.16 
 
2.5 
Overview of Proposed Pediatric Study 
This is a phase 2 trial of selumetinib (AZD6244 hydrogen sulfate) in children with 
recurrent or refractory solid tumors, CNS tumors, non-Hodgkin lymphomas and histiocytic 
disorders harboring specific activating mutations that result in pathologic activation of the 
MAPK pathway. 
 
Patients will receive selumetinib (AZD6244 hydrogen sulfate) for 28-day cycles at the 
MTD and recommended Phase 2 dose (RP2D) of 25 mg/m2/dose BID.   
 
The primary aim of this trial will be to establish the objective response rate to selumetinib 
(AZD6244 hydrogen sulfate).  While there will not be multiple pre-determined mutation-
based cohorts, responses will be analyzed retrospectively with respect to specific MAPK 
pathway activating mutations. 
 
Key secondary objectives include further evaluation of the tolerability of selumetinib 
(AZD6244 hydrogen sulfate) in pediatric patients.  Toxicity will be assessed using CTCAE 
V5.0.  Imaging for disease evaluation will occur every other cycle x 3, then every three 
cycles.  Disease response will be assessed according to RECIST v1.1 for solid tumors and 
2-dimensional measurement for CNS tumors. 
 
 
 


 
 
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3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
Patient enrollment for this study will be facilitated using the Oncology Patient Enrollment Network 
(OPEN), a web-based registration system available on a 24/7 basis. It is integrated with the NCI 
Cancer Trials Support Unit (CTSU) Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient position in the RAVE database. 
 
Access requirements for OPEN:  
Investigators and site staff will need to be registered with CTEP and have a valid and active Cancer 
Therapy Evaluation Program-Identity and Access Management (CTEP-IAM) account (check at < 
https://ctepcore.nci.nih.gov/iam/ >). This is the same account (user id and password) used for 
credentialing in the CTSU members' web site. To perform registrations in OPEN, the site user must 
have been assigned the 'Registrar' role on the relevant Group or CTSU roster. OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. Registrars must hold a minimum of an AP registration type.  If a DTL is 
required for the study, the registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise 
System for regulatory and roster data and, upon enrollment, initializes the patient position in the 
Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in OPEN, the 
IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on the site’s IRB 
approval.  If a DTL is required for the study, the IVR or NPIVR must also be assigned the 
appropriate OPEN-related tasks on the DTL. 
  
3.1 
Genetic Screening Procedures for Eligibility  
Patient enrollment onto the APEC1621SC screening protocol is required. Tumor and blood 
samples will be obtained and the results of the evaluation of the tumor specimens will 
determine if the patient's tumor has an actionable Mutation of Interest (aMOI) for which a 
MATCH treatment subprotocol is available. 
 
The treatment assignment to a MATCH subprotocol (if a relevant aMOI is detected)  will 
be communicated to the enrolling institution via the COG or MATCHBox treatment 
assignment mechanism at the time the results of MATCH are returned, upon which a 
reservation to APEC1621E will be secured by COG. Reservations should be withdrawn by 
the institution if at any point the patient indicates they do NOT intend to consent to 
participation or the site investigator indicates the patient will never be eligible for 
APEC1621E. 
 
3.2 
IRB Approval 
In order to participate in Pediatric MATCH, an institution must participate in the NCI 
Pediatric CIRB. NCI Pediatric CIRB approval of this study must be obtained by a site prior 
to enrolling patients.  
 
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 
 
Regulatory Help Desk: 866-651-2878 
 
 
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are not required to submit separate IRB approval documentation to the CTSU Regulatory 
Office for initial, continuing, or amendment review.  However, sites must submit a Study 
Specific Worksheet for Local Context (SSW) to the CIRB (via IRBManager) to indicate 
their intention to open the study locally. The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office for compliance in the RSS.  The Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study so that the study approval can be applied 
to those institutions. Other site registration requirements (e.g., laboratory certifications, 
protocol-specific training certifications, or modality credentialing) must be submitted to 
the CTSU Regulatory Office or compliance communicated per protocol instructions. 
 
3.3 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
 
3.4 
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 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. 
 
3.5 
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. 
 
3.6 
Study Enrollment 
Following a MATCH treatment assignment to a protocol, patients may be enrolled on the 
study once all eligibility requirements for the study have been met. Before enrolling a 
patient on study, the Study Chair or Vice Chair should be notified. 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.  Patients must not receive any protocol therapy prior to enrollment. 
 
Patients must be enrolled within 8 weeks (56 days) of treatment assignment. Protocol 
therapy must start no later than 7 calendar days after the date of enrollment. Patients 
enrolling onto APEC1621E will have a COG ID obtained through their prior enrollment 
onto the screening protocol or from a prior COG study.  
 
Note:  No starter supplies will be provided. Drug orders of selumetinib (AZD6244 
hydrogen sulfate) should be placed with CTEP after enrollment and treatment 
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to ensure receipt of drug supply prior to start of protocol therapy. 
 
3.7 
Institutional Pathology Report 
The institutional pathology report from the tumor specimen submitted for sequencing will 
have been uploaded into RAVE immediately following enrollment on the APEC1621SC 
screening protocol.  
3.8 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
4.0 
PATIENT ELIGIBILITY 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy.  Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum  creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging 
studies, bone marrow biopsy and/or aspirate (when applicable) must be obtained within 14 days 
prior to start of protocol therapy (repeat the tumor imaging if necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived.  All clinical and laboratory data required for determining eligibility of a patient 
enrolled on this trial must be available in the patient’s medical or research record which will 
serve as the source document for verification at the time of audit. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been 
given a treatment assignment to MATCH to APEC1621E based on the presence of 
an actionable mutation as outlined in Appendix VII. 
 
Note: Patients with BRAF V600 aMOIs will be preferentially assigned to 
APEC1621G (vemurafenib) if that study is open and they are otherwise eligible 
for it. 
 
4.1.2 
Age:  Patients must be  than 12 months and   21 years of age at the time of 
study enrollment. 
 
4.1.3 
BSA:  Patients must have a body surface area ≥ 0.5 m2 at enrollment. 
 
4.1.4 
Disease Status: Patients must have radiographically measurable disease (See 
section 12) at the time of study enrollment. Patients with neuroblastoma who do 
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Measurable disease in patients with CNS involvement is defined as tumor that is 
measurable in two perpendicular diameters on MRI and visible on more than one 
slice. 
 
Note:  The following do not qualify as measurable disease:  
- 
malignant fluid collections (e.g., ascites, pleural effusions) 
- 
bone marrow infiltration except that detected by MIBG scan for 
neuroblastoma 
- 
lesions only detected by nuclear medicine studies (e.g., bone, gallium or 
PET scans) except as noted for neuroblastoma 
- 
elevated tumor markers in plasma or CSF  
- 
previously radiated lesions that have not demonstrated clear progression 
post radiation  
- 
leptomeningeal lesions that do not meet the measurement requirements for 
RECIST 1.1. 
 
4.1.5 
Performance Level:  Karnofsky  50% for patients > 16 years of age and Lansky 
 50 for patients  16 years of age (See Appendix I).  Note:  Neurologic deficits in 
patients with CNS tumors must have been stable for at least 7 days prior to study 
enrollment.  Patients who are unable to walk because of paralysis, but who are up 
in a wheelchair, will be considered ambulatory for the purpose of assessing the 
performance score. 
 
4.1.6 
Prior Therapy 
 
4.1.6.1 
Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the numerical eligibility criteria are met, e.g. blood count 
criteria, the patient is considered to have recovered adequately. 
 
a. Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive. See https://members.childrensoncologygroup.org/
Disc/devtherapeutics/default.asp for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 
of this interval must be discussed with the study chair and the study-
assigned Research Coordinator prior to enrollment. 
 
i.  ≥ 21 days after the last dose of cytotoxic or myelosuppressive 
chemotherapy (42 days if prior nitrosourea).  
 
 
 
b. Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥ 7 days after the 
last dose of agent. See https://members.childrensoncologygroup.org/
Disc/devtherapeutics/default.asp for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 
of this interval must be discussed with the study chair and the study-
assigned Research Coordinator prior to enrollment.  
 
c. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 


 
 
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recovered to Grade ≤ 1. 
 
d. Corticosteroids: See Section 4.2.2.1. If used to modify immune 
adverse events related to prior therapy, ≥ 14 days must have elapsed 
since last dose of corticosteroid. 
 
e. Hematopoietic growth factors: ≥ 14 days after the last dose of a long-
acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting 
growth factor. For growth factors that have known adverse events 
occurring beyond 7 days after administration, this period must be 
extended beyond the time during which adverse events are known to 
occur.  The duration of this interval must be discussed with the study 
chair and the study-assigned Research Coordinator. 
 
f. Interleukins, Interferons and Cytokines (other than Hematopoietic 
Growth Factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than Hematopoietic Growth Factors) 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥ 84 
days after infusion and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion:  ≥ 42 
days. 
 
h. Cellular Therapy: ≥ 42 days after the completion of any type of 
cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.) 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days after 
local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to 
 50% of the pelvis; ≥ 42 days if other substantial BM radiation. 
 
Note: Radiation may not be delivered to “measurable disease” tumor 
site(s) being used to follow response to subprotocol treatment. 
 
j. 
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-
MIBG): ≥ 42 days after systemically administered 
radiopharmaceutical therapy. 
 
k. Patients must not have received prior exposure to selumetinib 
(AZD6244 hydrogen sulfate). 
 
4.1.7 
Organ Function Requirements 
 
4.1.7.1 
Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
- 
Peripheral absolute neutrophil count (ANC)  1000/mm3 
- 
Platelet count  100,000/mm3 (transfusion independent, defined 


 
 
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as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in 4.1.7.1.a 
(may receive transfusions provided they are not known to be 
refractory to red cell or platelet transfusions). These patients will 
not be evaluable for hematologic toxicity.  
 
4.1.7.2 
Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR  70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 
4.1.7.3 
Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated)  1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT)  135 U/L.  (For the purpose of this study, the ULN 
for SGPT is 45 U/L.)  
- 
Serum albumin  2 g/dL. 
 
4.1.7.4 
Adequate Cardiac Function Defined as: 
• 
Shortening fraction of   27% by echocardiogram, or 
Ejection fraction of ≥ 50% by gated radionuclide study. 
 
4.1.7.5 
Adequate Blood Pressure Control Defined as: 
A blood pressure (BP) ≤ the 95th percentile for age, height, and gender 
(Appendix IX) measured as described in Section 6.7. Please note that 3 
serial blood pressures should be obtained and averaged to determine 
baseline BP. Patients with hypertension controlled on antihypertensive 
medications will be allowed if otherwise eligible. 
 
4.1.7.6 
Adequate Metabolic Function Defined as:  
- Serum triglyceride level ≤ 300 mg/dL 
 - Serum total cholesterol level ≤ 300 mg/dL 
 
4.1.8 
Patients must be able to swallow intact capsules whole.  
 
4.1.9 
Informed Consent: All patients and/or their parents or legally authorized 


 
 
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representatives must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional guidelines.  
 
4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study because there 
is currently no available information regarding human fetal or teratogenic 
toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. 
Females of reproductive potential may not participate unless they have agreed to 
use an effective contraceptive method for the duration of study treatment. Males 
with sexual partners who are pregnant or who could become pregnant (ie, women 
of child-bearing potential) should use effective methods of contraception for 12 
weeks after completing the study to avoid pregnancy and/or potential adverse 
effects on the developing embryo. 
 
4.2.2 
Concomitant Medications 
 
4.2.2.1 
Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. If used to modify immune adverse events 
related to prior therapy, ≥ 14 days must have elapsed since last dose of 
corticosteroid (See Section 4.1.6.1.d). 
 
4.2.2.2 
Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
 
4.2.2.3 
Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible. 
 
4.2.2.4 
Anti-GVHD agents post-transplant:  
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease post bone marrow transplant are not 
eligible for this trial. 
 
4.2.2.5 
CYP3A4 Agents: Patients who are currently receiving drugs that are 
strong inducers or inhibitors of CYP3A4 are not eligible. Strong inducers 
or inhibitors of CYP3A4 should be avoided from 14 days prior to 
enrollment to the end of the study. See Appendix II for a list of agents.  
Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS 
tumors or metastases, on a stable dose, are allowed. 
 
4.2.2.6 
CYP2C19 Agents: Patients who are currently receiving drugs that are 
strong CYP2C19 inducers (eg, rifampin, ritonavir) or inhibitors (eg., 
fluoxetine, fluvoxamine, ticlopidine) are not eligible.  
 
 
4.2.3 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
4.2.4 
Patients with known significant ophthalmologic conditions (uncontrolled 
glaucoma, history of retinal vein occlusion or retinal detachment, excluding 


 
 
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patients with longstanding findings secondary to existing conditions) are not 
eligible. 
 
4.2.5 
Patients with Low Grade Glioma are not eligible. 
4.2.6 
Patients who have received a prior solid organ transplantation are not eligible. 
 
4.2.7 
Patients who in the opinion of the investigator may not be able to comply with 
the safety monitoring requirements of the study are not eligible. 
 
5.0 
TREATMENT PROGRAM 
 
5.1 
Overview of Treatment Plan 
 
Treatment Schedule Table 
Days 1-28 
Selumetinib (AZD6244 hydrogen sulfate)   
25 mg/m2/dose orally twice daily 
 (maximum 75 mg per dose) 
Day 28 
Evaluation 
 
Selumetinib (AZD6244 hydrogen sulfate) capsules will be administered orally in capsules 
given twice a day at a dose of 25 mg/m2 BID with a maximum dose of 75 mg per dose. 
Therapy will be discontinued if there is evidence of progressive disease or drug related 
dose-limiting toxicity that requires removal from therapy (Section 6.0). Therapy may 
otherwise continue for up to 2 years provided the patient meets the criteria for starting 
subsequent cycles (Section 5.2) and does not meet any of the criteria for removal from 
protocol therapy criteria (Section 10.0).  
 
A cycle of therapy is considered to be 28 days.  A cycle may be repeated up to a total 
duration of therapy of approximately 2 years. 
 
Patients will be treated at the established pediatric MTD/RP2D which is 25 mg/m2/dose 
BID. 
 
Drug doses should be adjusted based on the BSA calculated from height and weight 
measured within 7 days prior to the beginning of each cycle, and according to the dosing 
nomogram (see Appendix IV).  Patients should swallow the capsules as a whole and should 
not chew or crush them. Selumetinib (AZD6244 hydrogen sulfate) should be taken on an 
empty stomach at least 2 hours after food and patients should not eat or drink (except water) 
for at least one hour after taking selumetinib. If a patient vomits within 30 minutes after 
the dose of selumetinib (AZD6244 hydrogen sulfate), is administered, that dose may be 
repeated once. Otherwise, the dose will be missed. 
 
Therapy will be discontinued if there is evidence of progressive disease or drug related 
dose-limiting toxicity that requires removal from therapy (Section 6.0). Therapy may 
otherwise continue for up to 2 years provided the patient meets the criteria for starting 
subsequent cycles (Section 5.2) and does not meet any of the criteria for removal from 
protocol therapy criteria (Section 10.0). 
 
5.1.1 
Therapy Delivery Map 
See Appendix V for APEC1621E Therapy Delivery Map. 


 
 
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5.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease and has 
again met laboratory parameters as defined in the eligibility section, Section 4.0 and 
eligible to continue agent administration per the requirements in Section 6.0.  
5.3 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to version 5.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE).  All appropriate treatment areas 
should have access to a copy of version 5.0 of the CTCAE.  A copy of the CTCAE can be 
downloaded from the CTEP website (http://ctep.cancer.gov). Any suspected or confirmed 
dose-limiting toxicity should be reported immediately (within 24 hours) to the Study Chair. 
 
5.4 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to protocol therapy. Dose limiting hematological and non-hematological 
toxicities are defined differently.  
 
5.4.1 
Non-Hematological Dose-Limiting Toxicity 
5.4.1.1 
Any Grade 3 or greater non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
- 
Grade 3 nausea and vomiting of < 3 days duration 
- 
Grade 3 diarrhea ≤ 3 days duration  
- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to 
levels that meet initial eligibility criteria or baseline within 7 days. See 
Section 6.3. See Appendix XIII 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 
regardless of baseline. 
- 
Grade 3 or 4 fever < 5 days duration. 
- 
Grade 3 infection < 5 days duration. 
- 
Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to supplementation 
- 
Grade 3 papulopustular, acneiform, or maculo-papular rash that resolves 
to < Grade 1 or baseline within 14 days of initiation of topical steroid as 
described in Section 7.3.1.  However, any investigational drug-related 
Grade 3 rash that is considered intolerable by the patient or limits ADLs 
will be considered a DLT regardless of duration. 
- 
Grade 3 asymptomatic elevation of CPK  
 
• 
Any Grade 2 visual disturbance that persists for ≥ 1 week. 
• 
Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by 
patients that it requires treatment interruption. 
• 
Note: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
 
5.4.1.2 Dose-limiting hypertension 
• 
Any Grade 4 hypertension 
• 
A blood pressure > 25 mmHg above the 95th percentile for age, 
height, and gender (Appendix IX) confirmed by repeated 


 
 
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measurement is dose limiting. 
• 
In patients who begin antihypertensive therapy a blood pressure > 10 
mmHg but ≤ 25 mmHg above the 95th percentile for age, height, and 
gender (Appendix IX) for > 14 days is dose limiting. 
 
5.4.2 
Hematological dose limiting toxicity  
Hematological dose limiting toxicity is defined as: 
 
In patients evaluable for hematological toxicity (see Section 4.1.7.1),   
• 
Grade 4 thrombocytopenia or neutropenia, not due to malignant 
infiltration. 
• 
Grade 3 thrombocytopenia that persists for ≥ 7 days 
• 
Grade 3 thrombocytopenia requiring a platelet transfusion on 2 separate 
days 
• 
Grade 3 thrombocytopenia with clinically significant bleeding 
• 
Neutropenia or thrombocytopenia that causes a delay of > 14 days 
between treatment cycles" (e.g. platelets <100K or ANC<1000). 
 
Note:   Grade 3 or 4 febrile neutropenia will not be considered a dose-limiting 
toxicity. 
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. 
 
6.1 
Dose Modifications for Hematological Toxicity 
 
6.1.1 
If a patient experiences hematological dose-limiting toxicity as defined in Section 
5.4.2, the treatment will be held.  Counts should be checked every 3-4 days for 
thrombocytopenia and every other day for neutropenia during this time. If the 
toxicity resolves to meet eligibility parameters within 14 days of drug 
discontinuation, the patient may resume treatment at a reduced dose as outlined in 
the dose reduction table (Appendix IV). Doses reduced for toxicity will not be re-
escalated, even if there is minimal or no toxicity with the reduced dose. 
 
6.1.2 
If toxicity does not resolve to meet eligibility parameters within 14 days of drug 
discontinuation, the patient must be removed from protocol therapy. 
 
6.1.3 
If hematological dose-limiting toxicity recurs in a patient who has resumed 
treatment at the reduced dose, the patient must be removed from protocol 
therapy. 
 
 
 
 
 
6.2 
Dose Modifications for Non-Hematological Toxicity 
 
6.2.1 
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Section 5.4.1, the treatment will be held. When the toxicity resolves to meet 
eligibility parameters or baseline within 14 days of drug discontinuation, the 
patient may resume treatment at a reduced dose as outlined in the dose reduction 
table (Appendix IV). Doses reduced for toxicity will not be re-escalated, even if 
there is minimal or no toxicity with the reduced dose. 
 
6.2.2 
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. 
 
6.2.3 
If the same dose-limiting toxicity recurs in a patient who has resumed treatment, 
the patient must be removed from protocol therapy. 
 
6.3 
Dose Modifications for Hepatic Adverse Events 
 
6.3.1 
If a patient experiences Grade ≥ 3 ALT, treatment will be held. If toxicity resolves 
to meet eligibility criteria within 7 days, the drug may be resumed at the same 
dose. Grade ≥ 3 ALT that persists ≥ 7 days will be considered dose-limiting and 
require dose modification per Section 6.2. 
 
6.4 
Dose Modifications for Dermatology/Skin Disorders 
 
Grade  
Action 
Grade 1 or 2  
 
• 
Maintain dose 
Intolerable Grade 2; 
Grade 3  
 
• 
Hold AZD6244 selumetinib (AZD6244 hydrogen sulfate) 
until resolution to ≤ tolerable Grade 2 and dose reduce as per 
Section 6.2. See also Section 7.3.1 
6.5 
Dose Modifications for Visual Disturbances 
 
Grade  
Action 
Grade 1 
• 
Maintain Dose  
Grade 2 
 
• 
Hold selumetinib (AZD6244 hydrogen sulfate) until eye 
exam is completed; If the Ophthalmology exam is normal 
and the toxicity resolves to < Grade 1 within 1 week or an 
alternate cause for the vision problem is identified – restart 
selumetinib (AZD6244 hydrogen sulfate) at the same dose 
level. Otherwise Grade 2 visual disturbance that persists for ≥ 
1 week hours will be considered a DLT and require a dose 
reduction as per Section 6.2. 
Grade 3 or 4 
 
• 
Hold AZD6244 selumetinib (AZD6244 hydrogen sulfate) 
until Eye exam is completed; If alternate etiology for vision 
change is identified, contact study chair to discuss restarting 
of selumetinib (AZD6244 hydrogen sulfate). Otherwise ≥ 
Grade 3 visual disturbance will be considered a DLT and 
require a dose reduction as per Section 6.2. 
 
6.6 
Dose Modifications for Elevation of CPK 
 


 
 
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Grade  
Action 
Grade 1 or 2 or Grade 
3 asymptomatic 
 
• 
Maintain dose; continue monitoring as per protocol, or more 
frequently if clinically indicated. 
Grade 3 symptomatic 
or Grade 4 
 
• 
Hold AZD6244 selumetinib (AZD6244 hydrogen sulfate) 
until resolution to ≤ Grade 1 and dose reduce as per Section 
6.2. 
 
6.7 
Dose Modifications for Hypertension 
 
• Baseline blood pressure (BP) is defined as the blood pressure obtained at the 
examination used for study enrollment. This baseline BP should be obtained as 
follows: 1) Obtain 3 serial blood pressures from the same extremity with the 
patient in the same position at rest with an appropriately sized cuff. Measures 
must be obtained at least 5 minutes apart. Avoid using the lower extremity if 
possible. 2) Average the systolic blood pressure from the 2nd and 3rd 
measurements. 3) Average the diastolic blood pressure from the 2nd and 3rd 
measurements. 4) The baseline BP is the average of the systolic over the 
average of the diastolic measurements. 
 
• Elevation in either the systolic or diastolic blood pressure should be considered 
when following the algorithm below. 
 
• The upper limit of normal (ULN) is defined as a BP equal to the 95th 
percentile for age, height, and gender. See Appendix IX. 
 
• The NCI CTCAE version 5.0 will be utilized to determine the grade of 
hypertension for reporting purposes. 
 
• Elevated BP measurements should be repeated on the same day to confirm the 
elevation. If confirmed, patients with elevated BP should have BP 
measurements performed at least twice weekly until BP is ≤ ULN. 
 
• The algorithm below will be used to manage selumetinib-related hypertension. 
 
• Hypertension should be managed with appropriate anti-hypertensive agent(s) 
as clinically indicated. It is strongly recommended that nephrology or 
cardiology be consulted in the evaluation and management of hypertension. 
 
 
 
 
 


 
 
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Elevations in BP are based on systolic or diastolic pressures.  
† Elevated blood pressure (BP) measurements should be repeated on the same day to confirm the elevation. Patients with elevated BP at any time 
should have BP measurements performed at least twice weekly until BP is within the ULN. 
§ ULN (Upper Limit of Normal) is a BP equal to the 95th percentile from age, height, and gender-appropriate normal values (Appendix IX) 
* If BP > 25 mm Hg above ULN for age (verified) or Grade 4 HTN at any time, hold drug.  Study drug should also be held for BP ≤ 25 mm Hg 
above the ULN age for > 14 days or 35 mmHg above baseline for > 14 days. Antihypertensive agents can be used to control hypertension as 
Monitor BP
† 
(Appendix IX) 
Grade 4 HTN* 
10< BP† ≤ 25 mm Hg 
above ULN§ or > 35 mm 
Hg above baseline# 
Off Protocol 
Therapy 
Continue drug 
at same dose 
Start anti-HTN therapy^ 
(Section 6.7, Section 7.6) 
Hold study drug; 
start or continue anti-
HTN therapy^ 
BP† ≤ 10 mm Hg 
above ULN§ 
BP ≤ ULN§ 
Continue drug at same 
dose; recheck BP 
within 72 hrs 
BP ≤ ULN§ 
on recheck 
BP† > ULN§ 
on recheck 
1 
2 
3 
   5 
Restart drug at 
reduced dose 
(Section 6.7) 
Off Protocol 
Therapy 
BP ≤ULN§ 
within 14d 
BP† > ULN§       
for > 14d 
BP ≤ ULN     
within 14d 
BP† >25 mm Hg 
above ULN§ * 
BP
† ≤ 25 mm 
Hg above ULN§ 
or >35 mm Hg 
above baseline 
for > 14d* 
BP† > 25 mm 
Hg above ULN§ 
4 


 
 
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clinically indicated after study drug is held. 
^ Anti-hypertensive therapy should be prescribed as clinically indicated, including the use of multiple anti-hypertensive agents. 
# Baseline BP is defined in Section 4.1.7.5. 


 
 
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Arm 1 of algorithm: 
• 
If blood pressure (BP) ≤ 95% for age, height, and gender, continue selumetinib at the 
same dose. 
 
Arm 2 of algorithm: 
• 
If BP ≤ 10 mm Hg above the ULN for age, height, and gender, continue selumetinib at 
the same dose and recheck the BP within 72 hours. 
o If the BP is ≤ ULN on recheck, continue selumetinib at the same dose. 
o If the BP remains above the ULN on recheck, then start antihypertensive therapy 
(Section 7.6) and follow Arm 3 of the algorithm from the point that anti-
hypertensive therapy is started. 
 
Arm 3 of algorithm: 
• 
If BP is 11 to 25 mm Hg above the 95% for age, height, and gender on ≥ 2 of 3 
measurements or > 35 mmHg above baseline on ≥ 2 of 3 measurements, start anti-
hypertensive therapy (see Section 7.6), continue selumetinib at the same dose, and 
monitor BP at least twice weekly. 
o If the BP returns to ≤ ULN within 14 days, continue selumetinib at the same dose 
and continue anti-hypertensive therapy.  
o If the BP remains elevated ≤ 25 mm Hg above the 95% or > 35 mm Hg above 
baseline for more than 14 days after the institution of anti-hypertensive 
therapy, hold selumetinib, monitor BP at least every 3 days, and follow Arm 
4 of the algorithm from the point that selumetinib is held. If selumetinib is 
stopped, antihypertensives should be continued until BP is < ULN. If 
selumetinib is resumed, anihypertensives should continue for the duration of 
selumetinib therapy unless clinically indicated to discontinue. 
▪ 
If the BP returns to ≤ ULN within 14 days, restart selumetinib at a reduced 
dose (Section 6.2). 
▪ 
If the BP remains > ULN for more than 14 days, patient is Off Protocol 
Therapy. 
o  If the BP increases to > 25 mm Hg above the ULN despite anti-hypertensive 
therapy, hold selumetinib, but continue the anti-hypertensive agent(s). Monitor the 
BP as clinically indicated and follow Arm 4 of the algorithm from the point that 
selumetinib is held. 
▪ 
If the BP is ≤ ULN within 14 days, selumetinib may be restarted at a reduced 
dose (Section 6.2). 
▪ 
If the BP is > ULN for > 14 days, the patient is Off Protocol Therapy (Section 
10.1). 
 
Arm 4 of algorithm: 
• 
If BP is > 25 mm Hg above the 95% for age, height, and gender hold selumetinib, 
monitor BP and administer anti-hypertensive therapy as clinically indicated. 
o If the BP returns to ≤ ULN within 14 days, selumetinib may be restarted at a 
reduced dose (Section 6.2). 
o If the BP is > ULN for >14 days, the patient is Off Protocol Therapy (Section 10.1). 
 
 
 
 
Arm 5 of algorithm: 


 
 
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• 
If the participant develops Grade 4 hypertension, discontinue selumetinib, monitor BP 
and administer anti-hypertensive therapy as clinically indicated. The patient is Off 
Protocol Therapy (Section 10.1). 
 
6.8 
Dose Modification for Elevated Fasting Cholesterol 
The following guidelines should be used for patients who develop elevated fasting 
cholesterol.  
 
Grade 
Action 
Grade 2 
• 
Continue selumetinib; consider treatment with an HMG-CoA 
reductase inhibitor depending upon recommendations of 
institutional hyperlipidemia consultants. 
Grade 3 
• 
An HMG-CoA reductase inhibitor should be started, and dosages 
adjusted 
based 
upon 
recommendations 
of 
institutional 
hyperlipidemia consultants. 
• 
It is expected that optimal effects of the lipid lowering medication 
will be observed 2-4 weeks after its initiation. Treatment with 
selumetinib is to be restarted at the same dose level when 
recovery of hypercholesterolemia to ≤ Grade 2 is observed. 
Grade 4 
• 
Hold selumetinib. 
• 
An HMG-CoA reductase inhibitor should be started, and dosages 
should be adjusted based upon recommendations from 
institutional hyperlipidemia consultants. 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. See Section 7.5 for drugs that should not be used 
concomitantly due to potential interactions with selumetinib (AZD6244 hydrogen sulfate). 
See below for recommendations on management of specific toxicities associated with 
selumetinib (AZD6244 hydrogen sulfate). 
 
7.3.1 
Recommendations for Skin Toxicity: 
The most common drug related adverse event is rash, which have included many 
different types and can begin as early as cycle 1 or 2. Descriptions include: 
erythematous rash, maculopapular rash, pruritic rash, acneiform dermatitis, 
exfoliative rash. Grade 3 rashes are often associated with pruritus and can have 
scaling.  Based on the experience on the current adult Phase 1/2 study the following 
recommendations should be followed. For Grade 3 rash selumetinib (AZD6244 
hydrogen sulfate) should be held until resolution to Grade 1 or better and then 
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(Appendix IV). For eczematous rashes, moisturizers or low-dose topical 
corticosteroids may be used if based on the rash appearance they would be 
considered appropriate treatment. For pustular rash, topical clindamycin gel or 
lotion may be applied twice daily.  For more severe cases, oral teracyclines may 
be useful in older children.  Ketoconazole shampoo may be used for scalp rash.  If 
oral corticosteroids are required for severe rash, selumetinib (AZD6244 hydrogen 
sulfate) should be held until improvement to < Grade 1 at a reduced dose as 
outlined in the dose reduction table (Appendix IV). 
 
7.3.2 
Recommendations for Paronychiae: 
Patients who develop paronychiae may be treated with flurandrenolide tape, 
topical steroid cream, topical antibiotics or systemic antibiotics as clinically 
indicated. 
 
7.3.3 
Recommendations for Diarrhea: 
Patients who experience diarrhea may be treated symptomatically with oral 
hydration and anti-diarrheal medications according to institutional standards.  
Example loperamide dosing is outlined in Appendix VIII. 
 
7.3.4 
Recommendations for Visual Disturbance: 
Patients who experience visual disturbance should undergo complete 
ophthalmologic examination including visual acuity, visual fields (if feasible) and 
fundoscopic exam. 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. The Study Chair 
should be notified before growth factors are initiated. 
 
7.5 
Concomitant Medications 
 
7.5.1 
Selumetinib (AZD6244 hydrogen sulfate) is metabolized by CYP 1A2, 2C8, 2C9, 
2C19, 3A4/5 to form active N-desmethyl selumetinib (AZD6244 hydrogen sulfate) 
metabolite; In addition, UGT 1A1 and 1A3 form glucuronide conjugates. Use 
caution in patients who are taking strong inducers or inhibitors of these CYP or 
UGT enzymes. 
7.5.2 
CYP3A4/5 inhibitors or inducers: Strong CYP3A4/5 inhibitors and inducers are 
not permitted on this study (See Appendix II for list of agents). Note: CYP3A4 
inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, 
on a stable dose, are allowed. 
7.5.3 
The use of drugs that are strong CYP2C19 inducers (eg., rifampin, ritonavir) or 
inhibitors (eg., fluoxetine, fluvoxamine, ticlopidine) should be avoided during the 
study.  
7.5.4 
High vitamin E doses may potentiate warfarin’s anticoagulant activity.  Monitor 
PT/INR more frequently in patients receiving both warfarin and selumetinib 
(AZD6244 hydrogen sulfate) capsules.  Avoid concomitant intake of supplemental 
vitamin E. 
 
7.5.5 
Selumetinib (AZD6244 hydrogen sulfate) is also a substrate of BCRP (breast 


 
 
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cancer resistance protein) and P-glycoprotein (P-gp) transporters. Use caution in 
patients who are taking strong inducers or inhibitors of either transport protein. 
 
7.6 
Concurrent Anti-Hypertensive Therapy 
The algorithm in Section 6.7 will be used to manage selumetinib- related hypertension. 
Should initiation of anti-hypertensive therapy be required, single agent therapy (commonly 
including the calcium channel blockers amlodipine or nifedipine, which are permissible 
without discussion with the study chair) should be started and the blood pressure should be 
monitored at least twice weekly until BP is within the 95th percentile for age, height, and 
gender per Section 6.7. 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) must be no older than seven (7) days at the start of therapy.  Laboratory 
tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess 
eligibility.  If a post-enrollment lab value is outside the limits of eligibility, or laboratory 
values are older than 7 days, then the following laboratory evaluations must be re-checked 
within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) 
and serum  creatinine.  If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies, bone 
marrow aspirate and/or biopsy, must be obtained within 14 days prior to start of protocol 
therapy (repeat the tumor imaging if necessary). 
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Prior to Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
Neurologic Exam 
X 
 
 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
 
Pregnancy Test1 
X 
 
 
CBC, differential, platelets 
X 
Twice Weekly 
(every 3 to 4 days)2,3 
Weekly2,3 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Albumin 
X 
 
X 
Tumor Disease Evaluation4-A, 4-B, 4-C  
X 
 
Every other cycle x 3 
then q 3 cycles 4 
Bone Marrow Aspirate and/or biopsy5,6 
X6 
 
 
Patient Diary7 
 
Weekly 
X 
Circulating Tumor DNA (ctDNA-
optional)8 
 
 
Cycle 5, Day 1 and 
(for patients receiving 
≥ 5 cycles only) at 
end of protocol 
therapy OR disease 
progression 
ECHO or gated radionuclide study  
X 
 
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Creatine Kinase (CPK) 
X 
 
X 
Blood Pressure9 
X 
Weekly 
Prior to each cycle 
and every other week  
Ophthalmologic exam 
X 
 
Prior to cycle 3, then 
Prior to every other 
cycle 
Plain radiograph tibial growth plate 
(Bone X-Ray Tests)10 
 
X 
 
Prior to cycles 2, 5 
and every 6 months 
Total Cholesterol, Triglycerides11 
X 
X 
X 
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually 
active patients must use an acceptable method of birth control.  Abstinence is an acceptable method of 
birth control. 
2 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery 
to Grade 3 or until meeting the criteria for dose limiting toxicity. 
3 
If patients develop Grade 3 or greater thrombocytopenia then CBCs should be checked every 3 to 4 days 
until recovery per section 6.1. 
4 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation 
of either a PR or CR.  Subsequent scans may restart 2 cycles after the confirmatory scan. Please note 
that for solid tumor patients, if the institutional investigator determines that the patient has progressed 
based on clinical or laboratory evidence, he/she may opt not to confirm this finding radiographically. 
4-A     Neurological exam also required for CNS patients.  
4-B  Non- Hodgkin Lymphoma/ Histiocytosis patients are required to have PET scans within 2 weeks prior 
to start of therapy and should also be followed with PET scans if positive at diagnosis. Refer to Section 
12.8   
4-C    Patients with neuroblastoma must have both CT/MRI and MIBG scintigraphy prior to enrollment if the 
patient was enrolled with or has a history of having MIBG avid tumor. Otherwise the patient must have 
both CT/MRI and bone scan prior to enrollment. For patients with neuroblastoma and measurable disease 
by CT or MRI, lesions should be measured and followed using the same modality (CT or MRI) in 
addition to MIBG or bone scan. For patients with neuroblastoma and evaluable disease by MIBG 
scintigraphy or bone scan, use the same modality (MIBG scintigraphy or bone scan) to image and follow 
patients; CT/MRI are not required but may be performed as clinically indicated. Refer to Section 12.5.4 
and Section 12.9. 
5 
Bone marrow aspirate and/or biopsy only required in patients suspected of having bone marrow 
metastasis on the basis of history, symptoms, laboratory evaluation or other clinical data. Should only 
be performed on patients with known bone marrow involvement at baseline.   
6 
Bone marrow aspirate and/or biopsy should be performed only when complete response or partial 
response is identified in target disease or when progression in bone marrow is suspected. 
7  
Patient diary (see Appendix III) should be reviewed after completion of each treatment cycle and 
uploaded into RAVE. 
8  
With consent, two samples will be collected on this protocol (cycle 5 Day 1; and for patients receiving 
≥ 5 cycles only: at progression or end of protocol therapy), see Section 8.4 for details of the ctDNA 
studies. Note that a ctDNA sample is scheduled to be obtained on the APEC1621SC screening protocol 
prior to the initiation of treatment on this subprotocol. 
9 
Blood pressure will be measured with an appropriate sized cuff at rest. Blood pressure measurement will 
be repeated within the same day if the blood pressure (BP) is elevated (> the 95 th percentile for age, 
height, and gender). Please note that 3 serial blood pressures should be obtained and averaged to 
determine baseline BP (See Section 6.7). If both BP measurements are >95th percentile for age, height, 
and gender, follow the guidelines in Section 6.7. Patients with elevated BP at any time should have BP 
measurements performed at least twice weekly until BP is within the 95th percentile for age, height, and 
gender (See Appendix IX). 
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of protocol therapy. In patients with open growth plates, follow-up plain radiographs of the same growth 
plate(s) should be obtained according to Section 8.2.1. 
11     If Grade 3 or 4 hypercholesterolemia or Grade 3 or 4 hypertriglyceridemia is detected when routine (non-
fasting) laboratory studies are performed, the tests should be repeated within 3 days in the fasting state 
to permit accurate grading. 
 
8.2 
Monitoring for Specific Toxicities 
 
8.2.1 
Growth Plate Toxicity 
Patients will have a plain AP radiograph of a single proximal tibial growth plate 
obtained prior to the first dose of protocol therapy.  
a. If patients are found to have a closed tibial growth plate, no further radiographs 
will be required.  
b. If patients are found to have an open tibial growth plate, then repeat plain AP 
radiographs of the same tibial growth plate will be obtained prior to cycles 2, 
5 and every 6 months. 
• 
Patients with evidence of growth plate thickening or other changes should 
have a knee MRI performed to further assess the degree of physeal 
pathology and undergo more frequent x-ray follow up at least every 3 
cycles or as clinically indicated. MRI should be performed without 
contrast. 
• 
Patients with knee MRI changes should be managed in an individualized 
manner. Decisions regarding continuation of selumetinib should be made 
after discussion with the Study Chair or Study Vice-Chair and MATCH 
Leadership, taking into account the presence of any symptoms referable to 
the knee as well as the patient’s response to selumetinib. Consultation with 
an orthopedic surgeon may also be indicated. Plans for follow-up imaging 
will also be made on an individualized basis, taking into account the 
presence of symptoms at the knee or other joints as well as the decision to 
continue selumetinib or not. 
 
8.3 
Radiology Studies 
 
8.3.1 
Bone Age/Knee MRI 
All tibial radiographs and knee MRIs (if obtained) should be submitted for 
review. 
 
8.3.2 
Central Radiology Review for Response:   
Patients who respond (CR, PR) to therapy or have long term stable disease (SD) 
(≥ 6 cycles) on protocol therapy will be centrally reviewed.  The Operations center 
will notify the site when a patient has met the criteria for review. The tumor disease 
evaluations to be submitted for review include baseline (pre-study) evaluations as 
well as all end of cycle tumor disease evaluations which occurred while the patient 
was on the subprotocol therapy study. 
8.3.3 
Technical Details of Submission:  
To ensure an adequate interpretation of FDG-PET and CT with contrast scans, 
scans transferred between the treating institutions and the Imaging and Radiation 
Oncology Core Group IROC RI (QARC) must be submitted in Digital Imaging 
and Communications in Medicine (DICOM) format. BMP ﬁles, JPG ﬁles, or hard 
copies (ﬁlms) are unacceptable for adequate interpretation of PET and CT with 
contrast scans. Imaging studies must be submitted electronically as outlined in the 


 
 
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following paragraph. The images will be made available to study radiologists and 
nuclear medicine physicians for central review. 
 
Submission of Diagnostic Imaging data in DICOM format is required. Submission 
of the digital files and reports via TRIAD is preferred.  Instructions for TRIAD set 
up are below. 
 
Alternatively, the images and reports may be submitted via sFTP to IROC Rhode 
Island. Digital data submission instructions including instructions for obtaining a 
sFTP account, can be found at http://irocri.qarc.org. Follow the link labeled digital 
data.  Sites using the Dicommunicator software to submit imaging may continue 
to use that application. 
Corresponding Radiology reports may be submitted along with the electronic 
submission 
via 
TRIAD 
or 
sFTP 
or 
may 
be 
emailed 
to 
DataSubmission@QARC.org.   
 
Questions may be directed to DataSubmission@QARC.org or 401.753.7600. 
  
Digital RT Data Submission Using TRIAD (if TRIAD is available at your site): 
TRIAD is the American College of Radiology’s (ACR) image exchange 
application.  TRIAD provides sites participating in clinical trials a secure method 
to transmit DICOM and DICOM RT files and other digital objects, such as reports. 
TRIAD de-identifies and validates the images as they are transferred. 
 
TRIAD Access Requirements: 
Site physics staff who will submit images through TRIAD will need to be 
registered with the Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP Identity and Access Management (IAM) account.  Please refer to 
CTEP Registration Procedures of the protocol for instructions on how to request a 
CTEP-IAM account. 
To submit images, the site TRIAD user must be on the site roster and be assigned 
the 'TRIAD site user' role on the CTSU roster.  Users should contact the site’s 
CTSU Administrator or Data Administrator to request assignment of the TRIAD 
site user role.   
 
TRIAD Installations: 
 
When a user applies for a CTEP-IAM account with the proper user role, he/she 
will need to have the TRIAD application installed on his/her workstation to be able 
to submit images. TRIAD installation documentation can be found by following 
this link https://triadinstall.acr.org/triadclient/   
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password. 
 
If you have any questions regarding this information, please send an e-mail to the 
TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
IROC Rhode Island (formerly QARC) will facilitate the central reviews. 
 
For FDG-PET imaging, the transferred imaging data should include uncorrected 
and attenuation-corrected PET projection data, as well as the reconstructed PET or 


 
 
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PET/CT images used by the institution to achieve a response assessment. If low- 
dose CT was used for attenuation correction, the acquired CT images should also 
be submitted. The imaging data submitted for central review must allow the study 
to be reconstructed and displayed in transaxial, sagittal and coronal formats using 
standard reconstruction techniques. Reconstructed MPEG clips and similar types 
of reconstructions will not be accepted. CT and MRI images similarly should be 
submitted in a format that either includes properly reconstructed multi-planar 
viewing formats in soft tissue and bone windows, or includes the thin-section axial 
acquisition data from which multi-planar reconstructions can be re-created. 
 
Sites not able to submit imaging electronically may submit imaging via CD.   CD’s 
may be sent by courier to:  
 
Address for submission: IROC RI (QARC) 
Building B, Suite 201 
640 George Washington Highway Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax:     (401) 753-7601 
Web:    http://irocri.qarc.org 
 
8.4 
Circulating Tumor DNA Study (optional) 
 
8.4.1 
Sampling Schedule   
An initial sample was previously required at time of enrollment onto the 
APEC1621SC screening protocol. Additional samples will be collected into Streck 
Cell-Free DNA BCT tubes at the following timepoints: 
(1) Cycle 5 Day 1 
(2) At disease progression or end of protocol therapy (for patients receiving ≥ 5 
cycles of therapy only) 
 
Peripheral blood samples for cell-free DNA should be obtained as follows:  
• 
For patients ≥ 10 kg collect 20 mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥ 5 kg but < 10 kg collect 10 mL (one tube)  
• 
For patients < 5 kg research samples will not be collected  
 
In all cases, blood draw volumes should strictly adhere to institutional limitations, 
taking other blood draws into consideration. However, if a reduction in volume is 
required, samples should be collected in 10 mL increments (ie. 0, 10, or 20 mL 
should be collected such that each Streck Cell-Free DNA BCT is completely 
filled). 
 
Established institutional guidelines should be followed for blood collection via 
vascular access devices. Heparin should be avoided in pre-collection flush 
procedures. If therapeutic heparin dosing contamination is a possibility, 
venipuncture is recommended as a first choice collection method. If a Streck Cell-
Free DNA BCT tube immediately follows a heparin tube in the draw order, we 
recommend collecting an EDTA tube as a waste tube prior to collection in the 
Streck Cell-Free DNA BCT. 
 
For patients who do not have indwelling catheters, blood should be collected via 
venipuncture. To guard against backflow, observe the following precautions: 


 
 
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• 
Keep patient’s arm in the downward position during the collection 
procedure. 
• 
Hold the tube with the stopper in the uppermost position so that the tube 
contents do not touch the stopper or the end of the needle during sample 
collection. 
• 
Release tourniquet once blood starts to flow in the tube, or within 2 
minutes of application. 
• 
Fill tube completely. 
• 
Remove tube from adapter and immediately mix by gentle inversion 8 to 
10 times. Inadequate or delayed mixing may result in inaccurate test 
results.  
• 
Store blood in Streck tube at room temperature until shipment 
 
8.4.2 
Sample Processing 
Samples do not need to be processed at the collection site. 
8.4.3 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D (APEC1621E), and the date and time the sample was drawn.  Data should be 
recorded on the appropriate transmittal form found in RAVE, which must 
accompany the sample(s). 
 
8.4.4 
Sample Shipping Instructions 
Specimen should be shipped at room temperature to the BPC (address below). 
Upon arrival separation, extraction, and storage of plasma and cellular DNA will 
be performed. Samples should be shipped from Monday through Friday for 
Tuesday through Saturday delivery. If blood is collected over the weekend or on 
the day before a holiday, the sample should be stored in a refrigerator until shipped 
on the next business day.  Ship by FedEx Priority Overnight using the COG FedEx 
account. Blood samples should be shipped the same day as collection, ship blood 
for Saturday delivery if shipped on Friday. 
 
Ship specimens to the following address: 
 
 
 
Biopathology Center 
 
 
Nationwide Children’s Hospital 
 
 
Protocol APEC1621E- Peds MATCH 
 
 
700 Children’s Drive, WA1340* 
 
 
Columbus, OH 43205 
 
 
Phone: (614) 722-2865 
 
 
Fax: (614) 722-2897 
Email:BPCBank@nationwidechildrens.org 
 
*Labeling is extremely important for this project. Packages must be labeled “Peds 
MATCH” in order to expedite processing at the BPC. Be sure to include the room 
number. Packages received without the room number may be returned to the 
sender. 
 


 
 
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9.0 
AGENT INFORMATION 
 
9.1 
Selumetinib 
(AZD6244 hydrogen sulfate) NSC#748727 IND# 
  
9.1.1 
Structure and molecular weight  
Chemical Name or Amino Acid Sequence: 5-[(4-bromo-2-chlorophenyl)amino]-
4-fluoro-6-[(2-hydroxyethoxy)carbamoyl]-1-methyl-1H-benzimidazol-3-ium 
hydrogen sulfate 
 
Molecular Formula: C17H15BrClFN4O3• H2SO4 
 
Molecular Weight: 555.76 
 
9.1.2 
Supplied by: Astrazeneca supplies and CTEP, DCTD, NCI distributes 
selumetinib (AZD6244 hydrogen sulfate). 
 
9.1.3 
Formulation 
Selumetinib (AZD6244 hydrogen sulfate) is supplied for clinical trial use as size 
4 hydroxypropylmethylcellulose (HPMC) capsules available in 10 mg (plain 
white) and 25 mg (blue) strengths, expressed as free base. Capsules are packaged 
in white, high density polyethylene (HDPE) containers with induction-seals and 
child-resistant closures.  Each bottle contains 60 capsules with desiccant.  
 
Selumetinib (AZD6244 hydrogen sulfate) capsules contain a dispersion of drug in 
D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS; a water soluble form 
of vitamin E). Each 10 mg capsule contains 32.4 mg TPGS and each 25 mg capsule 
contains 35.9 mg TPGS. 
 
9.1.4 
Storage 
Store the selumetinib (AZD6244 hydrogen sulfate) capsules at controlled room 
temperature (20°C- 25°C). Bottles can be refrigerated between 2°C- 8°C if 
necessary.    
 
If a storage temperature excursion is identified (either above 25°C or below 2°C), 
promptly return selumetinib (AZD6244 hydrogen sulfate) to controlled room 
temperature and quarantine the supplies. Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of suitability.   
 
9.1.5 
Stability: Stability studies are ongoing. 
 
9.1.6 
Administration 
Oral. Do not eat or drink (except water only) for 2 hours prior to dosing and 1 hour 
after dosing selumetinib (AZD6244 hydrogen sulfate) capsules. 
9.1.7 
Potential Drug Interactions 
High vitamin E doses may potentiate warfarin’s anticoagulant activity.  Monitor 
PT/INR more frequently in patients receiving both warfarin and selumetinib 
(AZD6244 hydrogen sulfate) capsules.   
 
Avoid concomitant intake of supplemental vitamin E. 


 
 
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Selumetinib (AZD6244 hydrogen sulfate) is primarily metabolized by CYP 1A2 
to form the active N-desmethyl metabolite; in addition, UGT 1A1 and1A3 form 
glucuronide conjugates. CYP 2C8, 2C9, 2C19, 3A4/5 can also metabolize the 
parent agent to form N-desmethyl selumetinib; however, as observed during in 
vitro studies using a pan-CYP inhibitor, other available pathways contribute to 
selumetinib (AZD6244 hydrogen sulfate) and N-desmethyl selumetinib 
metabolism. Use caution in patients who are taking strong inducers or inhibitors 
of these CYP or UGT enzymes. 
 
Selumetinib (AZD6244 hydrogen sulfate) is also a substrate of BCRP (breast 
cancer resistance protein) and P-gp transporters. Use caution in patients who are 
taking strong inducers or inhibitors of either transport protein. 
 
Selumetinib (AZD6244 hydrogen sulfate) does not inhibit CYP 1A2, 2C8, 
2C19and 3A4 or UGT isoforms 1A1 and 2B7. It is a weak inducer of CYP enzymes 
3A, 1A and 2C9 and a weak inhibitor of CYP 2C9, 2B6 and 2D6. In vitro studies 
demonstrate selumetinib (AZD6244 hydrogen sulfate) is an inhibitor of BCRP, 
OATP1B1, OATP1B3, OCT2, OAT1 and OAT3 transporters. It does not inhibit 
OCT1, MATE1, MATE2K or P-glycoprotein (MDR1). The N-desmethyl 
metabolite is a weak inhibitor of CYP 3A4 and 1A2. In vitro data suggest that 
selumetinib (AZD6244 hydrogen sulfate) is unlikely to cause clinically relevant 
drug-drug interactions by these mechanisms. 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Care Implications: Study participants should be counseled to avoid 
excessive sun exposure and use adequate sun protection measures if sun exposure 
is anticipated during the study. 
 
9.1.8 
Selumetinib (AZD6244) Toxicities 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Selumetinib (AZD6244 hydrogen sulfate [NSC 748727]), AZD6244 (NSC 
741078) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 986 patients. 
Below is the CAEPR for Selumetinib (AZD6244 hydrogen sulfate). 
 
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. 
 


 
 
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Version 2,8, June 13, 20191 
 
 Adverse Events with Possible  
 Relationship to Selumetinib (AZD6244 hydrogen sulfate), AZD6244 
 (CTCAE 5.0 Term) 
[n= 986] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
Anemia (Gr 3) 
Febrile neutropenia2 
 
CARDIAC DISORDERS 
 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction (Gr 2) 
EYE DISORDERS 
 
Blurred vision 
 
Eye disorders - Other (central 
serous retinopathy) 
 
Eye disorders - Other (retinal 
pigment epithelial detachment) 
 
Eye disorders - Other (retinal vein 
occlusion) 
 
Periorbital edema 
 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
Abdominal pain (Gr 3) 
Constipation 
 
Constipation (Gr 2) 
Diarrhea3 
 
Diarrhea3 (Gr 3)  
Dry mouth 
 
 
Mucositis oral 
 
Mucositis oral (Gr 3) 
Nausea 
 
Nausea (Gr 3) 
Vomiting 
 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Edema face 
 
Edema face (Gr 2) 
Edema limbs 
 
Edema limbs (Gr 3) 
Fatigue 
 
Fatigue (Gr 3) 
Fever 
 
Fever (Gr 2) 
Pain 
 
 
INFECTIONS AND INFESTATIONS 
 
 Folliculitis  
 
 Nail infection  
 
 
 Papulopustular rash  
 
Paronychia 
 
 
 Skin infection 
 
INVESTIGATIONS 
 
Alanine aminotransferase increased  
Alanine aminotransferase 
increased (Gr 3) 
Aspartate aminotransferase 
increased 
 
Aspartate aminotransferase 
increased (Gr 3) 
CPK increased 
 
CPK increased (Gr 3) 
Ejection fraction decreased 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 


 
 
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 Adverse Events with Possible  
 Relationship to Selumetinib (AZD6244 hydrogen sulfate), AZD6244 
 (CTCAE 5.0 Term) 
[n= 986] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
White blood cell decreased 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
Anorexia (Gr 2) 
Hyperphosphatemia 
 
Hypoalbuminemia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Growth suppression 
 
Musculoskeletal and connective 
tissue disorder - Other (neck 
extensor muscle weakness) 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 
Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
Cough (Gr 2)  
Dyspnea 
 
Dyspnea (Gr 3) 
Pneumonitis 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
 
Dry skin 
 
Dry skin (Gr 2) 
Pruritus 
 
 
Rash acneiform 
 
Rash acneiform (Gr 3) 
Rash maculo-papular 
 
Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
 
Hypertension 
 
 
 
1. 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. 
2. Febrile neutropenia/neutropenic infection has been observed primarily in trials combining Selumetinib (AZD6244) 
and docetaxel. 
3. SBE-CD (Captisol®, vehicle) in the mix and drink formulation is known to cause soft stools and/or diarrhea in 
rats and dogs; however, it is possible that some of these findings might be related to exacerbation of the vehicle 
effect by Selumetinib (AZD6244) 
 
Adverse events reported on Selumetinib (AZD6244) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that Selumetinib (AZD6244) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(hemorrhagic anemia) 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Atrioventricular block first degree; 
Cardiac disorders - Other (Takotsubo cardiomyopathy syndrome); Cardiac disorders - Other (valvular heart disease); 
Chest pain - cardiac; Heart failure; Myocardial infarction; Palpitations; Pericardial effusion; Right ventricular 
dysfunction; Sinus bradycardia; Sinus tachycardia 
EYE DISORDERS - Dry eye; Eye disorders - Other (bilateral macular edema); Eye disorders - Other (black haze in 
line of vision); Eye disorders - Other (chalazion); Eye disorders - Eye disorders - Other (diplopia); Eye disorders - 
Other (retinal bleeding); Eye disorders - Other (spotty vision; itchy vision); Flashing lights; Floaters; Glaucoma; Optic 


 
 
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nerve disorder; Papilledema; Photophobia; Retinal detachment; Retinopathy; Uveitis; Vision decreased 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Bloating; Cheilitis; Colitis; Duodenal 
ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastric hemorrhage; Gastritis; Gastroesophageal 
reflux disease; Gastrointestinal disorders - Other (pneumatosis coli); Gingival pain; Ileal stenosis; Oral hemorrhage; 
Rectal hemorrhage; Stomach pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Disease 
progression; Facial pain; Flu like symptoms; Generalized edema; Localized edema; Malaise; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (liver dysfunction/ failure 
[clinical]) 
INFECTIONS AND INFESTATIONS - Biliary infection; Bone infection; Bronchial infection; Conjunctivitis; 
Kidney infection; Laryngitis; Lung infection; Mucosal infection; Penile infection; Periorbital infection; Sepsis; Upper 
respiratory infection; Urinary tract infection; Wound infection 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Cardiac troponin I increased; 
Creatinine increased; Electrocardiogram QT corrected interval prolonged; Electrocardiogram T wave abnormal; 
Hemoglobin increased; INR increased; Investigations - Other (ECG signs of myocardial ischemia); Lipase increased; 
Lymphocyte count decreased; Lymphocyte count increased; Serum amylase increased; Weight gain; Weight loss 
METABOLISM AND 
NUTRITION DISORDERS - 
Dehydration; Hyperglycemia; 
Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; 
Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other 
(electrolyte abnormalities); 
Metabolism and nutrition disorders - Other (elevated calcium phosphorus product); Metabolism and nutrition 
disorders - Other (sensation of warmth) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Back pain; Bone 
pain; Chest wall pain; Generalized muscle weakness; Joint effusion; Joint range of motion decreased; Muscle 
weakness lower limb; Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other (bilateral 
stiffness hands and feet [intermittent]); Musculoskeletal and connective tissue disorder - Other (neck myopathy); 
Myalgia; Myositis; Neck pain; Pain in extremity; Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment 
related secondary malignancy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Cognitive disturbance; Concentration impairment; Depressed level 
of consciousness; Dysarthria; Dysgeusia; Dysphasia; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; 
Leukoencephalopathy; Memory impairment; Oculomotor nerve disorder; Paresthesia; Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy syndrome; Seizure; Spinal cord 
compression; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delusions; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Nephrotic syndrome 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Bronchopulmonary hemorrhage; Epistaxis; Hoarseness; Hypoxia; Nasal congestion; Pharyngolaryngeal pain; Pleural 
effusion; Pulmonary edema; Sore throat; Voice alteration; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Erythroderma; Nail loss; Pain of 
skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Scalp pain; Skin and subcutaneous tissue 
disorders - Other (skin fissures); Skin ulceration; Stevens-Johnson syndrome; Urticaria 
VASCULAR DISORDERS - Flushing; Hypotension; Lymphedema; Thromboembolic event 
 
Note: Selumetinib (AZD6244 hydrogen sulfate) 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, 


 
 
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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. 
Note:  No starter supplies will be provided. Drug orders of selumetinib (AZD6244 
hydrogen sulfate) should be placed with CTEP after enrollment and treatment 
assignment to APEC1621E with consideration for timing of processing and shipping 
to ensure receipt of drug supply prior to start of protocol therapy. If expedited 
shipment is required, sites should provide an express courier account through the Online 
Agent Order Processing (OAOP) application. Provide the patient ID number in the 
comment box when submitting an order request. 
 
9.3 
Clinical Drug Request and Investigator Brochure Availability 
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, and a 
“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. 
 
9.4.1 
Useful Links and Contacts  
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
 
 
http://ctep.cancer.gov/branches/pmb/agent_management.htm    
• PMB Online Agent Order Processing (OAOP) application:  
 
 
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account:  
     https://ctepcore.nci.nih.gov/iam/ 
• CTEP  IAM account help: 
 
ctepreghelp@ctep.nci.nih.gov  
• PMB email: PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575  
Monday through Friday between 8:30 am and 4:30 pm (ET) 
• PMB IB Coordinator: IBcoordinator@mail.nih.gov 
• Registration and Credential Repository (RCR): 
https://ctepcore.nci.nih.gov/rcr/  


 
 
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10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12). 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6). 
c) 
Refusal of protocol therapy by patient/parent/guardian 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Completion of 26 cycles of therapy. 
f) 
Physician determines it is not in the patient’s best interest. 
g) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of protocol therapy (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
j) 
Patient did not receive protocol treatment after study enrollment. 
 
 
 
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent from the APEC1621SC screening protocol. Patients who are removed from 
protocol therapy in subsequent cycles should have the necessary observations to 
ensure adequate clinical care.  
 
10.2 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
Patients who are off subprotocol therapy will continue to be followed on the APEC1621SC 
screening protocol. Follow-up data submission will occur until one of the APEC1621SC 
Off Study Criteria is met (See Section 10 of APEC1621SC for details). Ongoing adverse 
events, or adverse events that emerge after the patient is removed from protocol therapy, 
but within 30 days of the last dose of investigational agent, must be followed and reported 
via RAVE and CTEP-AERS (if applicable).  Follow-up data will be required until off study 
criteria are met unless consent is withdrawn or the patient dies or is lost to follow-up. 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
APEC1621E will require a minimum of 20 evaluable patients and a maximum of 49 
patients, allowing for 15% inevaluability. Assuming an enrollment rate of 4-6 biomarker 
positive patients per year, this subprotocol is expected to be completed within 8-12 years. 
 
11.2 
Dosing Considerations  
A pediatric MTD/RP2D dose has been established for selumetinib (AZD6244 hydrogen 
sulfate)16; therefore patients will be treated at that dose. Please see Section 5.1 for a specific 
discussion of the dosing of selumetinib (AZD6244 hydrogen sulfate) to be used in this 


 
 
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study.   
 
11.3 
Study Design 
The primary cohort will employ a single stage A’Hern designs of N=20. The agent will be 
deemed worthy of further study in the relevant subset of patients (i.e. biomarker positive 
in any histology, biomarker positive in a particular histology, etc) if the decision rule is 
met. Operating characteristics are shown below. 
 
Cohort 
N 
Decision Rule Alpha 
Power 
Primary biomarker positive 20 ≥ 3 responses 
10% 
90% 
 
Histology-specific biomarker positive expansion cohorts will, by definition, be deemed 
worthy of further study, since they will have at least 3 responses. The table below shows 
90% confidence intervals (Wilson method) for a range of observable response rates. 
 
Cohort Size Observed Response Rate 90% Confidence Interval 
10 
30% 
13% - 56% 
10 
40% 
19% - 65% 
10 
50% 
27% - 73% 
 
 
11.3.1 Primary Cohort:  
APEC1621E will evaluate a primary cohort of 20 mutation-matched (“biomarker 
positive”) evaluable patients of any histology for the primary study aim of 
determining the objective response rate (CR/PR according to the response criteria 
in Section 12.3) to selumetinib (AZD6244 hydrogen sulfate). Using an A’Hern 
design47 with alpha=10%, a sample of N=20 will provide 90% power to detect an 
improvement in response rate from 5%, if the treatment is ineffective, to 25% if 
the targeted therapy is sufficiently effective to warrant further study. If there are at 
least 3 responses out of 20 in the primary cohort, the biomarker/therapy match will 
be deemed a success.  
 
11.3.2 Histology-Specific Biomarker Positive Expansion Cohorts:  
If ≥ 3 patients in the primary cohort with the same histology show signs of 
objective response (CR/PR according to the response criteria in Section 12.3), a 
histology-specific biomarker positive expansion cohort will open after the primary 
cohort is completed to up to 7 evaluable patients for a total sample size of 10 
evaluable biomarker positive patients with that histology. This will allow us to 
estimate more precisely the activity in biomarker positive patients of that 
histology. See Appendix VI for a list of target tumor histologies.  
We will open up to 3 such expansion cohorts for biomarker positive patients (i.e., 
if 3 histologies have ≥ 3 responses, we will open a total of 3 expansion cohorts as 
described above). Note that this can only happen if the response rate in the primary 
cohort is at least 45% (9/20) and there cannot be more than 21 additional evaluable 
patients in total for these expansion cohorts. 
 
 
11.4 
Methods of Analysis 
Response criteria are described in Section 12. A responder is defined as a patient who 
achieves a best response of PR or CR on the study. Response rates will be calculated as the 
percent of evaluable patients who are responders, and confidence intervals will be 


 
 
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constructed using the Wilson score interval method.48 Decision making for A’Hern design 
cohorts will follow rules described above. 
 
Toxicity tables will be constructed to summarize the observed incidence by type of toxicity 
and grade. A patient will be counted only once for a given toxicity for the worst grade of 
that toxicity reported for that patient. Toxicity information recorded will include the type, 
severity, time of onset, time of resolution, and the probable association with the study 
regimen.   
 
11.5 
Evaluability for Response 
Any eligible patient who is enrolled and receives at least one dose of protocol therapy will 
be considered evaluable for response. Any patient who receives non-protocol anti-cancer 
therapy during the response evaluation period will be considered a non-responder for the 
purposes of the statistical rule, unless they show an objective response prior to receiving 
the non-protocol anti-cancer therapy (in which case they will be considered a responder). 
Patients who demonstrate a complete or partial response confirmed by central review will 
be considered to have experienced a response. When opening expansion cohorts, the 
evaluation period for determination of best response will be 6 treatment cycles. All other 
patients will be considered non-responders. Patients who are not evaluable for response 
evaluation may be replaced for the purposes of the statistical rule. All patients considered 
to have a response (CR or PR) must have imaging studies reviewed centrally at the COG. 
Centers will be notified by the COG about requests for scans of patients with stable disease. 
Preliminary assessment of activity using institutionally provided tumor measurements will 
be entered into CDUS quarterly. The central review by COG will be provided as the final 
reviewed assessment of response when such becomes available. 
 
11.6 
Evaluability for Toxicity 
All patients who receive at least one dose of protocol therapy will be considered in the 
evaluation of toxicity. 
11.7 
Progression free survival (PFS) 
Progression free survival will be defined as time from the initiation of protocol treatment 
to the occurrence of any of the following events: disease progression or disease 
recurrence or death from any cause. All patients surviving at the time of analyses without 
events will be censored at their last follow-up date. 
 
PFS along with the confidence intervals will be estimated using the Kaplan-Meier method. 
Patients with local calls of disease progression (i.e. calls made by the treating institution), 
will be counted as having had an event, even if the central review does not declare 
progression. We will also report PFS based on central radiology review as a secondary 
analysis, if adequate number of disagreements in progressions exist between the treating 
institutions and the central radiology review to make such an analysis meaningful.     
 
11.8 
Correlative Studies 
A descriptive analysis of the exploratory aims described in Section 1.3 will be performed 
and will be summarized with simple summary statistics. All of these analyses will be 
descriptive in nature. 
 
11.9 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
 


 
 
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Racial category 
Ethnicity 
Total 
Not Hispanic 
or Latino 
Hispanic or 
Latino 
Female Male Female Male 
American Indian/Alaska Native 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
2 
Native 
Hawaiian 
or 
Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
3 
5 
0 
0 
8 
White 
12 
20 
4 
2 
38 
More than one race 
1 
0 
0 
0 
1 
Total 
17 
26 
4 
2 
49 
 
This distribution was derived from the demographic data for patients enrolled on recent COG 
Phase 2 trials. 
 


 
 
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12.0 
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in version 5.0 of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) will be utilized for AE reporting.  All appropriate 
treatment areas should have access to a copy of CTCAE version 5.0.  A copy of the CTCAE 
v5.0 can be downloaded from the CTEP website (http://ctep.cancer.gov). 
 
12.2 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of subprotocol 
treatment to time of progression or death, whichever occurs first. 
 
Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions – e.g., when multiple lesions 
show opposite responses, the progressive disease takes precedence. 
 
12.3 
Response Criteria for Patients with Solid Tumors  
See the table in Section 8.0 for the schedule of tumor evaluations. Eligible patients must 
have measurable disease present at baseline and have had their disease re-evaluated after 
one dose of protocol therapy. In addition to the scheduled scans, a confirmatory scan should 
be obtained on the next consecutive cycle following initial documentation of objective 
response. 
 
As outlined, patients will be assigned to one of the following categories for assessment of 
response:  a) solid tumor (non-CNS) and measurable disease (Section 12.4); b) 
neuroblastoma with MIBG positive lesions (Section 12.5); c) CNS tumor (Section 12.7); 
and d) non-Hodgkin lymphoma/hystiocytosis (Section 12.8). Note: Neuroblastoma patients 
who do not have MIBG positive lesions should be assessed for response as solid tumor 
patients with measurable disease. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009].  Key points are that 5 target lesions are identified and that changes in the largest 
diameter (unidimensional measurement) of the tumor lesions but the shortest diameter of 
malignant lymph nodes are used in the RECIST v 1.1 criteria. 
 
12.3.1 Definitions 
12.3.1.1 
Evaluable for objective response: Eligible patients who receive at least one 
dose of protocol therapy will be considered evaluable for response. 
Evaluable patients who demonstrate a complete or partial response 
confirmed by central review before receiving non-protocol anti-cancer 
therapy will be considered a responder. All other evaluable patients will 
be considered non-responders.  
 
12.3.1.2 
Evaluable Non-Target Disease Response: Eligible patients who have 
lesions present at baseline that are evaluable but do not meet the 
definitions of measurable disease and have received at least one dose of 
protocol therapy will be considered evaluable for non-target disease. The 
response assessment is based on the presence, absence, or unequivocal 
progression of the lesions. 
 


 
 
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12.3.2 Disease Parameters 
 
12.3.2.1 
Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 
mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable. If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 
 
12.3.2.2 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed 
by CT scan (CT scan slice thickness no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
12.3.2.3 
Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter < 10 mm or pathological lymph nodes with 
≥ 10 to < 15 mm short axis), are considered non-measurable disease.  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
12.3.2.4 
Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the 
next largest lesion that can be measured reproducibly should be selected.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
 
12.3.2.5 
Non-target lesions: All other lesions (or sites of disease) including any 


 
 
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measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
12.3.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
12.3.3.1 
Clinical lesions:  Clinical lesions will only be considered measurable when 
they are superficial (e.g., skin nodules and palpable lymph nodes) and  
10 mm diameter as assessed using calipers (e.g., skin nodules).  In the case 
of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  
 
12.3.3.2 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
 
12.3.3.3 
Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans). Ideally, 
the same type of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans.  
 
12.3.3.4 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements.  However, if the site can document that 
the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST or International Pediatric non-Hodgkin 
Lymphoma Response Criteria measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer 
lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
12.3.3.5 
Tumor markers: Tumor markers alone cannot be used to assess response.  
If markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response.  
 
12.3.3.6 
Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare cases 


 
 
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(e.g., residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.3.3.7 
FDG-PET: While FDG-PET response assessments need additional study, 
it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly 
possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
For patients with a positive PET scan at diagnosis, PET can be used to 
follow response in addition to a CT scan using the International Pediatric 
non-Hodgkin Lymphoma Response Criteria.49  
 
12.4 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 


 
 
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diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions 
is also considered progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
 
12.4.3 Overall Response Assessment 
 
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥ 28 days Confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
≥ 28 days Confirmation 


 
 
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CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once ≥ 
28 days from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Table 3: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
12.4.4 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.9  from a sequence of overall response assessments. 
 
12.5 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
12.5.1 MIBG Positive Lesions 


 
 
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Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
12.5.2 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease: Development of new MIBG positive lesions 
 
12.5.3 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess 
efficacy for study endpoint. See Section 8.2 for details on transferring images to 
the Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 
 
 
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by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
12.5.4 Overall Response Assessment 
 
Table 4: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease 
Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly 
identified lesion by CT/MRI that occurs during therapy would be considered 
progressive disease. 
 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 
12.5.5 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.9. 
 
12.6 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
12.6.1 Bone Marrow Involvement  
Note: patients with bone marrow as the ONLY site of disease are not eligible for 
this study. Response criteria in this section are intended to be used when 
assessing marrow involvement as a component of overall response.  
 
Histologic analysis at the local institution of marrow tumor cell involvement is 
required for patients with a history of marrow involvement. Marrow aspirate and 
biopsy should be evaluated at baseline and every 2 cycles thereafter. Note: If 
progressive disease is documented by RECIST criteria using tumor measurements 
or by MIBG scan, then a repeat BM is not needed to confirm PD.  


 
 
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Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there 
is a doubling in the amount of tumor in the marrow AND 
a minimum of 25% tumor in bone marrow by 
morphology. (For example, a patient entering with 5% 
tumor in marrow by morphology must increase to ≥ 25% 
tumor to have progressive disease; a patient entering with 
30% tumor must increase to > 60%). 
 
In patients who enroll without evidence of neuroblastoma 
in bone marrow will be defined as progressive disease if 
tumor is detected in 2 consecutive bone marrow biopsies 
or aspirations done at least 21 days apart. 
 
Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
12.6.2 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.9. 
 
12.7 
Response Criteria for Patients with CNS Tumors 
 
12.7.1 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
12.7.2 Evaluable Disease  
Evaluable disease is defined as at least one lesion, with no lesion that can be 
accurately measured in at least one dimension. Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures. 
 
12.7.3 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 


 
 
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accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice). 
 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
12.7.4 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in 
other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions: 
 
• 
Complete Response (CR): Disappearance of all target lesions. Off all steroids 
with stable or improving neurologic examination. 
 
• 
Partial response (PR): ≥ 50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements; on a stable or decreasing dose of steroids with 
a stable or improving neurologic examination. 
 
• 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of 
the two perpendicular diameters of all target lesions to qualify for PR, nor 
sufficient increase in a single target lesion to qualify for PD; on a stable or 
decreasing dose of steroids with a stable or improving neurologic examination. 
 
• 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
Increasing doses of corticosteroids required to maintain stable neurological 
status should be strongly considered as a sign of clinical progression unless in 
the context of recent wean or transient neurologic change due e.g. to radiation 
effects.  
 
12.7.5 Response Criteria for Non-Target Lesions: 
 
• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
• 
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
12.7.6 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 


 
 
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12.7.7 Overall Response Assessment 
The overall response assessment takes into account response in both target and 
non-target lesions, the appearance of new lesions and normalization of markers 
(where applicable), according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns.   
 
 
Target Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 
Response 
CR 
CR 
Normal 
No 
CR 
CR 
IR/SD 
Normal 
No 
PR 
CR  
CR, IR/SD 
Abnormal 
No 
PR 
PR 
CR, IR/SD 
Any 
No 
PR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.9 from a sequence of overall response assessments. 
 
 
12.8 
Response Criteria for Patients with non-Hodgkin Lymphoma/Histiocytosis 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Pediatric non-Hodgkin 
Lymphoma Criteria, with modification from the Lugano classification.50 
 
12.8.1 Disease Parameters 
 
12.8.1.1 Measurable disease: A measurable node must have an LDi (longest 
diameter) greater than 1.5 cm. A measurable extranodal lesion should 
have an LDi greater than 1.0 cm. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
12.8.1.2 Non-measured disease: All other lesions (including nodal, extranodal, and 
assessable disease) should be followed as nonmeasured disease (e.g., 
cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial 
effusions, ascites).   
 
12.8.1.3 Target lesions: For patients staged with CT, up to six of the largest target 
nodes, nodal masses, or other lymphomatous lesions that are measurable 
in two diameters (longest diameter [LDi] and shortest diameter) should 
be identified from different body regions representative of the patient’s 


 
 
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overall disease burden and include mediastinal and retroperitoneal 
disease, if involved. 
 
12.8.2 Evaluation of Measurable Disease 
 
Complete Response (CR) 
Disappearance of all disease. CT or MRI should be free of residual mass or 
evidence of new disease. FDG-PET should be negative. 
 
Complete Response Unconfirmed (CRu) 
Residual mass is negative by FDG-PET; no new lesions by imaging examination; 
no new and/or progressive disease elsewhere 
 
Partial Response (PR) 
50% decrease in SPD (the sum of the products of the largest diameter and the 
perpendicular diameter for a tumor mass) on CT or MRI; FDG-PET may be 
positive (Deauville score or 4 or 5 with reduced lesional uptake compared with 
baseline); no new and/or PD; morphologic evidence of disease may be present in 
BM if present at diagnosis; however, there should be 50% reduction in percentage 
of lymphoma cells. 
 
No Response (Stable Disease) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
Progressive disease 
For those with > 25% increase in SPD on CT or MRI, Deauville score 4 or 5 on 
FDG-PET with increase in lesional uptake from baseline, or development of new 
morphologic evidence of disease in BM  
 
12.8.3 Evaluation of Non-measured Lesions (CT-based response, PET/CT based 
response not applicable)50 
 
Complete Response (CR): Absent non-measured lesions.  
 
Partial response (PR): 
Absent/normal, regressed, lesions, but no increase. 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): New 
or 
clear 
progression 
of 
preexisting 
non-measured lesions. 
 
12.8.4 Evaluation of organ enlargement50  
 
Complete Response (CR): Regress to normal  
 
Partial response (PR): 
Spleen must have regressed by >50% in length 
beyond normal 
 
Stable Disease (SD): 
No increase consistent with progression 


 
 
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Progressive Disease (PD): In the setting of splenomegaly, the splenic length 
must increase by 50% of the extent of its prior 
increase beyond baseline. If no prior splenomegaly, 
must increase by at least 2 cm from baseline.  
 
New or recurrent splenomegaly 
 
 
12.9 
Best Response 
Two objective status determinations of disease status, obtained on two consecutive 
determinations, separated by at least a 3 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. 
 
12.9.1 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
 
 
 
 
Table 5.  Sequences of overall response assessments with corresponding best 
response. 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
12.9.2 Duration of Response 


 
 
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Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  Adverse events are reported in a routine manner at scheduled times 
during a trial.  (Please follow directions for routine reporting provided in the Case Report Forms 
for this protocol).  Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  The following sections provide information 
about expedited reporting. 
 
 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered serious; 
3) the grade (severity); and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
 
 
 
13.1 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 


 
 
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6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug experience 
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. 
 
13.1.1 Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair 
have the primary responsibility for AE identification, documentation, grading, and 
assignment of attribution to the investigational agent/intervention. It is the 
responsibility of the treating physician to supply the medical documentation 
needed to support the expedited AE reports in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via 
routine reporting. Routine reporting is accomplished via the Adverse Event (AE) 
Case Report Form (CRF) within the study database.   
 
13.1.2 CTEP-AERS Expedited Reporting Methods  
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed 
via the 
CTEP 
home page 
https://ctepcore.nci.nih.gov/ctepaers/pages/task. 
 
Send supporting documentation to the NCI by fax (fax# 301-230-0159) and by 
email to the APEC1621E COG Study Assigned Research Coordinator.  ALWAYS 
include the ticket number on all faxed and emailed documents. 
 
13.2 
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 current version of the NCI CTCAE 
V5.0.  The descriptions and grading scales found in the current version of CTCAE 
V5.0 will be used for AE reporting. All appropriate treatment areas should have 
access to a copy of the CTCAE.  A copy of the CTCAE v5 can be downloaded 
from the CTEP website (http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAE V5.0. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported regardless 
of attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions. 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or 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. 


 
 
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• 
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. 
• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via 
the web at http://ctep.cancer.gov (telephone CTEP at: 301-897-7497 within 24 hours of 
becoming aware of the event if the CTEP-AERS 24-Hour Notification web-based 
application is unavailable). Once internet connectivity is restored, a 24-hour notification 
phoned in must be entered electronically into CTEP-AERS by the original submitter at 
the site. 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 


 
 
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Table A: Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported via CTEP-AERS within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found 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 
 
13.3 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements: 
 
• 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. 


 
 
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Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD/LYMPHATICS DISORDERS 
Anemia 
 
• Grade 1 and 2 adverse events listed in the table below do not require expedited reporting 
via CTEP-AERS, unless it is associated with hospitalization. 
Category 
Adverse Events 
GASTROINTESTINAL DISORDERS 
Dry Mouth 
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS 
Pain 
NERVOUS SYSTEM DISORDERS 
Dizziness 
PSYCHIATRIC DISORDERS 
Insomnia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Pruritus 
 
• See also the Specific Protocol Exceptions to Expedited Reporting (SPEER) in Section 9.1.8 
of the protocol.   
 
13.4 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG case report 
forms and do not alter the guidelines for CTEP-AERS reporting. 
 
13.4.1 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
13.4.2 If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported. 
 
13.4.3 The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects.  
 
13.4.4 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than or equal to Grade 1, whichever level is higher (note that the 
resolution date may therefore be different from the date at which the grade of the 
AE decreased from its highest grade).  If the AE does not return to baseline the 
resolution date should be recorded as "ongoing."   
 
13.4.5 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
13.5 
Other Recipients of Adverse Event Reports 
 
13.5.1 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the CRF 
packet (See Section 14.1). 


 
 
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13.5.2 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 
Specific Examples for Expedited Reporting 
 
13.6.1 Reportable Categories of Death 
• Death attributable to a CTCAE v5.0 term.  
• Death Neonatal: A disorder characterized by “Newborn deaths occurring during 
the first 28 days after birth.”  
• Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be attributed 
to a CTCAE v5.0 term associated with Grade 5.  
• Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
• 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” under the system organ class (SOC) of General disorders and 
administration site conditions.” Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
• Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 
hours.  
 
• Any death that occurs more than 30 days after the last dose of treatment with 
an investigational agent which can be attributed (possibly, probably, or 
definitely) to the agent and is not clearly due to progressive disease must be 
reported via CTEP-AERS per the timelines outlined in the table above. 
 
13.6.2 Reporting Secondary Malignancy 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., 
treatment 
with 
investigational 
agent/intervention, radiation 
or 
chemotherapy). A secondary malignancy is not considered a metastasis of the 
initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an 
agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute 
myelocytic leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
 


 
 
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Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy).  Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 
13.6.3 Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Neonatal 
loss”, 
the 
Pregnancy 
Information 
Form, 
available 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to 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” 
section of the CTEP-AERS report. 
 
Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the fetus to 
agents that may be teratogenic. For this reason, pregnancy needs to 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. 
 
• 
Pregnancy needs to be followed 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/protocolDevelopmen
t/electronic_applications/docs/PregnancyReportForm.pdf. 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 v5.0 as “Death in utero.” 
 
Any pregnancy loss needs to be reported expeditiously, as Grade 4 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy loss)”. 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 v5.0 as “Newborn deaths occurring during 
the first 28 days after birth” that is felt by the investigator to be at least possibly 
due to the investigational agent/intervention, should be reported expeditiously, as 
Grade 4 “Death Neonatal” under the system organ class (SOC) of “General 
disorders and administration site conditions.” 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 on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event 
as a patient death.  


 
 
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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 protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, July 
31 and October 31.  This is not a responsibility of institutions participating in this trial. 
Note:  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.   
 
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 
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. 


 
 
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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 
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 


 
 
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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. 
 
14.4.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the developmental therapy 
scientific committee; and a member from the NCI. The DSMC meets at least every 
6 months to review current study results, as well as data available to the DSMC 
from other related studies. Approximately 6 weeks before each meeting of the 
Phase 1 and 2 DSMC, study chairs will be responsible for working with the study 
statistician to prepare study reports for review by the DSMC. The DSMC will 
provide recommendations to the COG Developmental Therapeutics Chair and the 
Group Chair for each study reviewed to change the study or to continue the study 
unchanged. Data and Safety Committee reports for institutional review boards can 
be prepared using the public data monitoring report as posted on the COG Web 
site. 
 
14.4.2 Monitoring by the Study Chair and MATCH 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 
MATCH Chair, Vice Chair and Statistician on a weekly conference call. 


 
 
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REFERENCES 
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Zhao Y, Adjei AA: The clinical development of MEK inhibitors. Nat. Rev. Clin. Oncol 11:385-
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2. 
Marks JL, Gong Y, Chitale D, et al: Novel MEK1 mutation identified by mutational analysis of 
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68:5524-5528, 2008 
3. 
Murugan AK, Dong J, Xie J, et al: MEK1 mutations, but not ERK2 mutations, occur in melanomas 
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4. 
Pui CH, Carroll WL, Meshinchi S, et al: Biology, risk stratification, and therapy of pediatric acute 
leukemias: an update. J Clin Oncol 29:551-65, 2011 
5. 
Shukla N, Ameur N, Yilmaz I, et al: Oncogene mutation profiling of pediatric solid tumors reveals 
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6. 
Bentires-Alj M, Paez JG, David FS, et al: Activating mutations of the noonan syndrome-associated 
SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res 
64:8816-20, 2004 
7. 
Puissant A, Frumm SM, Alexe G, et al: Targeting MYCN in neuroblastoma by BET bromodomain 
inhibition. Cancer Discov 3:308-323, 2013 
8. 
Lu C, Zhang J, Nagahawatte P, et al: The genomic landscape of childhood and adolescent 
melanoma. J. Invest Dermatol 135:816-823, 2015 
9. 
Flaherty KT, Robert C, Hersey P, et al: Improved survival with MEK inhibition in BRAF-mutated 
melanoma. N. Engl. J. Med 367:107-114, 2012 
10. 
Long GV, Stroyakovskiy D, Gogas H, et al: Combined BRAF and MEK inhibition versus BRAF 
inhibition alone in melanoma. N. Engl. J. Med 371:1877-1888, 2014 
11. 
Ascierto PA, Schadendorf D, Berking C, et al: MEK162 for patients with advanced melanoma 
harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet 
Oncol 14:249-256, 2013 
12. 
Janne PA, Shaw AT, Pereira JR, et al: Selumetinib plus docetaxel for KRAS-mutant advanced non-
small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 
14:38-47, 2013 
13. 
Jessen WJ, Miller SJ, Jousma E, et al: MEK inhibition exhibits efficacy in human and mouse 
neurofibromatosis tumors. J. Clin. Invest 123:340-347, 2013 
14. 
Nissan MH, Pratilas CA, Jones AM, et al: Loss of NF1 in cutaneous melanoma is associated with 
RAS activation and MEK dependence. Cancer Res 74:2340-2350, 2014 
15. 
Spunt SL, Million L, Anderson JR, et al: Risk-based treatment for nonrhabdomyosarcoma soft 
tissue sarcomas (NRSTS) in patients under 30 years of age: Children's Oncology Group study 
ARST0332. J. Clin. Oncol 32, 2014 
16. 
Dombi E, Baldwin A, Marcus LJ, et al: Activity of Selumetinib in Neurofibromatosis Type 1-
Related Plexiform Neurofibromas. N Engl J Med 375:2550-2560, 2016 
17. 
Carvajal RD, Sosman JA, Quevedo JF, et al: Effect of selumetinib vs chemotherapy on progression-
free survival in uveal melanoma: a randomized clinical trial. JAMA 311:2397-2405, 2014 
18. 
Marampon F, Bossi G, Ciccarelli C, et al: MEK/ERK inhibitor U0126 affects in vitro and in vivo 
growth of embryonal rhabdomyosarcoma. Mol. Cancer Ther 8:543-551, 2009 
19. 
Guenther MK, Graab U, Fulda S: Synthetic lethal interaction between PI3K/Akt/mTOR and 
Ras/MEK/ERK pathway inhibition in rhabdomyosarcoma. Cancer Lett 337:200-209, 2013 
20. 
Renshaw J, Taylor KR, Bishop R, et al: Dual blockade of the PI3K/AKT/mTOR (AZD8055) and 
RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in 
vitro and in vivo. Clin. Cancer Res 19:5940-5951, 2013 
21. 
Eleveld TF, Oldridge DA, Bernard V, et al: Relapsed neuroblastomas show frequent RAS-MAPK 
pathway mutations. Nat Genet 47:864-71, 2015 
22. 
See WL, Tan IL, Mukherjee J, et al: Sensitivity of glioblastomas to clinically available MEK 


 
 
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inhibitors is defined by neurofibromin 1 deficiency. Cancer Res 72:3350-3359, 2012 
23. 
Chakraborty R, Hampton OA, Shen X, et al: Mutually exclusive recurrent somatic mutations in 
MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 
124:3007-15, 2014 
24. 
Goetz EM, Ghandi M, Treacy DJ, et al: ERK mutations confer resistance to mitogen-activated 
protein kinase pathway inhibitors. Cancer Res 74:7079-7089, 2014 
25. 
Adjei AA, Cohen RB, Franklin W, et al: Phase I pharmacokinetic and pharmacodynamic study of 
the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-
142886) in patients with advanced cancers. J Clin Oncol 26:2139-46, 2008 
26. 
Banerji U, Camidge DR, Verheul HM, et al: The first-in-human study of the hydrogen sulfate (Hyd-
sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label 
multicenter trial in patients with advanced cancer. Clin Cancer Res 16:1613-23, 2010 
27. 
Boers-Sonderen MJ, Desar IM, Blokx W, et al: A prolonged complete response in a patient with 
BRAF-mutated melanoma stage IV treated with the MEK1/2 inhibitor selumetinib (AZD6244). 
Anticancer Drugs 23:761-4, 2012 
28. 
Leijen S, Middleton MR, Tresca P, et al: Phase I dose-escalation study of the safety, 
pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in 
patients with advanced solid tumors. Clin Cancer Res 18:4794-805, 2012 
29. 
Kirkwood JM, Bastholt L, Robert C, et al: Phase II, open-label, randomized trial of the MEK1/2 
inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. 
Clin Cancer Res 18:555-67, 2012 
30. 
Bennouna J, Lang I, Valladares-Ayerbes M, et al: A Phase II, open-label, randomised study to 
assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus 
capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior 
chemotherapeutic regimens. Invest New Drugs 29:1021-8, 2011 
31. 
Bodoky G, Timcheva C, Spigel DR, et al: A phase II open-label randomized study to assess the 
efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients 
with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. 
Invest New Drugs 30:1216-23, 2012 
32. 
Hainsworth JD, Cebotaru CL, Kanarev V, et al: A phase II, open-label, randomized study to assess 
the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small 
cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol 
5:1630-6, 2010 
33. 
O'Neil BH, Goff LW, Kauh JS, et al: Phase II study of the mitogen-activated protein kinase 1/2 
inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 29:2350-6, 
2011 
34. 
Bekaii-Saab T, Phelps MA, Li X, et al: Multi-institutional phase II study of selumetinib in patients 
with metastatic biliary cancers. J Clin Oncol 29:2357-63, 2011 
35. 
Prado CM, Bekaii-Saab T, Doyle LA, et al: Skeletal muscle anabolism is a side effect of therapy 
with the MEK inhibitor: selumetinib in patients with cholangiocarcinoma. Br J Cancer 106:1583-
6, 2012 
36. 
Hayes DN, Lucas AS, Tanvetyanon T, et al: Phase II efficacy and pharmacogenomic study of 
Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with 
or without follicular elements. Clin Cancer Res 18:2056-65, 2012 
37. 
Jain N, Curran E, Iyengar NM, et al: Phase II study of the oral MEK inhibitor selumetinib in 
advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin 
Cancer Res 20:490-8, 2014 
38. 
Farley J, Brady WE, Vathipadiekal V, et al: Selumetinib in women with recurrent low-grade serous 
carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol 
14:134-40, 2013 
39. 
Holkova B, Zingone A, Kmieciak M, et al: A Phase II Trial of AZD6244 (Selumetinib, ARRY-


 
 
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142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma. Clin Cancer Res 
22:1067-75, 2016 
40. 
Coleman RL, Sill MW, Thaker PH, et al: A phase II evaluation of selumetinib (AZD6244, ARRY-
142886), a selective MEK-1/2 inhibitor in the treatment of recurrent or persistent endometrial 
cancer: an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 138:30-5, 2015 
41. 
Carvajal RD, Sosman JA, Quevedo JF, et al: Effect of selumetinib vs chemotherapy on progression-
free survival in uveal melanoma: a randomized clinical trial. JAMA 311:2397-405, 2014 
42. 
Catalanotti F, Solit DB, Pulitzer MP, et al: Phase II trial of MEK inhibitor selumetinib (AZD6244, 
ARRY-142886) in patients with BRAFV600E/K-mutated melanoma. Clin Cancer Res 19:2257-
64, 2013 
43. 
Lopez-Chavez A, Thomas A, Rajan A, et al: Molecular profiling and targeted therapy for advanced 
thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J Clin 
Oncol 33:1000-7, 2015 
44. 
Banerjee Aea: A phase 1 study of AZD6244 in children with recurrent or refractory low-grade 
gliomas: A Pediatric Brain Tumor Consortium report. . J Clin Oncol 32, 5s, (suppl; abstr 10065), 
2014 
45. 
Widemann BCea: Phase I study of the MEK1/2 inhibitor selumetinib (AZD6244) hydrogen sulfate 
in children and young adults with neurofibromatosis type 1 (NF1) and inoperable plexiform 
neurofibromas (PNs). J Clin Oncol 32, 5s (suppl; abstr 10018) 2014 
46. 
Gross AMea: Phase II Study of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in 
children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN). J Clin 
Oncol 34, (suppl; abstr TPS10586), 2016 
47. 
A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 20:859-66, 2001 
48. 
Agresti A, Coull BA: Approximate Is Better than "Exact" for Interval Estimation of Binomial 
Proportions. The American Statistician 52:119-126, 1998 
49. 
Sandlund JT, Guillerman RP, Perkins SL, et al: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. J Clin Oncol 33:2106-11, 2015 
50. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 32:3059-68, 2014 
 
 


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


 
 
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ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
nefazodone 
nilotinib 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
quetiapine5 
quinidine4  
regorafenib 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
telaprevir 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 7.5 regarding use of corticosteroids. 
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥ 5-fold with strong inhibitors) 


 
 
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APPENDIX III-A:  PATIENT DIARY FOR SELUMETINIB 
 
COG Patient ID:___________   Acc#_________________ 
 
 
 
 
  
 
Institution :________________________________  
Please do not write patient names on this form. 
 
Complete each day with the time and dose given for selumetinib (AZD6244 hydrogen sulfate). 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.  Selumetinib (AZD6244 hydrogen sulfate) capsules should not be opened or crushed but should be swallowed whole. 
If capsule is broken and the powder of the capsules gets on skin, wash the exposed area with as much water as necessary.  
Inform your study doctor or nurse if that occurs. Selumetinib (AZD6244 hydrogen sulfate) should be taken on an empty 
stomach at least 2 hours after food, do not eat or drink (except water) for at least one hour after taking selumetinib. If vomiting 
occurs within 30 minutes after the dose of selumetinib (AZD6244 hydrogen sulfate) is administered, that dose may be repeated 
once. Otherwise, the dose will be missed. Add the dates to the calendar below and return the completed diary to the study clinic 
at each visit.   
 
EXAMPLE 
 
 
Number of  selumetinib 
(AZD6244 hydrogen sulfate) 
capsules 
Comments 
 
 
Date 
Time 
10 mg 
25 mg 
 
Day 1 
1/15/14 
8:30 AM 
2 
1 
He felt nauseated an hour after taking 
the drug but did not vomit. 
 
 
Cycle #: _____    Start Date: |__/__|__/__|__/__|     
                              End Date: |__/__|__/__|__/__|              Dose Level:            mg/m2/dose           
WEEK 1 
Date 
Time 
# of Selumetinib (AZD6244 hydrogen 
sulfate) capsules prescribed to take 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
10 mg 
25 mg 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
 
# of Selumetinib (AZD6244 hydrogen 
sulfate) capsules taken  
10 mg 
25 mg 
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 
# of Selumetinib (AZD6244 hydrogen 
sulfate) capsules prescribed to take 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
10 mg 
25 mg 
AM#___ 
PM#___ 
AM#___ 
PM#___ 


 
 
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# of Selumetinib (AZD6244 hydrogen 
sulfate) capsules taken  
10 mg 
25 mg 
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 
# of Selumetinib (AZD6244 hydrogen 
sulfate) capsules prescribed to take 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
 10 mg 
25 mg 
AM#___ 
PM#___ 
AM#___ 
PM#___ 
 
# of Selumetinib (AZD6244 hydrogen 
sulfate) capsules taken  
10 mg 
25 mg 
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 
 
 
 
WEEK 4 
Date 
Time 
# of Selumetinib (AZD6244 hydrogen 
sulfate) capsules prescribed to take 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
10 mg 
25 mg 
AM#___ 
PM#___ 
AM#___ 
PM#___ 


 
 
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# of Selumetinib (AZD6244 hydrogen 
sulfate) capsules taken  
10 mg 
25  mg 
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 
 
 
 
 
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 III-B:  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  
 
The patient ____________________________ is enrolled on a clinical trial using the experimental study 
drug, selumetinib (AZD6244 hydrogen sulfate).  This clinical trial is sponsored by the National Cancer 
Institute (NCI).  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: 
  
Selumetinib (AZD6244 hydrogen sulfate) interacts with certain specific enzymes in the liver and certain 
transport 
proteins 
that 
help 
move 
drugs 
in 
and 
out 
of 
cells. 
 
• The enzymes in question are CYP 1A2, 2C8, 2C9, 2C19, 3A4/5 and UGT 1A1 and 1A3. 
Selumetinib (AZD6244 hydrogen sulfate) is metabolized by these enzymes and may be affected 
by other drugs that inhibit or induce these enzymes.  
• The proteins in question are P-gp and BCRP. Selumetinib (AZD6244 hydrogen sulfate) is a 
substrate of BCRP and P-gp transporters and may be affected by other drugs that inhibit or induce 
these transporters.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
     March 2016 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Selumetinib (AZD6244 hydrogen sulfate) interacts with many drugs which can cause side effects. Because 
of this, it is very important to tell your study doctors about all of your medicines before you enroll on this 
clinical trial.  It is also very important to tell them 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 medications with your 
doctors, include medicine you buy without a prescription (over-the-counter remedy), or any 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 prescribers can write prescriptions.  You must also tell your health care providers (doctors, 
physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know: 
 
Selumetinib (AZD6244 hydrogen sulfate) must be used very carefully with other medicines that need 
certain liver enzymes and transport proteins to be effective or to be cleared from your system.  Before you 
enroll onto the clinical trial, your study doctor will work with your regular health care providers to review 
any medicines and herbal supplements that are considered “strong inducers/inhibitors of CYP 1A2, 2C8, 
2C9, 2C19, 3A/5, UGT 1A1 and 1A3, P-gp and BCRP.” 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctor or pharmacist to 
determine if there could be any side effects.  
• Avoid taking extra vitamin E found in vitamins or supplements.  
• Your regular health care provider should check a frequently updated medical reference or call your 


 
 
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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  
 
             _____________________________________.  
 
  
                   March 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental drug 
selumetinib (AZD6244 hydrogen sulfate).  This clinical trial is 
sponsored by the NCI.  AZD6244 hydrogen sulfate (selumetinib) 
interacts with drugs that are processed by your liver, or use certain 
transport proteins in your body.  Because of this, it is very important to: 
➢ Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistant, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 
 
 
 
➢ Selumetinib (AZD6244 hydrogen sulfate) interacts with CYP 1A2, 
2C8, 2C9, 2C19, 3A4/5, UGT 1A1 and 1A3, P-gp, and BCRP, and 
must be used very carefully with other medicines that interact with 
these enzymes and proteins.  
➢ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines that are considered “strong inducers/inhibitors of CYP 
1A2, 2C8, 2C9, 2C19, 3A4/5, UGT 1A1 and 1A3, P-gp and BCRP.” 
➢ You should avoid taking extra vitamin E found in vitamins or 
supplements. 
➢ Before prescribing new medicines, your regular health care 
providers 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 _________________________________.  


 
 
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APPENDIX IV:  SELUMETINIB (AZD6244 HYDROGEN SULFATE) DOSING NOMOGRAM 
 
Drug doses should be adjusted based on the BSA calculated from height and weight measured within 7 
days prior to the beginning of each cycle.   
 
Patients must have a body surface area of ≥ 0.5 m2 at enrollment.  
 
Selumetinib (AZD6244 hydrogen sulfate) Dose Assignment: 25 mg/m2/dose BID 
 
BSA (m2) 
Selumetinib 
(AZD6244 
hydrogen 
sulfate)  
AM Dose (mg)  
Selumetinib 
(AZD6244 
hydrogen 
sulfate)  
PM Dose (mg) 
Selumetinib (AZD6244 
hydrogen sulfate)  
Dose Reduction for 
Toxicity 
AM Dose (mg)  
Selumetinib (AZD6244 
hydrogen sulfate)  
Dose Reduction for 
Toxicity 
PM Dose (mg) 
0.5-0.67 
10 
20 
10 
10 
0.68-0.89 
20 
20 
10 
20 
0.9-1.09 
25 
25 
10 
25 
1.1-1.29 
30 
30 
20 
20 
1.3-1.49 
35 
35 
25 
25 
1.5-1.69 
40 
40 
30 
30 
1.7-1.89 
45 
45 
30 
30 
1.9-2.1 
50 
50 
35 
35 
2.11-2.3 
55 
55 
40 
40 
  
 


  
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Page 1 of 3 
Version Date: 08/19/2019 
 
Page 80 
Cycle 1  
APPENDIX V: APEC1621E THERAPY DELIVERY MAP 
 
Therapy Delivery Map – Cycle 1 
This Therapy Delivery Map (TDM) relates to Cycle 1. Each cycle lasts 28 days.  
____________________________ 
Patient COG ID number 
_______________________ 
Accession number 
 
Criteria to start each cycle are listed in Section 5.2. Extensive treatment details are in Section 5.1. 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS IMPORTANT NOTES 
Selumetinib 
  
PO 
25 mg/m2/dose BID 
(maximum 75 mg per 
dose) 
 
Refer to dosing 
nomogram in Appendix 
IV. 
1-28 
Patients should swallow the capsules as a whole and 
should not chew or crush them. Selumetinib (AZD6244 
hydrogen sulfate) should be taken on an empty stomach 
at least 2 hours after food and not eat or drink (except 
water) for at least one hour after taking selumetinib. If a 
patient vomits within 30 minutes after the dose of 
selumetinib (AZD6244 hydrogen sulfate), is 
administered, that dose may be repeated once. Otherwise, 
the dose will be missed. 
 
 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
Selumetinib 
_________ mg 
Studies 
 
 
 
Enter calculated dose above as per dosing 
nomogram and actual dose administered below 
 
 
 
1 
_________mg AM     ________mg PM 
 
 
 
2 
_________mg AM     ________mg PM 
 
 
 
3 
_________mg AM     ________mg PM 
 
 
 
4 
_________mg AM     ________mg PM 
f 
 
 
5 
_________mg AM     ________mg PM 
 
 
 
6 
_________mg AM     ________mg PM 
 
 
 
7 
_________mg AM     ________mg PM 
 
 
 
8 
_________mg AM     ________mg PM 
a, f, h, i, m, p 
 
 
9 
_________mg AM     ________mg PM 
 
 
 
10 
_________mg AM     ________mg PM 
 
 
 
11 
_________mg AM     ________mg PM 
f 
 
 
12 
_________mg AM     ________mg PM 
 
 
 
13 
_________mg AM     ________mg PM 
 
 
 
14 
_________mg AM     ________mg PM 
 
 
 
15 
_________mg AM     ________mg PM 
a, f, h, i, m, p, s 
 
 
16 
_________mg AM     ________mg PM 
 
 
 
17 
_________mg AM     ________mg PM 
 
 
 
18 
_________mg AM     ________mg PM 
f 
 
 
19 
_________mg AM     ________mg PM 
 
 
 
20 
_________mg AM     ________mg PM 
 
 
 
21 
_________mg AM     ________mg PM 
 
 
 
22 
_________mg AM     ________mg PM 
a, f, h, i, m, p 
 
 
23 
_________mg AM     ________mg PM 
 
 
 
24 
_________mg AM     ________mg PM 
 
 
 
25 
_________mg AM     ________mg PM 
f 
 
 
26 
_________mg AM     ________mg PM 
 
 
 
27 
_________mg AM     ________mg PM 
 
 
 
28/1 
_________mg AM     ________mg PM 
a, c, f,  h, i, j,  m, o, p, s 
See Section 6.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 


  
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Page 2 of 3 
Version Date: 08/19/2019 
 
Page 81 
Cycle 1  
 
For information related to prestudy observations please refer to Section 8.1
 
 
 
 
Required Observations in Cycle 1  
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. History/Physical Exam (including VS) 
b. Neurological Exam 
c. 
Ht/Wt/BSA 
d. Performance Status 
e. 
Pregnancy Test. Women of childbearing potential require a negative pregnancy test 
prior to starting treatment; sexually active patients must use an acceptable method of 
birth control.  Abstinence is an acceptable method of birth control. 
f. 
CBC/differential/platelets- If patients have Grade 4 neutropenia then CBCs should 
be checked at least every other day until recovery to Grade 3 or until meeting the 
criteria for dose limiting toxicity.  
g. 
Urinalysis 
h. Electrolytes including Ca++, PO4, Mg++ 
i. 
Creatinine, ALT, bilirubin 
j. 
Albumin 
k. Tumor Disease Evaluation  
l. 
Bone Marrow Aspirate and/or biopsy- Only required in patients suspected of having 
bone marrow metastasis on the basis of history, symptoms, laboratory evaluation or 
other clinical data. Should only be performed on patients with known bone marrow 
involvement at baseline. Bone marrow aspirate and/or biopsy should be performed 
only when complete response or partial response is identified in target disease or 
when progression in bone marrow is suspected. 
m. Patient Diary- (see Appendix III) should be reviewed weekly during cycle 1, after 
completion of each treatment cycle; and uploaded into RAVE. The patient diary 
should be collected weekly.  
n. ECHO or gated radionuclide study 
o.    Creatine Kinase (CPK) 
p.    Blood Pressure. Blood pressure will be measured with an appropriate sized cuff at 
rest. Blood pressure measurement will be repeated within the same day if the blood 
pressure (BP) is elevated (> the 95th percentile for age, height, and gender). Please 
note that 3 serial blood pressures should be obtained and averaged to determine 
baseline BP (See Section 6.7). If both BP measurements are >95th percentile for age, 
height, and gender, follow the guidelines in Section 6.7. Patients with elevated BP at 
any time should have BP measurements performed at least twice weekly until BP is 
within the 95th percentile for age, height, and gender (See Appendix IX). 
q.    Ophthalmologic exam. 
r.     Plain radiograph tibial growth plate.  Plain radiographs of at least one tibial growth 
plate should be obtained in all patients prior to first dose of protocol therapy. In 
patients with open growth plates, follow-up plain radiographs of the same growth 
plate(s) should be obtained according to Section 8.2.1. 
s.    Total Cholesterol, Triglycerides-If Grade 3 or 4 hypercholesterolemia or Grade 3 or 
4 hypertriglyceridemia is detected when routine (non-fasting) laboratory studies are 
performed, the tests should be repeated within 3 days in the fasting state to permit 
accurate grading 


  
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Page 3 of 3 
Version Date: 08/19/2019 
 
Page 82 
Cycle 1  
 
 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
Comments 
(Include any held doses, or dose modifications) 
 
Treatment Details: Cycle 1 
 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are 
met (whichever occurs later).  
 


  
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                                                                                                                                                      Page 1 of 3 
Version Date: 08/19/2019 
 
Page 83 
Subsequent Cycles 
All Subsequent Cycles 
 
Therapy Delivery Map – All Subsequent Cycles 
This Therapy Delivery Map (TDM) relates to all subsequent cycles. Each cycle lasts 28 
days. Treatment may continue in the absence of disease progression or unacceptable 
toxicity. Use a copy of this page once for each cycle (please note cycle number below).  
____________________________ 
Patient COG ID number 
_______________________ 
Accession number  
Criteria to start each cycle are listed in Section 5.2. Extensive treatment details are in Section 5.1. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Selumetinib 
  
PO 
25 mg/m2/dose BID 
(maximum 75 mg per 
dose) 
 
Refer to dosing 
nomogram in Appendix 
IV. 
1-28 
Patients should swallow the capsules as a whole and 
should not chew or crush them. Selumetinib (AZD6244 
hydrogen sulfate) should be taken on an empty stomach 
at least 2 hours after food and not eat or drink (except 
water) for at least one hour after taking selumetinib. If a 
patient vomits within 30 minutes after the dose of 
selumetinib 
(AZD6244 
hydrogen 
sulfate), 
is 
administered, that dose may be repeated once. 
Otherwise, the dose will be missed. 
 
 
Enter Cycle #: _____  
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
Selumetinib 
_________ mg 
Studies 
 
 
 
Enter calculated dose above as per dosing 
nomogram and actual dose administered below 
 
 
 
1 
_________mg AM     ________mg PM 
a,b,c,d,e,f, m, 
 
 
2 
_________mg AM     ________mg PM 
 
 
 
3 
_________mg AM     ________mg PM 
 
 
 
4 
_________mg AM     ________mg PM 
 
 
 
5 
_________mg AM     ________mg PM 
 
 
 
6 
_________mg AM     ________mg PM 
 
 
 
7 
_________mg AM     ________mg PM 
 
 
 
8 
_________mg AM     ________mg PM 
c 
 
 
9 
_________mg AM     ________mg PM 
 
 
 
10 
_________mg AM     ________mg PM 
 
 
 
11 
_________mg AM     ________mg PM 
 
 
 
12 
_________mg AM     ________mg PM 
 
 
 
13 
_________mg AM     ________mg PM 
 
 
 
14 
_________mg AM     ________mg PM 
 
 
 
15 
_________mg AM     ________mg PM 
c,  m, 
 
 
16 
_________mg AM     ________mg PM 
 
 
 
17 
_________mg AM     ________mg PM 
 
 
 
18 
_________mg AM     ________mg PM 
 
 
 
19 
_________mg AM     ________mg PM 
 
 
 
20 
_________mg AM     ________mg PM 
 
 
 
21 
_________mg AM     ________mg PM 
 
 
 
22 
_________mg AM     ________mg PM 
c,  
 
 
23 
_________mg AM     ________mg PM 
 
 
 
24 
_________mg AM     ________mg PM 
 
 
 
25 
_________mg AM     ________mg PM 
 
 
 
26 
_________mg AM     ________mg PM 
 
 
 
27 
_________mg AM     ________mg PM 
 
 
 
28/1 
_________mg AM     ________mg PM 
a, b, c,  d, e, f, g*, h*, i, j*, k* l, m*, n*, o* 
p 
See Section 6.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines 


  
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APEC1621E 
                                                                                                                                                      Page 2 of 3 
Version Date: 08/19/2019 
 
Page 84 
Subsequent Cycles 
* Please refer to section 8.1 for the specific timing of these observations
Required Observations in All Subsequent Cycles 
 
a. History/Physical Exam (including VS) 
b. Ht/Wt/BSA 
c. 
CBC/differential/platelets If patients develop Grade 3 or greater thrombocytopenia 
then CBCs should be checked every 3 to 4 days until recovery per Section 6.1 
d. Electrolytes including Ca++, PO4, Mg++ 
e. 
Creatinine, ALT, bilirubin 
f. 
Albumin 
g. 
Tumor Disease Evaluation – Every other cycle x 3 then q 3 cycles. Tumor Disease 
Evaluation should be obtained on the next consecutive cycle after initial 
documentation of either a PR or CR.  Subsequent scans may restart 2 cycles after the 
confirmatory scan. If the institutional investigator determines that the patient has 
progressed based on clinical or laboratory evidence, he/she may opt not to confirm 
this finding radiographically 
h. Bone Marrow Aspirate and/or biopsy- Only required in patients suspected of having 
bone marrow metastasis on the basis of history, symptoms, laboratory evaluation or 
other clinical data.  Should only be performed on patients with known bone marrow 
involvement at baseline. Bone marrow aspirate and/or biopsy should be performed 
only when complete response or partial response is identified in target disease or when 
progression in bone marrow is suspected. 
i. 
Patient Diary- (see Appendix III) should be reviewed after completion of each 
treatment cycle and uploaded into RAVE. The patient diary should be collected 
weekly.  
j. 
Circulating Tumor DNA (ctDNA-optional)- With consent two samples will be 
collected on this protocol (Cycle 5 Day 1; and for patients receiving ≥ 5 cycles,  at 
progression or end of protocol therapy) see Section 8.4 for details of the ctDNA 
studies.  
k. ECHO or gated radionuclide study. Every 3 months. 
l.     Creatine Kinase (CPK) 
m.   Blood Pressure. Blood pressure will be measured with an appropriate sized cuff at 
rest. Blood pressure measurement will be repeated within the same day if the blood 
pressure (BP) is elevated (> the 95th percentile for age, height, and gender). Please 
note that 3 serial blood pressures should be obtained and averaged to determine 
baseline BP (See Section 6.7). If both BP measurements are >95th percentile for age, 
height, and gender, follow the guidelines in Section 6.7. Patients with elevated BP at 
any time should have BP measurements performed at least twice weekly until BP is 
within the 95th percentile for age, height, and gender (See Appendix IX). 
n.     Ophthalmologic exam. Prior to every other cycle 
o.    Plain radiograph tibial growth plate.  Plain radiographs of at least one tibial growth 
plate should be obtained in all patients prior to first dose of protocol therapy. In 
patients with open growth plates, follow-up plain radiographs of the same growth 
plate(s) should be obtained according to Section 8.2.1. 
p.    Total Cholesterol, Triglycerides-If Grade 3 or 4 hypercholesterolemia or Grade 3 or 4 
hypertriglyceridemia is detected when routine (non-fasting) laboratory studies are 
performed, the tests should be repeated within 3 days in the fasting state to permit 
accurate grading  
 


  
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APEC1621E 
 
 
Page 3 of 3 
Version Date: 08/19/2019 
 
Page 85 
Subsequent Cycles 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
Treatment Details: Subsequent Cycles 
 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are 
met (whichever occurs later). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
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APEC1621E 
 
 
Version Date: 08/19/2019 
 
Page 86 
 
APPENDIX VI: TARGET HISTOLOGIES FOR APEC1621E EXPANSION COHORTS 
Target tumor types considered for biomarker-positive expansion cohorts in the event of agent activity 
in a specific tumor type. 
 
 
 
 
 
Tumor type 
1. Ependymoma 
2. Ewing Sarcoma/Peripheral PNET 
3. Hepatoblastoma 
4. Glioma, high grade 
5. Langerhans Cell Histiocytosis 
6. Malignant Germ Cell Tumor 
7. Medulloblastoma  
8. Neuroblastoma 
9. Non-Hodgkin Lymphoma 
10. Non-RMS Soft Tissue Sarcoma 
11. Osteosarcoma 
12. Rhabdoid Malignancy 
13. Rhabdomyosarcoma 
14. Wilms Tumor 
15. Other Histology (based on COG/NCI-CTEP approval) 


  
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Version Date: 08/19/2019 
 
Page 87 
APPENDIX VII: APEC1621E ACTIONABLE MUTATIONS OF INTEREST 
 
 
NON-
HOTSPOT 
RULES 
  
  
Gene Name 
Description 
Variant Type 
LOE 
NF1  
Include 
Deleterious 
3 
INCLUSION 
VARIANTS 
  
  
  
Hotspots 
  
Gene Name 
Variant ID 
Variant Type 
aMOI 
LOE 
NRAS 
COSM586 
SNV 
p.Q61H 
2 
NRAS 
COSM585 
SNV 
p.Q61H 
2 
NRAS 
COSM583 
SNV 
p.Q61L 
2 
NRAS 
COSM582 
SNV 
p.Q61P 
2 
NRAS 
COSM584 
SNV 
p.Q61R 
2 
NRAS 
COSM30646 
MNV 
p.Q61L 
2 
NRAS 
COSM33693 
MNV 
p.Q61R 
2 
NRAS 
COSM580 
SNV 
p.Q61K 
2 
NRAS 
COSM581 
SNV 
p.Q61E 
2 
NRAS 
COSM53223 
MNV 
p.Q61K 
2 
NRAS 
COSM12725 
MNV 
p.Q61L 
2 
NRAS 
COSM579 
MNV 
p.Q61R 
2 
NRAS 
COSM12730 
MNV 
p.Q61K 
2 
NRAS 
COSM574 
SNV 
p.G13V 
2 
NRAS 
COSM573 
SNV 
p.G13D 
2 
NRAS 
COSM575 
SNV 
p.G13A 
2 
NRAS 
COSM572 
MNV 
p.G13V 
2 
NRAS 
COSM569 
SNV 
p.G13R 
2 
NRAS 
COSM570 
SNV 
p.G13C 
2 
NRAS 
COSM571 
SNV 
p.G13S 
2 
NRAS 
COSM564 
SNV 
p.G12D 
2 
NRAS 
COSM565 
SNV 
p.G12A 
2 
NRAS 
COSM566 
SNV 
p.G12V 
2 
NRAS 
COSM561 
SNV 
p.G12R 
2 
NRAS 
COSM563 
SNV 
p.G12S 
2 
NRAS 
COSM562 
SNV 
p.G12C 
2 
HRAS 
COSM503 
SNV 
p.Q61H 
2 
HRAS 
COSM502 
SNV 
p.Q61H 
2 
HRAS 
COSM499 
SNV 
p.Q61R 
2 
HRAS 
COSM500 
SNV 
p.Q61P 
2 
HRAS 
COSM498 
SNV 
p.Q61L 
2 
HRAS 
COSM33695 
MNV 
p.Q61R 
2 


  
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Version Date: 08/19/2019 
 
Page 88 
HRAS 
COSM501 
MNV 
p.Q61R 
2 
HRAS 
COSM497 
SNV 
p.Q61E 
2 
HRAS 
COSM496 
SNV 
p.Q61K 
2 
HRAS 
COSM52978 
MNV 
p.Q61L 
2 
HRAS 
COSM490 
SNV 
p.G13D 
2 
HRAS 
COSM489 
SNV 
p.G13V 
2 
HRAS 
COSM488 
SNV 
p.G13C 
2 
HRAS 
COSM487 
SNV 
p.G13S 
2 
HRAS 
COSM486 
SNV 
p.G13R 
2 
HRAS 
COSM483 
SNV 
p.G12V 
2 
HRAS 
COSM484 
SNV 
p.G12D 
2 
HRAS 
COSM485 
SNV 
p.G12A 
2 
HRAS 
COSM482 
SNV 
p.G12R 
2 
HRAS 
COSM481 
SNV 
p.G12C 
2 
HRAS 
COSM480 
SNV 
p.G12S 
2 
KRAS 
COSM19900 
SNV 
p.A146V 
2 
KRAS 
COSM19404 
SNV 
p. A146T 
2 
KRAS 
COSM19940 
SNV 
p.K117N 
2 
KRAS 
COSM28519 
SNV 
p.K117N 
2 
KRAS 
COSM554 
SNV 
p.Q61H 
2 
KRAS 
COSM555 
SNV 
p.Q61H 
2 
KRAS 
COSM553 
SNV 
p.Q61L 
2 
KRAS 
COSM552 
SNV 
p.Q61R 
2 
KRAS 
COSM551 
SNV 
p.Q61P 
2 
KRAS 
COSM1168052 
MNV 
p.Q61R 
2 
KRAS 
COSM550 
SNV 
p.Q61E 
2 
KRAS 
COSM549 
SNV 
p.Q61K 
2 
KRAS 
COSM87298 
MNV 
p.Q61K 
2 
KRAS 
COSM539 
SNV 
p.G15D 
2 
KRAS 
COSM538 
SNV 
p.G15S 
2 
KRAS 
COSM87280 
SNV 
p.G13E 
2 
KRAS 
COSM30567 
SNV 
p.G13E 
2 
KRAS 
COSM533 
SNV 
p.G13A 
2 
KRAS 
COSM534 
SNV 
p.G13V 
2 
KRAS 
COSM532 
SNV 
p.G13D 
2 
KRAS 
COSM531 
MNV 
p.G13D 
2 
KRAS 
COSM530 
MNV 
p.G13V 
2 
KRAS 
COSM12721 
MNV 
p.G13V 
2 
KRAS 
COSM528 
SNV 
p.G13S 
2 
KRAS 
COSM527 
SNV 
p.G13C 
2 
KRAS 
COSM529 
SNV 
p.G13R 
2 
KRAS 
COSM13643 
SNV 
p.G12N 
2 
KRAS 
COSM512 
SNV 
p.G12F 
2 


  
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Page 89 
KRAS 
COSM514 
SNV 
p.G12L 
2 
KRAS 
COSM87281 
MNV 
p.G13C 
2 
KRAS 
COSM520 
SNV 
p.G12V 
2 
KRAS 
COSM521 
SNV 
p.G12D 
2 
KRAS 
COSM522 
SNV 
p.G12A 
2 
KRAS 
COSM14209 
MNV 
p.G12D 
2 
KRAS 
COSM515 
MNV 
p.G12V 
2 
KRAS 
COSM518 
SNV 
p.G12R 
2 
KRAS 
COSM517 
SNV 
p.G12S 
2 
KRAS 
COSM516 
SNV 
p.G12C 
3 
KRAS 
COSM513 
MNV 
p.G12C 
2 
KRAS 
PM_COSM5413585 
MNV 
p.G12A 
2 
KRAS 
PM_COSM1716372 
MNV 
p.G12L 
2 
KRAS 
PM_COSM249888 
MNV 
p.G12R 
2 
KRAS 
PM_COSM4387522 
MNV 
p.G12V 
2 
KRAS 
PM_COSM4745557 
MNV 
p.G13R 
2 
ARAF 
COSM5044705 
SNV 
p.S214C 
3 
ARAF 
COSM1742787 
SNV 
p.S214A 
3 
ARAF 
COSM612884 
SNV 
p.S214F 
3 
BRAF 
COSM308550 
MNV 
p.V600D 
2.1 
BRAF 
COSM477 
MNV 
p.V600D 
2.1 
BRAF 
COSM475 
MNV 
p.V600E 
1.1 
BRAF 
COSM1127 
MNV 
p.V600R 
2.1 
BRAF 
COSM1583011 
MNV 
p.V600R 
2.1 
BRAF 
COSM473 
MNV 
p.V600K 
1.1 
BRAF 
COSM474 
MNV 
p.V600R 
2.1 
BRAF 
COSM6137 
SNV 
p.V600G 
2.1 
BRAF 
COSM18443 
SNV 
p.V600A 
2.1 
BRAF 
COSM249889 
MNV 
p.V600Q 
2.1 
BRAF 
COSM476 
SNV 
p.V600E 
1.1 
BRAF 
COSM1130 
SNV 
p.V600M 
2.1 
BRAF 
COSM219798 
SNV 
p.V600L 
2.1 
BRAF 
COSM33808 
SNV 
p.V600L 
2.1 
BRAF 
COSM1132 
SNV 
p.K601N 
3 
BRAF 
COSM6265 
SNV 
p.K601N 
3 
BRAF 
COSM1133 
DEL 
p.V600_K601>E 
3 
BRAF 
PM_COSM30730 
INS 
p.T599_V600insT 
3 
BRAF 
PM_COSM26625 
INS 
p.A598_T599insV 
3 
BRAF 
COSM457 
SNV 
p.G469R 
3 
BRAF 
COSM455 
SNV 
p.G469R 
3 
BRAF 
COSM1112 
SNV 
p.G466R 
3 
BRAF 
COSM478 
SNV 
p.K601E 
3 
BRAF 
COSM472 
SNV 
p.T599I 
3 


  
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Page 90 
BRAF 
COSM21549  
SNV 
p.A598V 
3 
BRAF 
COSM1126 
MNV 
p.L597S 
3 
BRAF 
COSM1125 
SNV 
p.L597Q 
3 
BRAF 
COSM471 
SNV 
p.L597R 
3 
BRAF 
COSM470  
SNV 
p.L597V 
3 
BRAF 
COSM469  
SNV 
p.G596R 
3 
BRAF 
COSM53198 
SNV 
p.F595L 
3 
BRAF 
COSM468 
SNV 
p.F595L 
3 
BRAF 
COSM21612 
SNV 
p.F595L 
3 
BRAF 
COSM466 
SNV 
p.D594V 
3 
BRAF 
COSM467 
SNV 
p.D594G 
3 
BRAF 
COSM211600 
MNV 
p.D594N 
3 
BRAF 
COSM1583010 
SNV 
p.D594A 
3 
BRAF 
COSM27639 
SNV 
p.D594N 
3 
BRAF 
COSM463 
SNV 
p.E586K 
3 
BRAF 
COSM462 
SNV 
p.N581S 
3 
BRAF 
COSM1133046  
SNV 
p.Y472C 
3 
BRAF 
COSM459 
SNV 
p.G469V 
3 
BRAF 
COSM460 
SNV 
p.G469A 
3 
BRAF 
COSM461 
SNV 
p.G469E 
3 
BRAF 
COSM451 
SNV 
p.G466V 
3 
BRAF 
 COSM453 
SNV 
p.G466E 
3 
BRAF 
COSM452 
SNV 
p.G466A 
3 
BRAF 
COSM253328  
SNV 
p.G466R 
3 
BRAF 
COSM449 
SNV 
p.G464E 
3 
BRAF 
COSM450 
SNV 
p.G464V 
3 
BRAF 
COSM1448615 
SNV 
p.G464R 
3 
BRAF 
COSM1111  
SNV 
p.G464R 
3 
BRAF 
COSM448 
SNV 
p.I463S 
3 
BRAF 
COSM447  
SNV 
p.R462I 
3 
MAP2K1 
PM_E1 
MNV 
p.F53_Q58delFLTQKQaddL 
3 
MAP2K1 
PM_E2 
DEL 
p.Q56_V60delQKQKV 
2 
MAP2K1 
COSM1235481 
SNV 
p.Q56P 
2 
MAP2K1 
COSM4756761 
SNV 
p.K57T 
3 
MAP2K1 
COSM1235478 
SNV 
p.K57N 
2 
MAP2K1 
COSM5520914 
SNV 
p.K57N 
2 
MAP2K1 
PM_COSM4166150 
DEL 
p.K57_G61del 
3 
MAP2K1 
PM_COSM5031101 
DEL 
p.Q58_E62delQKVGE 
3 
MAP2K1 
PM_COSM5031100 
DEL 
p.Q58_E62delQKVGE 
3 
MAP2K1 
PM_COSM1235479 
SNV 
p.D67N 
3 
MAP2K1 
COSM1678546 
SNV 
p.D67N 
3 
MAP2K1 
PM_COSM404998 
DEL 
p.E102_I103delEI 
3 
MAP2K1 
PM_COSM4166152 
DEL 
p.E102_I103del 
3 


  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
APEC1621E 
 
 
Version Date: 08/19/2019 
 
Page 91 
MAP2K1 
PM_COSM4166153 
DEL 
p.E102_I103del 
3 
MAP2K1 
PM_COSM5730253 
DEL 
p.I103_K104delIK 
3 
MAP2K1 
PM_COSM5702512 
DEL 
p.I103_K104del 
3 
MAP2K1 
PM_E3 
SNV 
p.E120Q 
3 
MAP2K1 
PM_COSM555601 
SNV 
p.C121S 
3 
MAP2K1 
COSM1315829 
SNV 
p.C121S 
3 
MAP2K1 
PM_E4 
SNV 
p.S123T 
3 
MAP2K1 
COSM1374186 
SNV 
p.G128D 
3 
MAP2K1 
COSM232755 
SNV 
p.E203K 
3 
GNA11 
COSM52969 
SNV 
p.Q209L 
2 
GNA11 
COSM52970 
SNV 
p.Q209P 
2 
GNAQ 
COSM28757 
SNV 
p.Q209L 
2 
GNAQ 
COSM28758 
SNV 
p.Q209P 
2 
GNAQ 
COSM28760 
SNV 
p.Q209R 
2 
GNAQ 
COSM52975 
SNV 
p.R183Q 
3 
  
 
 
 
  
FUSIONS: 
  
  
  
  
BRAF 
AGAP3-BRAF.A10B11 
Fusion 
AGAP3-BRAF.A10B11 
2 
BRAF 
AGAP3-BRAF.A9B9 
Fusion 
AGAP3-BRAF.A9B9 
2 
BRAF 
AGK-BRAF.A2B8 
Fusion 
AGK-BRAF.A2B8 
2 
BRAF 
AGTRAP-BRAF.A5B8.COSF828.1 
Fusion 
AGTRAP-BRAF.A5B8.COSF828.1 
2 
BRAF 
AKAP9-BRAF.A21B10 
Fusion 
AKAP9-BRAF.A21B10 
2 
BRAF 
AKAP9-BRAF.A22B9 
Fusion 
AKAP9-BRAF.A22B9 
2 
BRAF 
AKAP9-BRAF.A28B9 
Fusion 
AKAP9-BRAF.A28B9 
2 
BRAF 
AKAP9-BRAF.A7B11 
Fusion 
AKAP9-BRAF.A7B11 
2 
BRAF 
AKAP9-BRAF.A8B9.COSF1013.1 
Fusion 
AKAP9-BRAF.A8B9.COSF1013.1 
2 
BRAF 
AP3B1-BRAF.A22B9 
Fusion 
AP3B1-BRAF.A22B9 
2 
BRAF 
ARMC10-BRAF.A4B11 
Fusion 
ARMC10-BRAF.A4B11 
2 
BRAF 
ATG7-BRAF.A18B9 
Fusion 
ATG7-BRAF.A18B9 
2 
BRAF 
BAIAP2L1-BRAF.B12B9 
Fusion 
BAIAP2L1-BRAF.B12B9 
2 
BRAF 
BBS9-BRAF.B19B4 
Fusion 
BBS9-BRAF.B19B4 
2 
BRAF 
BCL2L11-BRAF.B3B10 
Fusion 
BCL2L11-BRAF.B3B10 
2 
BRAF 
BRAF-AP3B1.B8A23 
Fusion 
BRAF-AP3B1.B8A23 
2 
BRAF 
BRAF-BRAF.B1B11 
Fusion 
BRAF-BRAF.B1B11 
2 
BRAF 
BRAF-BRAF.B1B9 
Fusion 
BRAF-BRAF.B1B9 
2 
BRAF 
BRAF-BRAF.B3B11 
Fusion 
BRAF-BRAF.B3B11 
2 
BRAF 
BRAF-BRAF.B3B9 
Fusion 
BRAF-BRAF.B3B9 
2 
BRAF 
BRAF-CIITA.B9C6 
Fusion 
BRAF-CIITA.B9C6 
2 
BRAF 
BRAF-MACF1.B8M15 
Fusion 
BRAF-MACF1.B8M15 
2 
BRAF 
BRAF-MRPS33.B1M2 
Fusion 
BRAF-MRPS33.B1M2 
2 
BRAF 
BRAF-SLC26A4.B3S7 
Fusion 
BRAF-SLC26A4.B3S7 
2 
BRAF 
BRAF-SUGCT.B1S13 
Fusion 
BRAF-SUGCT.B1S13 
2 
BRAF 
BTF3L4-BRAF.B3B11 
Fusion 
BTF3L4-BRAF.B3B11 
2 


  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
APEC1621E 
 
 
Version Date: 08/19/2019 
 
Page 92 
BRAF 
C7orf73-BRAF.C2B9 
Fusion 
C7orf73-BRAF.C2B9 
2 
BRAF 
CCDC6-BRAF.C1B9 
Fusion 
CCDC6-BRAF.C1B9 
2 
BRAF 
CCDC91-BRAF.C11B9 
Fusion 
CCDC91-BRAF.C11B9 
2 
BRAF 
CCNY-BRAF.C1B10 
Fusion 
CCNY-BRAF.C1B10 
2 
BRAF 
CDC27-BRAF.C16B9.1 
Fusion 
CDC27-BRAF.C16B9.1 
2 
BRAF 
CEP89-BRAF.C16B9 
Fusion 
CEP89-BRAF.C16B9 
2 
BRAF 
CLCN6-BRAF.C2B11.COSF1440 
Fusion 
CLCN6-BRAF.C2B11.COSF1440 
2 
BRAF 
CLIP2-BRAF.C6B11 
Fusion 
CLIP2-BRAF.C6B11 
2 
BRAF 
CUL1-BRAF.C7B9 
Fusion 
CUL1-BRAF.C7B9 
2 
BRAF 
CUX1-BRAF.C10B9 
Fusion 
CUX1-BRAF.C10B9 
2 
BRAF 
DYNC1I2-BRAF.D7B10 
Fusion 
DYNC1I2-BRAF.D7B10 
2 
BRAF 
EML4-BRAF.E6B10 
Fusion 
EML4-BRAF.E6B10 
2 
BRAF 
EPS15-BRAF.E22B10 
Fusion 
EPS15-BRAF.E22B10 
2 
BRAF 
ERC1-BRAF.E12B10 
Fusion 
ERC1-BRAF.E12B10 
2 
BRAF 
ERC1-BRAF.E17B8 
Fusion 
ERC1-BRAF.E17B8 
2 
BRAF 
FAM114A2-BRAF.F9B11 
Fusion 
FAM114A2-BRAF.F9B11 
2 
BRAF 
FAM131B-BRAF.F1B10.COSF1191 
Fusion 
FAM131B-BRAF.F1B10.COSF1191 
2 
BRAF 
FAM131B-BRAF.F2B9.COSF1189.1 
Fusion 
FAM131B-BRAF.F2B9.COSF1189.1 
2 
BRAF 
FAM131B-BRAF.F3B9.COSF1193 
Fusion 
FAM131B-BRAF.F3B9.COSF1193 
2 
BRAF 
FCHSD1-BRAF.F13B9.COSF403 
Fusion 
FCHSD1-BRAF.F13B9.COSF403 
2 
BRAF 
FXR1-BRAF.F13B10 
Fusion 
FXR1-BRAF.F13B10 
2 
BRAF 
GATM-BRAF.G2B11 
Fusion 
GATM-BRAF.G2B11 
2 
BRAF 
GHR-BRAF.G1B10 
Fusion 
GHR-BRAF.G1B10 
2 
BRAF 
GNAI1-BRAF.G1B10.COSF1442 
Fusion 
GNAI1-BRAF.G1B10.COSF1442 
2 
BRAF 
GTF2I-BRAF.G4B10 
Fusion 
GTF2I-BRAF.G4B10 
2 
BRAF 
HERPUD1-BRAF.H4B7 
Fusion 
HERPUD1-BRAF.H4B7 
2 
BRAF 
KCTD7-BRAF.K3B8 
Fusion 
KCTD7-BRAF.K3B8 
2 
BRAF 
KCTD7-BRAF.K4B8 
Fusion 
KCTD7-BRAF.K4B8 
2 
BRAF 
KDM7A-BRAF.K11B11 
Fusion 
KDM7A-BRAF.K11B11 
2 
BRAF 
KIAA1549-BRAF.K12B11 
Fusion 
KIAA1549-BRAF.K12B11 
2 
BRAF 
KIAA1549-BRAF.K12B9.COSF1474 
Fusion 
KIAA1549-BRAF.K12B9.COSF1474 
2 
BRAF 
KIAA1549-BRAF.K13B9 
Fusion 
KIAA1549-BRAF.K13B9 
2 
BRAF 
KIAA1549-BRAF.K14B11.COSF1226 
Fusion 
KIAA1549-BRAF.K14B11.COSF1226 
2 
BRAF 
KIAA1549-BRAF.K14B9.COSF483 
Fusion 
KIAA1549-BRAF.K14B9.COSF483 
2 
BRAF 
KIAA1549-
BRAF.K15B10.COSF1283.1 
Fusion 
KIAA1549-
BRAF.K15B10.COSF1283.1 
2 
BRAF 
KIAA1549-BRAF.K15B11.COSF485.1 
Fusion 
KIAA1549-BRAF.K15B11.COSF485.1 
2 
BRAF 
KIAA1549-BRAF.K15B9.COSF481.1 
Fusion 
KIAA1549-BRAF.K15B9.COSF481.1 
2 
BRAF 
KIAA1549-BRAF.K16B10 
Fusion 
KIAA1549-BRAF.K16B10 
2 
BRAF 
KIAA1549-BRAF.K17B10.COSF509 
Fusion 
KIAA1549-BRAF.K17B10.COSF509 
2 
BRAF 
KIAA1549-BRAF.K18B9.COSF511 
Fusion 
KIAA1549-BRAF.K18B9.COSF511 
2 
BRAF 
KIAA1549-BRAF.K9B9 
Fusion 
KIAA1549-BRAF.K9B9 
2 
BRAF 
KLHL7-BRAF.K5B9 
Fusion 
KLHL7-BRAF.K5B9 
2 


  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
APEC1621E 
 
 
Version Date: 08/19/2019 
 
Page 93 
BRAF 
LSM12-BRAF.L3B9 
Fusion 
LSM12-BRAF.L3B9 
2 
BRAF 
LSM14A-BRAF.L9B9 
Fusion 
LSM14A-BRAF.L9B9 
2 
BRAF 
MACF1-BRAF.M60B9 
Fusion 
MACF1-BRAF.M60B9 
2 
BRAF 
MAD1L1-BRAF.M16B9 
Fusion 
MAD1L1-BRAF.M16B9 
2 
BRAF 
MAD1L1-BRAF.M17B10 
Fusion 
MAD1L1-BRAF.M17B10 
2 
BRAF 
MKRN1-BRAF.M4B11.COSF1444 
Fusion 
MKRN1-BRAF.M4B11.COSF1444 
2 
BRAF 
MKRN1-BRAF.M4B9 
Fusion 
MKRN1-BRAF.M4B9 
2 
BRAF 
MYRIP-BRAF.M16B9 
Fusion 
MYRIP-BRAF.M16B9 
2 
BRAF 
MZT1-BRAF.M2B11 
Fusion 
MZT1-BRAF.M2B11 
2 
BRAF 
NUB1-BRAF.N3B9 
Fusion 
NUB1-BRAF.N3B9 
2 
BRAF 
NUDCD3-BRAF.N4B9 
Fusion 
NUDCD3-BRAF.N4B9 
2 
BRAF 
NUP214-BRAF.N21B10 
Fusion 
NUP214-BRAF.N21B10 
2 
BRAF 
PAPSS1-BRAF.P5B9.1 
Fusion 
PAPSS1-BRAF.P5B9.1 
2 
BRAF 
PLIN3-BRAF.P1B9 
Fusion 
PLIN3-BRAF.P1B9 
2 
BRAF 
RAD18-BRAF.R7B10 
Fusion 
RAD18-BRAF.R7B10 
2 
BRAF 
RBMS3-BRAF.R11B11 
Fusion 
RBMS3-BRAF.R11B11 
2 
BRAF 
RNF11-BRAF.R1B11 
Fusion 
RNF11-BRAF.R1B11 
2 
BRAF 
RNF130-BRAF.R3B9.COSF1483 
Fusion 
RNF130-BRAF.R3B9.COSF1483 
2 
BRAF 
RP2-BRAF.R3B10 
Fusion 
RP2-BRAF.R3B10 
2 
BRAF 
SLC12A7-BRAF.S17B11 
Fusion 
SLC12A7-BRAF.S17B11 
2 
BRAF 
SLC45A3-BRAF.S1B8.COSF871 
Fusion 
SLC45A3-BRAF.S1B8.COSF871 
2 
BRAF 
SND1-BRAF.S10B11 
Fusion 
SND1-BRAF.S10B11 
2 
BRAF 
SND1-BRAF.S10B9 
Fusion 
SND1-BRAF.S10B9 
2 
BRAF 
SND1-BRAF.S11B11 
Fusion 
SND1-BRAF.S11B11 
2 
BRAF 
SND1-BRAF.S14B11 
Fusion 
SND1-BRAF.S14B11 
2 
BRAF 
SND1-BRAF.S14B9 
Fusion 
SND1-BRAF.S14B9 
2 
BRAF 
SND1-BRAF.S16B9.1 
Fusion 
SND1-BRAF.S16B9.1 
2 
BRAF 
SND1-BRAF.S18B10 
Fusion 
SND1-BRAF.S18B10 
2 
BRAF 
SND1-BRAF.S9B2 
Fusion 
SND1-BRAF.S9B2 
2 
BRAF 
SND1-BRAF.S9B9 
Fusion 
SND1-BRAF.S9B9 
2 
BRAF 
SOX6-BRAF.S5B9 
Fusion 
SOX6-BRAF.S5B9 
2 
BRAF 
SOX6-BRAF.S6B9 
Fusion 
SOX6-BRAF.S6B9 
2 
BRAF 
STRN3-BRAF.S3B10 
Fusion 
STRN3-BRAF.S3B10 
2 
BRAF 
TANK-BRAF.T4B9 
Fusion 
TANK-BRAF.T4B9 
2 
BRAF 
TAX1BP1-BRAF.T8B11.1 
Fusion 
TAX1BP1-BRAF.T8B11.1 
2 
BRAF 
TMEM178B-BRAF.T2B9 
Fusion 
TMEM178B-BRAF.T2B9 
2 
BRAF 
TMPRSS2-BRAF.T3B11 
Fusion 
TMPRSS2-BRAF.T3B11 
2 
BRAF 
TRIM24-BRAF.T10B9 
Fusion 
TRIM24-BRAF.T10B9 
2 
BRAF 
TRIM24-BRAF.T11B2 
Fusion 
TRIM24-BRAF.T11B2 
2 
BRAF 
TRIM24-BRAF.T3B10 
Fusion 
TRIM24-BRAF.T3B10 
2 
BRAF 
TRIM24-BRAF.T3B11 
Fusion 
TRIM24-BRAF.T3B11 
2 
BRAF 
TRIM24-BRAF.T5B8 
Fusion 
TRIM24-BRAF.T5B8 
2 
BRAF 
TRIM24-BRAF.T9B9.1 
Fusion 
TRIM24-BRAF.T9B9.1 
2 


  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
APEC1621E 
 
 
Version Date: 08/19/2019 
 
Page 94 
BRAF 
TRIM4-BRAF.T6B10 
Fusion 
TRIM4-BRAF.T6B10 
2 
BRAF 
UBN2-BRAF.U3B11 
Fusion 
UBN2-BRAF.U3B11 
2 
BRAF 
ZC3HAV1-BRAF.Z3B10 
Fusion 
ZC3HAV1-BRAF.Z3B10 
2 
BRAF 
ZC3HAV1-BRAF.Z7B11 
Fusion 
ZC3HAV1-BRAF.Z7B11 
2 
BRAF 
ZKSCAN5-BRAF.Z2B9 
Fusion 
ZKSCAN5-BRAF.Z2B9 
2 
BRAF 
ZSCAN30-BRAF.Z3B10 
Fusion 
ZSCAN30-BRAF.Z3B10 
2 
 
 


  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
APEC1621E 
 
 
Version Date: 08/19/2019 
 
Page 95 
APPENDIX VIII:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
 
LOPERAMIDE DOSING RECOMMENDATIONS FOR DIARRHEA 
(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 
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. 
 
 
 
 


  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
APEC1621E 
 
 
Version Date: 08/19/2019 
 
Page 96 
 
APPENDIX IX: BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT PERCENTILE 
 
 
Blood pressure (BP) levels for BOYS  
 
 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm Hg 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) Percentile 5th 10th 25th 50th 75th 90th 95th 5th 10th 25th 50th 75th 90th 95th 
1 
95th 
98 
99 
101 
103 
104 
106 
106 
54 
54 
55 
56 
57 
58 
58 
2 
95th 
101 
102 
104 
106 
108 
109 
110 
59 
59 
60 
61 
62 
63 
63 
3 
95th 
104 
105 
107 
109 
110 
112 
113 
63 
63 
64 
65 
66 
67 
67 
4 
95th 
106 
107 
109 
111 
112 
114 
115 
66 
67 
68 
69 
70 
71 
71 
5 
95th 
108 
109 
110 
112 
114 
115 
116 
69 
70 
71 
72 
73 
74 
74 
6 
95th 
109 
110 
112 
114 
115 
117 
117 
72 
72 
73 
74 
75 
76 
76 
7 
95th 
110 
111 
113 
115 
117 
118 
119 
74 
74 
75 
76 
77 
78 
78 
8 
95th 
111 
112 
114 
116 
118 
119 
120 
75 
76 
77 
78 
79 
79 
80 
9 
95th 
113 
114 
116 
118 
119 
121 
121 
76 
77 
78 
79 
80 
81 
81 
10 
95th 
115 
116 
117 
119 
121 
122 
123 
77 
78 
79 
80 
81 
81 
82 
11 
95th 
117 
118 
119 
121 
123 
124 
125 
78 
78 
79 
80 
81 
82 
82 
12 
95th 
119 
120 
122 
123 
125 
127 
127 
78 
79 
80 
81 
82 
82 
83 
13 
95th 
121 
122 
124 
126 
128 
129 
130 
79 
79 
80 
81 
82 
83 
83 
14 
95th 
124 
125 
127 
128 
130 
132 
132 
80 
80 
81 
82 
83 
84 
84 
15 
95th 
126 
127 
129 
131 
133 
134 
135 
81 
81 
82 
83 
84 
85 
85 
16 
95th 
129 
130 
132 
134 
135 
137 
137 
82 
83 
83 
84 
85 
86 
87 
≥17 
95th 
131 
132 
134 
136 
138 
139 
140 
84 
85 
86 
87 
87 
88 
89 
Instructions for using this BP Chart: 
1. 
Measure the patient’s blood pressure using an appropriate size cuff. 
2. 
Select appropriate chart for a female or male patient. 
3. 
Using the “age” row and “height” column determine if the BP is within the ULN. 
4. 
See Section 5.4.1.2 for definition of dose limiting hypertension, Section 6.7 for management and grading of hypertension, and Section 7.6 for medical 
treatment of selumetinib- related hypertension.  
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents” PEDIATRICS 
Vol. 114 No. 2 August 2004, pp. 555-576. 


  
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APEC1621E 
 
 
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Page 97 
 
Blood pressure (BP) levels for GIRLS  
 
 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm Hg 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) Percentile 5th 10th 25th 50th 75th 90th 95th 5th 10th 25th 50th 75th 90th 95th 
1 
95th 
100 101 
102 
104 
105 
106 
107 
56 
57 
57 
58 
59 
59 
60 
2 
95th 
102 103 
104 
105 
107 
108 
109 
61 
62 
62 
63 
64 
65 
65 
3 
95th 
104 104 
105 
107 
108 
109 
110 
65 
66 
66 
67 
68 
68 
69 
4 
95th 
105 106 
107 
108 
110 
111 
112 
68 
68 
69 
70 
71 
71 
72 
5 
95th 
107 107 
108 
110 
111 
112 
113 
70 
71 
71 
72 
73 
73 
74 
6 
95th 
108 109 
110 
111 
113 
114 
115 
72 
72 
73 
74 
74 
75 
76 
7 
95th 
110 111 
112 
113 
115 
116 
116 
73 
74 
74 
75 
76 
76 
77 
8 
95th 
112 112 
114 
115 
116 
118 
118 
75 
75 
75 
76 
77 
78 
78 
9 
95th 
114 114 
115 
117 
118 
119 
120 
76 
76 
76 
77 
78 
79 
79 
10 
95th 
116 116 
117 
119 
120 
121 
122 
77 
77 
77 
78 
79 
80 
80 
11 
95th 
118 118 
119 
121 
122 
123 
124 
78 
78 
78 
79 
80 
81 
81 
12 
95th 
119 120 
121 
123 
124 
125 
126 
79 
79 
79 
80 
81 
82 
82 
13 
95th 
121 122 
123 
124 
126 
127 
128 
80 
80 
80 
81 
82 
83 
83 
14 
95th 
123 123 
125 
126 
127 
129 
129 
81 
81 
81 
82 
83 
84 
84 
15 
95th 
124 125 
126 
127 
129 
130 
131 
82 
82 
82 
83 
84 
85 
85 
16 
95th 
125 126 
127 
128 
130 
131 
132 
82 
82 
83 
84 
85 
85 
86 
≥17 
95th 
125 126 
127 
129 
130 
131 
132 
82 
83 
83 
84 
85 
85 
86 
Instructions for using this BP Chart: 
1. 
Measure the patient’s blood pressure using an appropriate size cuff. 
2. 
Select appropriate chart for a female or male patient. 
3. 
Using the “age” row and “height” column determine if the BP is within the ULN. 
4. 
See Section 5.4.1.2 for definition of dose limiting hypertension, Section 6.7 for management and grading of hypertension, and Section 7.6 for medical 
treatment of selumetinib related hypertension.  
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents” PEDIATRICS 
Vol. 114 No. 2 August 2004, pp. 555-576. 
 
 
 


  
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Version Date: 08/19/2019 
 
Page 98 
APPENDIX X: YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621E 
(for children from 7 through 12 years of age) 
A study of Molecular Analysis for Therapy Choice (MATCH) in children 
with a cancer that has come back after treatment or is difficult to treat 
 
1. We have been talking with you about your cancer. You have had treatment for the cancer already 
but it did not go away or it came back after treatment.  
 
2. We are asking you to take part in a research study because other treatments did not get rid of the 
cancer. A research study is when doctors work together to try out new ways to help people who are 
sick. In this study, we are trying to learn more about how to treat the kind of cancer that you have.  
 
3. You agreed to be part of a study to see if your cancer has any specific changes that could help us 
decide what medicine might “match” best to your cancer. 
 
4. We have found a medicine called selumetinib that could “match” your tumor. The doctors want to 
see if selumetinib will help children with your type of cancer get better. We don’t know if 
selumetinib will work well to get rid of your cancer. That is why we are doing the study. 
 
5. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is that selumetinib 
may cause your cancer to stop growing or to shrink for a period of time but we don’t know for sure 
if there is any benefit of being part of this study. 
 
6. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that you may have problems, or side effects 
from selumetinib. There may be risks that we don’t know about. 
 
7. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your cancer that your 
doctor can tell you about.  
8. If you decide to be treated with selumetinib you might have some tests and check-ups done more 
often that you might if you weren’t part of the study. 
 
9. As part of the study we are also trying to learn more about children’s cancers and how 
selumetinib works in them. We will draw some extra blood samples for this if your family agrees. 
 
 
 
 
 
 


  
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Page 99 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621E 
(for teens from 13 through 17 years of age) 
A study of Molecular Analysis for Therapy Choice (MATCH) in children 
with a cancer that has come back after treatment or is difficult to treat 
 
1. We have been talking with you about your cancer. You have had treatment for the cancer already but 
the cancer did not go away or it came back after treatment.  
 
2. We are asking you to take part in a research study because other treatments did not get rid of the cancer. 
A research study is when doctors work together to try out new ways to help people who are sick. In this 
study, we are trying to learn more about how to treat the kind of cancer that you have. 
 
3. The main purpose of this study is to learn how well cancers that have specific changes (mutations) 
respond to medicines that are aimed at those changes. This combination of a tumor with a mutation and 
a medicine that aims at that mutation is called a “match”. 
 
4.  Your tumor has a mutation that matches selumetinib, and so you have been assigned to selumetinib. 
The doctors want to see if selumetinib will make children with your type of cancer get better. We don’t 
know if selumetinib will work well to get rid of your cancer. That is why we are doing the study. 
 
5.  You will get selumetinib by mouth twice daily for a 28-day period. This entire 28-day period is called 
a cycle. Selumetinib should be swallowed whole. Do not chew or open. You may continue to 
receive selumetinib for up to about 24 months (approximately 26 cycles) as long as you do not have 
bad effects from it and your cancer does not get any worse. If you decide to be treated with selumetinib, 
you will also have exams and tests done that are part of normal cancer care. Some of these may be done 
more often while you are being treated with selumetinib. The doctors want to see if selumetinib will 
help children or adolescents with your type of cancer get better. We don’t know if selumetinib is better 
than other medicines. That is why we are doing this study.  
 
6. Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that selumetinib may cause 
your cancer to stop growing or to shrink for a period of time but we don’t know for sure if there is any 
benefit of being part of this study. 
 
7. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The primary risk to you from this study is that you may have side effects, from 
selumetinib. Your doctor will talk to you about the risks we know about from selumetinib. There may 
be other risks from selumetinib that we don’t know about yet.  
 
8. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. There may be other treatments for your illness that your doctor can 
tell you about. Make sure to ask your doctors any questions that you have.  
 
9. As part of the study we are also trying to learn more about the mutations that occur in cancers that happen 
in children and teens, as well as how selumetinib works. If your family agrees we will draw some extra 
blood samples to do these tests. 
 
 
 
 
 
 


  
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APEC1621E 
 
 
Version Date: 08/19/2019 
 
Page 100 
APPENDIX XI CORRELATIVE STUDIES GUIDE 
Correlative 
Study 
 
Section 
Blood Volume 
Tube Type 
Volume per Sample 
Total 
Cycle 5 
Day 1 
Circulating tumor 
DNA (optional) 
8.4 
• 
For patients ≥ 10 kg collect 
20 mLs (10 mL per tube x 2 
tubes)  
• 
For patients ≥ 5 kg but < 10 
kg collect 10 mL (one tube)  
• 
For patients < 5 kg research 
samples will not be collected  
 
10- 20mL 
Streck Cell-Free DNA BCT 
tubes 
Total Blood Volume in 
Cycle 5 Day 1 
 
10 mL 
 
 
Correlative 
Study 
 
Section 
Blood Volume 
Tube Type 
Volume per Sample 
Total  ‘Time of 
progression’ or 
‘End of protocol 
therapy’ 
Circulating tumor 
DNA (optional) 
8.4 
• 
For patients ≥ 10 kg collect 20 
mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥ 5 kg but < 10 kg 
collect 10 mL (one tube)  
• 
For patients < 5 kg research 
samples will not be collected  
 
10- 20mL 
Streck Cell-Free 
DNA BCT tubes 
Total Blood Volume in 
‘Time of progression or 
End of protocol therapy’ 
 
10- 20mL 
 
 


  
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Page 101 
APPENDIX XII: CTEP AND CTSU REGISTRATION PROCEDURES 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require 
all investigators participating in any NCI-sponsored clinical trial to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program 
(CTEP) Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In 
addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), 
or Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, or TRIAD or 
acting as a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation 
requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs 
must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in 
RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
Additional information can be found on the CTEP website at https://ctep.cancer.gov
/investigatorResources/default.htm. For questions, please contact the RCR Help Desk by email at 
RCRHelpDesk@nih.gov. 
 
 
 
 
   


  
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Page 102 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements For APEC1621E Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
IROC Credentialing Status Inquiry (CSI) Form  
NOTE: For studies with a radiation and/or imaging (RTI) component, the enrolling site must 
be aligned to a RTI provider.  To manage provider associations access the Provider Association 
tab on the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or 
remove associated providers.  Sites must be linked to at least one IROC credentialed provider 
to participate on trials with an RT component.   
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory 
Office immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
Data Submission / Data Reporting 
 


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


  
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Bilirubin 
 
Grade 1: 
> ULN-1.5 X ULN 
Grade 2: 
> 1.5 X ULN - 3 X ULN 
Grade 3: 
> 3 X ULN -10 X ULN 
Grade 4: 
> 10 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 X ULN 
Grade 3: 
> 5 X ULN -20 X ULN 
Grade 4: 
> 20 X ULN