A Phase 2 Study of the MEK Inhibitor Trametinib (NSC# 763093) in Children With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
Phase: PHASE2
Conditions: Juvenile Myelomonocytic Leukemia, Neurofibromatosis Type 1
Sponsor: National Cancer Institute (NCI)

  
 
 
 
i 
 
Group Chair 
Douglas S. Hawkins, MD 
Seattle Children's Research  
Institute 
doug.hawkins@seattlechildrens 
.org  
 
Group Vice Chair 
Lia Gore, MD 
Children's Hospital Colorado 
lia.gore@cuanschutz.edu  
 
Group Statistician 
Todd Alonzo, PhD 
talonzo@childrensoncology 
group.org 
 
Executive Director of Clinical  
Research Operations 
Mary Beth Sullivan, MPH 
msullivan@childrensoncology 
group.org  
 
Executive Director of 
Data Operations 
Thalia Beeles, MPH 
tbeeles@childrensoncology 
group.org 
 
Group Operations Center  
and 
Statistics & Data Center  
(SDC) Headquarters 
1333 S. Mayflower Avenue 
Suite 260 
Monrovia, CA 91016 
P 626 241 1500 
F 626 445 4334 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A National Cancer Institute- 
funded group member of the  
National Clinical Trials Network 
 
July 22, 2022 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #7 to protocol ADVL1521, A Phase 2 Study of the MEK 
inhibitor Trametinib (NSC# 763093) in Children with Relapsed or Refractory Juvenile 
Myelomonocytic Leukemia. 
 
Amendment #7 is in response to Mr. Howells’ May 23, 2022 Request for Amendment 
regarding updates to the trametinib tablet formulation pharmaceutical information. The 
protocol was updated to reflect this change.  
 
 
Please let me know if you have any questions or need additional information. 
 
Sincerely, 
 
 
Christine Petrossian, Associate Director (for) 
 
Elliot Stieglitz, M.D., ADVL1521 Study Chair  
Brenda J. Weigel, MD, COG Developmental Therapeutics Chair 
 

 
ii 
 
SUMMARY OF CHANGES: PROTOCOL 
In accordance with the above discussion, the following specific revisions have been made to the protocol. 
Additions are in boldfaced font and deletions in strikethrough font. 
# 
Section 
Page(s) 
Change 
1.  
General 
- 
Updated protocol version date in the footer.  
2.  
Cover Page 
1 
Updated version date and amendment number.  
3.  
Table of 
Contents 
3-4 
Updated for re-pagination.  
4.  
6.1 
49 
Updated drug monograph date 
5.  
6.1 
54-55 
Revised formulation and stability to include additional details 
regarding investigationally-labeled bottles and commercially-labeled 
bottles. 
6.  
6.1 
55 
Added clarification for water for irrigation during reconstitution of 
powder. 
 
 
 
 
 

 
Page 1 
Version Date: 07/22/2022 
Activated: 
10/06/17 
Version Date: 
07/22/22 
Closed: 
      
Amendment #: 
7 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
ADVL1521 
 
 
A Phase 2 Study of the MEK inhibitor Trametinib (NSC# 763093) 
in Children with Relapsed or Refractory Juvenile Myelomonocytic Leukemia 
 
 
 
 
A Groupwide Phase 2 Study limited to the United States 
 
 
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 
 
Elliot Stieglitz, MD 
University of California, San Francisco 
HDFCCC 
1450 3rd Street. Rm 283 
Box 3112 
San Francisco, CA 94158 
Phone: (415) 502-2649 
Fax: 
(888) 379-2523 
E-mail: Elliot.Stieglitz@ucsf.edu 
 
 
 
 
For Statistics and Data Center Contact Person see:  http://members.childrensoncologygroup.org 
 
 

 
Page 2 
Version Date: 07/22/2022 
 
 
CONTACT INFORMATION 
For Regulatory Requirements 
For patient enrollments: 
For Data Submission 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
 (Sign in at www.ctsu.org, and 
select the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment section 
of the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN). OPEN is accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or 
https://open.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or email:  
1-888-823-5923, or  ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. Please 
see the Data Submission 
Schedule in the CRF packet for 
further instructions. 
The most current version of the study protocol and all supporting documents must be downloaded from the protocol-
specific page located on the CTSU members’ website (https://www.ctsu.org). Access to the CTSU members’ website is 
managed through the Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) 
registration system and requires log in with a CTEP-IAM username and password. Permission to view and download 
this protocol and its supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU Regulatory Support System (RSS). 
For clinical questions (ie, patient eligibility or treatment-related)  
Contact the Study PI of the Lead Protocol Organization. 
For non-clinical questions (ie, unrelated to patient eligibility, treatment, or clinical data submission)  
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence will be 
triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 
 
 
 
 
 
 
 

  
 
ADVL1521 
Page 3 
Version Date: 07/22/2022 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
CHILDREN'S ONCOLOGY GROUP 
1 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
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 
9 
2.1 
Rationale for Development 
9 
2.2 
Preclinical Studies 
9 
2.3 
Adult Studies 
11 
2.4 
Pediatric Studies 
13 
2.5 
Overview of Proposed Pediatric Phase 2 Trial 
14 
2.6 
Rationale for Amendment #1- Dosing and Reduced Age Range 
14 
2.7 
Rationale for Amendment #3 
15 
3.0 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 
15 
3.1 
Study Enrollment 
15 
3.2 
Eligibility: Inclusion Criteria 
18 
3.3 
Eligibility: Exclusion Criteria 
21 
3.4 
Regulatory 
23 
4.0 
TREATMENT PROGRAM 
23 
4.1 
Overview of Treatment Plan 
23 
4.2 
Cycle 1 
25 
4.3 
Cycle 2 
29 
4.4 
Cycle 3 and All Subsequent Cycles 
32 
5.0 
DEFINITIONS AND DOSE MODIFICATION FOR TOXICITY 
35 
5.1 
Definition of Dose-Limiting Toxicity (DLT) 
35 
5.2 
Dose Modifications for Hematological Toxicity 
36 
5.3 
Dose Modifications for Non-Hematological Toxicity 
36 
5.4 
Guidelines and Dose Modifications for Trametinib Events of Special Interest 
36 
6.0 
DRUG INFORMATION 
49 
6.1 
Trametinib         (06/09/22) 
49 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
57 
7.1 
End of Therapy& Follow-up 
57 
7.2 
Retrospective Central Pathology Review 
58 
7.3 
Mutant Allele Burden Measurement REQUIRED 
59 
7.4 
Correlative Biology Studies 
60 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA63 
8.1 
Criteria for Removal From Protocol Therapy 
63 
8.2 
Off Study Criteria 
64 

  
 
ADVL1521 
Page 4 
Version Date: 07/22/2022 
9.0 
STATISTICAL CONSIDERATIONS 
64 
9.1 
Sample Size and Study Duration 
64 
9.2 
Study Design 
64 
9.3 
Methods of Analysis 
65 
9.4 
Evaluability for Response 
66 
9.5 
Evaluability for Toxicity 
66 
9.6 
Gender and Minority Accrual Estimates 
66 
9.7 
Analysis of the Pharmacokinetic Parameters 
67 
9.8 
Analysis of Biological and Correlative Endpoints 
67 
10.0 
EVALUATION CRITERIA 
67 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
67 
10.2 
Response Criteria 
68 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
68 
11.1 
Purpose 
68 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
68 
11.3 
Specific Examples for Expedited Reporting 
69 
11.4 
Reporting Requirements for Specialized AEs 
71 
11.5 
Exceptions to Expedited Reporting 
72 
11.6 
Reporting Requirements - Investigator Responsibility 
72 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
72 
11.8 
Reporting Table for Late Phase 2 and Phase 3 Studies 
74 
11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
76 
11.10 
Routine Reporting of Adverse Events 
76 
12.0 
STUDY REPORTING AND MONITORING 
76 
12.1 
CDUS 
76 
12.2 
Data and Safety Monitoring Committee 
76 
12.3 
CRADA/CTA 
77 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
79 
APPENDIX II: DOSING NOMOGRAM 
82 
APPENDIX III: RESPONSE CRITERIA FOR PATIENTS WITH JMML 
83 
APPENDIX IV: YOUTH INFORMATION SHEETS 
85 
APPENDIX V: DETERMINATION OF PATHOGENICITY 
87 
APPENDIX VI: TRAMETINIB MEDICATION DIARY (TABLET) 
88 
APPENDIX VII: TRAMETINIB MEDICATION DIARY (ORAL SOLUTION) 
91 
APPENDIX VIII: WALLET CARD 
94 
APPENDIX IX: BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT 
PERCENTILE 
95 
APPENDIX X:  
 TOXICITY-SPECIFIC GRADING 
97 
REFERENCES 
98 
 
 

  
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STUDY COMMITTEE 
 
STUDY CHAIR 
Todd Cooper, D.O. 
Elliot Stieglitz, M.D. 
Hematology/Oncology 
Hematology/Oncology 
Seattle Children’s Hospital 
Helen Diller Family Comprehensive Cancer Center- 
Mailstop B6553 
Box 3112 
4500 Sand Point Way NE 
1450 3rd St., Room 283 
Seattle, WA 98105 
San Francisco, CA 94158 
Phone:(207) 987-2106 
Phone: (415) 502-2649 
e-mail: Todd.Cooper@seattlechildrens.org 
Fax: 
(415) 353-2657 
 
e-mail: Elliot.Stieglitz@ucsf.edu 
Christopher Dvorak, M.D. 
 
Cellular Therapy 
STUDY VICE CHAIR 
UCSF Medical Center- Mission Bay 
Mignon L. Loh, MD 
550 16th St.  
Hematology/Oncology 
4th Floor, Box 0434 
Helen Diller Family Comprehensive Cancer Center- 
San Francisco, CA 94143 
Box 3112 
Phone: (415) 476-2188 
1450 3rd St., Room 284 
Fax: (415) 476-5356 
San Francisco, CA 94158 
e-mail: Christopher.Dvorak@ucsf.edu 
Phone: (415) 476-3831  
 
Fax: 
(415) 353-2657 
Brenda J. Weigel, M.D. 
e-mail: lohm@peds.ucsf.edu 
Hematology/Oncology 
 
University of Minnesota/ Masonic Cancer Center 
STUDY STATISTICIAN 
420 Delaware Street, SE. MMC 366 
Donald A. Barkauskas, Ph.D 
Minneapolis, MN 55455 
Biostatistics 
Phone: (612) 626-5501 
Phone: (626) 241-1540  
Fax: (612) 624-3913 
Fax: 
(626) 445-4334 
Email: weige007@umn.edu 
e-mail: dbarkauskas@childrensoncologygroup.org 
 
 
Elizabeth Fox, M.D. 
STUDY COMMITTEE MEMBERS 
Hematology/Oncology 
Teena Bhatla, M.D. 
Saint Jude Children’s Research Hospital 
Hematology/Oncology 
262 Danny Thomas Place 
Laura and Isaac Perlmutter Cancer Center at NYU 
MS 281 
160 E. 32 Street 
Memphis, TN 38105 
New York, NY 10016 
Phone: (901) 595- 3300 
Phone: (212) 263-8400  
Fax: 
(901) 595- 7031 
Fax: 
(212) 263-8410 
e-mail: elizabeth.fox@stjude.org 
e-mail: teena.bhatla@nyumc.org 
 
 
 
Scott Kogan, M.D. 
 
Pathology 
AGENT 
 
NSC#  
IND# 
University of California, San Francisco 
Trametinib 
 
NSC#763093 
 
513 Parnassus Avenue 
 
San Francisco, CA 94117 
IND Sponsor: 
Phone: (415) 514-1590 
DCTD, NCI 
email: scott.kogan@ucsf.edu 
 
 
 
 
 

  
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STUDY COMMITTEE MEMBERS 
Soheil Meshinchi, M.D., Ph.D. 
Olga Militano, PharmD 
Hematology/Oncology 
Pharmacy 
Seattle Children’s Hospital 
Children’s Oncology Group 
Fred Hutchinson Cancer Research Center 
Phone: (626) 241-1557 
1100 Fairview Avenue North, D5-380 
Fax: 
(626) 445-4334 
Seattle, WA 98109 
e-mail: omilitano@childrensoncologygroup.org 
Phone: (206) 667-4077 
 
Fax: 
(206) 667-4310 
 
e-mail: smeshinc@fhcrc.org 
 
 
Sharon DeAnn Bergeron, R.N., BSN, CPON 
Emily Theobald, BA 
Nursing 
Clinical Research Associate 
Children’s Hospital of Orange County 
UCSF Medical Center -  Mission Bay 
1201 West La Veta 
Pediatric Oncology 
Orange, CA 92868 
1450 Third Street 
Phone: (714) 509-4396 
San Francisco, CA 94158 
Fax: 
(714) 509-4365 
Phone:  (415) 476-3838 
e-mail: sbergeron@choc.org 
Email: emily.theobald@ucsf.edu 
 
 
 
 
COG OPERATIONS 
 
Patrice Navrude, MS 
Jeffrey Carpio, BS 
Protocol Coordinator 
Research Coordinator 
Children’s Oncology Group 
Children’s Oncology Group, Statistics and Data 
Phone: (626) 241- 1607 
Phone: (626) 241-1610 
Fax: 
(626) 445-4334 
Fax: 
(626) 445-4334 
e-mail: pnavrude@childrensoncologygroup.org 
e-mail: jcarpio@childrensoncologygroup.org 
 
 
David Hall, MS 
 
Statistician 
 
Children’s Oncology Group 
 
Phone: (626) 241- 1536 
 
Fax: 
(626) 445-4334 
 
e-mail: dhall@childrensoncologygroup.org 
 
 
 
 
 
 
 
 
 
SEE SECTION 7.2 FOR SPECIMEN SHIPPING ADDRESSES 

  
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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 your 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 
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of childhood. 
The biochemical hallmark of JMML is aberrant signaling through the Ras pathway caused by initiating 
mutations in NF1, NRAS, KRAS, RRAS, RRAS2, PTPN11 and CBL. The only known cure for JMML is 
hematopoietic stem cell transplantation (HSCT), yet 5-year event free survival after transplant is only 
~50%, with relapse being the most common cause of morbidity and mortality. 
 
Trametinib is an orally bioavailable, reversible, highly selective allosteric inhibitor of MEK1/2 which is 
downstream of Ras/MAPK signaling. Trametinib is FDA-approved for the treatment of adults with 
advanced melanoma with a BRAF V600E or V600K mutation. It is currently being investigated in over 
50 trials as a single agent or in combination with other targeted/cytotoxic therapies in patients with a 
variety of solid tumors and hematologic malignancies. This trial will evaluate the activity of trametinib in 
children and adolescents with relapsed or refractory JMML. The planned starting dose is 0.032 mg/kg/day 
for children aged 1 month to < six years of age and 0.025 mg/kg/day for children six years of age and 
older. These are the recommended phase 2 doses (RP2D) that were established in a pediatric trial for 
children with solid tumors. No further dose escalation is planned. 
 
Based on the genetics and predicted biochemical sequelae of increased signaling through the Ras/MAPK 
pathway, MEK inhibition is a logical treatment approach for patients with JMML. We will collect 
sequential samples from all patients enrolled to assess the clinical and molecular response at study entry 
and at disease progression if applicable. This trial will provide an opportunity to interrogate the genetic, 
biochemical, and functional perturbations of response and resistance to trametinib in patients with JMML. 
 
The primary objective of this study is to determine the response rate to trametinib after twelve cycles of 
therapy in children with relapsed/refractory JMML. Secondary objectives are (1) to further define and 
describe the toxicities of trametinib administered as monotherapy (2) to further characterize the 
pharmacokinetics (steady state trough concentration) of trametinib in children with JMML (3) to 
prospectively evaluate mutant allele burden as a marker of disease activity in JMML (4) to measure the rate 
of complete responses in children with JMML and (5) to measure the duration of response among responders. 
 
 
 

  
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EXPERIMENTAL DESIGN SCHEMA 
Treatment Schema: 
 
Day 1: 
 
 
 
Day 28: 
Begin Trametinib 
 
 
End of cycle 
 
Cycle:   
 
*Trametinib is administered orally. 
 
A cycle of therapy is 28 days. Therapy may consist of up to 12 cycles, for a total duration of therapy 
approximating 12 months, absent disease progression or unacceptable toxicity. 
 
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To determine the objective response rate to trametinib in children with recurrent 
or refractory Juvenile Myelomonocytic Leukemia (JMML). 
 
1.2 
Secondary Aims 
 
1.2.1 To further define and describe the toxicities of single agent trametinib in 
children with recurrent or refractory JMML. 
 
1.2.2 To further characterize the pharmacokinetics of trametinib in children with 
recurrent or refractory JMML. 
 
1.2.3 To prospectively evaluate mutant allele burden as a marker of disease 
activity in JMML. 
 
1.2.4 To measure the rate of complete responses in children with recurrent or 
refractory JMML. 
 
1.2.5 To measure the duration of response among responders. 
 
1.3 
Exploratory Aims 
 
1.3.1 
To describe the distribution of JMML diagnostic criteria in children with 
recurrent or refractory JMML. 
 

  
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2.0 
BACKGROUND 
 
2.1 
Rationale for Development 
Whereas many pediatric cancers are curable, the outcome remains dismal for patients 
with JMML. Following high dose chemotherapy and allogeneic hematopoietic stem cell 
transplant (HSCT), relapse occurs in about half of patients, with death resulting from 
progressive infiltration of myeloid cells into major organs or transformation to an 
incurable secondary acute leukemia.2 Moreover, the quality of life for patients with 
JMML is compromised by massive splenomegaly, failure to thrive, chronic anemia and 
thrombocytopenia. Innovative new approaches to treat and cure this devastating disorder 
are needed. 
 
2.1.1 
Defining the Genetic Basis of JMML 
The association between JMML and certain inherited syndromes advanced 
understanding of both disorders. The incidence of JMML is increased 200-500 
fold in neurofibromatosis type 1 (NF1).3 NF1 encodes neurofibromin, a GTPase 
activating protein (GAP) for Ras, which negatively regulates Ras output.4 
Noonan syndrome (NS) is characterized by multiple developmental defects, and 
some patients develop a transient JMML-like myeloproliferative neoplasm 
(MPN).5 The discovery of germline missense mutations in the PTPN11 in ~50% 
of NS6 patients proved critical for understanding the associated transient MPN 
and led to the discovery that somatic PTPN11 mutations are the most common 
cause of JMML.7 8 The discovery of homozygous CBL mutations in JMML led to 
further investigations demonstrating that such lesions are usually heterozygous 
germline events with somatic loss of heterozygosity in the hematopoietic 
compartment, similar to what occurs in NF1 mutated JMML. 9 In total, 95% of 
patients with JMML harbor mutations in genes that regulate the Ras pathway: 
PTPN11 40%, NRAS/KRAS/RRAS/RRAS2 35%, NF1 loss 10% 
10 and 
homozygous CBL 10%. 7,11-15 The majority of these mutations are mutually 
exclusive in individual patients, which suggests that these aberrant proteins act as 
drivers, encoding components of a conserved biochemical network that regulates 
the proliferation, differentiation, and survival of cancer initiating stem cells 
(HSC) and their progeny. However, recent analyses have shown that certain 
JMML patients will harbor compound mutations in Ras related genes and others 
and that they have a higher risk of relapse compared to patients with a single Ras 
pathway mutation. Emerging targeted therapies for JMML are based on findings 
that Ras pathway mutations drive disease.16 In the absence of viable strategies to 
directly inhibit Ras-GTP, targeting the RAF-MEK-ERK pathway is a rational 
treatment approach for JMML. 
 
2.2 
Preclinical Studies 
 
2.2.1 
Antitumor Activity 
Mx1-Cre, Nf1flox/flox mice and Mx1-Cre, KrasG12D mice develop an MPN with 
many similarities to JMML.17 18 Treatment with the MEK inhibitor PD0325901 
in these Nf1 and Kras mutant mice induced a durable decrease in leukocyte 
counts, enhanced erythropoietic function, reduced spleen size and prolonged 

  
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survival. MEK inhibition restored a normal pattern of erythroid differentiation, 
reduced extramedullary hematopoiesis, and normalized aberrantly increased early 
progenitors, including the stem-like KLS (c-Kit+ lin–Sca-1+) cells, which are 
likely required for leukemia initiation and maintenance.19,20 Genetic analysis 
revealed persistence of mutant hematopoietic cells, indicating that MEK 
inhibition modulates the proliferation and differentiation of mutant cells in vivo 
rather than eliminating them. Similar responses were seen in Nf1 and Kras 
mutant mice treated with the MEK inhibitor trametinib (T. Chang, unpublished 
data). In primary human cells, MEK inhibitors abrogate the classic JMML 
features of hypersensitivity of myeloid progenitors to granulocyte-macrophage 
colony stimulating factor (GM-CSF), which functionally supports a behavioral 
shift in cytokine sensitive myelopoiesis. 
 
2.2.2 
Animal Toxicology 
In juvenile rat toxicity studies, there were dose-dependent effects on growth 
(body weight and long bone length), bone (physeal thickening), serum 
phosphorus (increased), eye (corneal mineralization/dystrophy), skin, liver, heart 
(increased heart weight) and the female reproductive system (delay in a physical 
landmark of sexual maturity and mammary gland development, lower corpora 
lutea and ovarian weights). All of the female reproductive effects were 
reversible. With the exception of the heart and eye findings, similar effects have 
been observed in adult animals given trametinib. 
 
In bone, physeal thickening was reversible following a recovery period. Bone 
changes may be associated with inhibition of MEK-dependent fibroblast growth 
factor (FGF) signaling, as similar effects have been observed in rats given a small 
molecule inhibitor of FGF receptor (FGFR) tyrosine kinase21 as well as in FGFR-
3-deficient mice22. Unlike in adults, where bone growth has completed and the 
physeal plates have closed, children (2 to 11 years of age) and adolescents (12 to 
<18 years of age) may represent sensitive populations to chronic MEK inhibitor 
treatment, manifested as decreased growth velocity. 
 
Gonadal maturation and development is a potentially sensitive process in 
children who have yet to reach sexual maturity. In female rats given trametinib at 
subclinical exposures, ovarian function perturbations were observed, including 
increases in cystic follicles and decreases in cystic corpora lutea. Pharmacologic 
inhibition of MEK activity in ovarian granulosa cell cultures blocked ovulatory 
gene expression, follistatin signaling and granulosa cell survival,23-25 indicating a 
potential role of MEK in folliculogenesis. In juvenile rats, similar ovarian 
findings occurred, as well as delays in onset of physical hallmarks of sexual 
maturity and mammary gland development. Therefore, onset of female 
reproductive maturation is a theoretical concern in pediatric populations 
receiving trametinib. 
 
2.2.3 
Preclinical Pharmacology 
Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, 
chromosomal aberrations in mammalian cells, and micronuclei in the bone 
marrow of rats.26 
 

  
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2.3 
Adult Studies 
 
2.3.1 
Adult Phase I Studies 
A phase 1/2 trial of single agent trametinib in adults with RAS mutated, multiply 
relapsed or refractory myeloid malignancies (n=57) demonstrated a 21% 
response rate compared with a 3% response rate in patients with RAS wild-type 
or unknown leukemia (n=30). Hepatic toxicities (9%), gastrointestinal disorders 
(7%) and rash (5%) were the most frequent Grade 3/4 AEs. AEs possibly related 
to inhibition of MEK signaling were blurred vision (total, 13%; Grade 3, 1%) and 
decreased cardiac ejection fraction (total, 9%; Grade 3, 6%).27 
 
The Maximum Tolerated Dose (MTD) of trametinib in adults is 3 mg once daily, 
and the RP2D of trametinib is 2 mg once daily. Five monotherapy studies 
administered trametinib 2 mg daily to 499 adult subjects. The most common 
adverse events were rash, diarrhea, fatigue, peripheral edema, nausea, dermatitis 
acneiform, vomiting, constipation, anemia, pruritus, alopecia, hypertension, 
decreased appetite, dyspnea and dry skin. In these studies, up to 32% of subjects 
reported serious AEs (SAEs), and up to 13% permanently discontinued study 
treatment due to AEs. Rash, diarrhea, visual disorders, hepatic disorders, cardiac-
related AEs, and pneumonitis are considered AEs of special interest because they 
are either known class effects (observed with other MEK inhibitors) or 
potentially life-threatening. 
Cardiac-related adverse events are known to occur in adults treated with 
trametinib. In a phase 2 trial, patients (n=97) underwent serial assessment of 
LVEF, three patients (3%) developed asymptomatic and reversible Grade 3 
LVEF reduction.28 In a phase 3 trial comparing trametinib versus dacarbazine 
plus paclitaxel, 14 of the 211 patients who received at least one dose of 
trametinib developed cardiac-related adverse events (7%), 11 developed 
decreased LVEF, and three had LV dysfunction.29 Cardiomyopathy resolved in 
10 of the 14, but four patients had serious cardiac-related events that were 
considered to be drug-related and led to permanent discontinuation of the study 
drug. Across clinical trials of trametinib at the recommended adult dose (2 mg 
daily), approximately 11% of patients have developed evidence of decrease in 
LVEF below the institutional lower limits of normal with an absolute decrease in 
LVEF ≥10% below baseline; 5% have developed decrease in LVEF below the 
institutional lower limits of normal with an absolute decrease in LVEF of ≥20% 
below baseline.30 
Ocular effects and visual impairments, including central serous retinopathy 
(CSR), retinal pigment epithelium detachment, and retinal vein occlusion (RVO), 
are reported with trametinib as well as other MEK inhibitors in clinical 
development. At the 2 mg daily dose, 14% to 18% of the subjects in three clinical 
trials experienced visual disorders. The majority of these were Grades 1 or 2 in 
severity (71% to 93%); 7% to 29% of subjects experienced Grade 3 and none 
experienced Grade 4 visual disorders. With the exception of Grade 3 RVO and 
Grade 2 CSR, all cases were reversible with or without drug interruption. CSR is 
a visual impairment due to fluid accumulation under the retina, which causes 
blurry vision. As of September 18th 2014, 17 (1.2%) cases of CSR have been 
reported amongst subjects treated with trametinib, either as monotherapy or in 
combination with other anti-cancer agents. Two cases (0.3%) of RVO have been 

  
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observed with trametinib, of which one case was considered drug-related. 
(5.6.7.2. Investigator Brochure). 
 
2.3.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
In adults, the mean trametinib area under the concentration-time curve over the 
dosing interval (AUC0-) and Cmax increased in a dose proportional manner. 
The trametinib terminal half-life was 5.3 days with steady state achieved by 
Day 15. In adults receiving the recommended phase 2 trametinib for 15 days 
(n=13) the geometric mean (coefficient of variation [CV] %) AUC (0-24h) was 
370 (22%) ng h/mL, Cmax 22.2 (28%) ng/mL, Tmax 1.75 (range 1-3), and C 
12.1 (19%, 95% CI 10.9, 13.4 ng/mL). An oral liquid formulation (0.05 mg/mL) 
had similar bioavailability to the trametinib tablet (0.125, 0.5, 2 mg) formulation. 
Single dose administration of trametinib as a 2 mg oral solution compared to the 
oral tablet resulted in a 10% increase in AUC (0-last). 

  
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2.3.3 
Efficacy (Phase 2 and 3 studies) 
Data from phase 1, 2 and 3 studies indicate substantial clinical activity of 
trametinib in unresectable, BRAF mutation positive melanoma31-33. The pivotal 
phase 3 study, MEK114267 (METRIC), showed significant improvement in 6 
month overall survival (OS, 81% vs 67%, P=0.01) and progression-free survival 
(PFS, 4.8 months versus 1.5 months, P<0.001) in favor of trametinib over 
standard dacarbazine or paclitaxel chemotherapy in the treatment of patients with 
advanced or metastatic BRAF V600E/K mutation positive melanoma.34,35 
2.4 
Pediatric Studies 
 
2.4.1 
Pediatric Phase 1 Studies 
A 3-part phase 1/2, open-label, multicenter study of trametinib in pediatric 
subjects 1 month or older with recurrent or refractory tumors (NCT02124772) is 
underway. Results from part A, the dose escalation portion of the study which 
included 40 subjects has been presented in abstract form.36 Dose limiting toxicity 
(rash and mucositis) occurred in 5/15 patients (33.3%) receiving 0.04 
mg/kg/dose, whereas a dose of 0.025 mg/kg resulted in dose limiting toxicity in 
3/19 (16%) patients. However, more than 50% of patients under the age of 6 
receiving a dose of 0.025mg/kg were noted to have steady state trough levels (see 
‘ctrough trametinib’ table below) below the target level established in adults with 
melanoma treated at the approved trametinib dose that is associated with efficacy 
(ctrough of ~11 ng/mL).  
 
 
A dose of 0.032 mg/kg/dose was therefore evaluated in 12 patients under the age 
of 6 and there were no dose limiting toxicities. Ten of those 12 patients are still 
on treatment (range of 3-18 months) and two patients experienced progression of 
disease and have come off therapy. Steady state trough levels are not yet 
available for all 12 patients treated at 0.032 mg/kg/day (3 patients are included 
above) but there has been a linear trend in terms of pharmacokinetic troughs and 
previous dose levels. The recommended phase 2 dose, based on this exposure and 
tolerability data, is therefore 0.032 mg/kg per day in children one month to < six 
years of age and 0.025mg/kg/dose for children six years and older.  
 
No significant safety concerns specific to pediatric patients were noted in a 
preliminary analysis beyond what is already known from prior adult studies 
including in patients between 1 month and 6 years of age. In particular, the only 

  
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serious adverse event in the 12 patients under 6 years of age treated at 0.032 
mg/kg/day was mitral valve regurgitation in one patient who had received 
trametinib for 6 months which resolved after holding treatment and the patient 
has since resumed trametinib at 0.025 mg/kg/day without further toxicity. In total 
there have been 5 patients who are 2 years of age or younger (including two 
infants, 5 and 6 months of age) who have been treated at 0.032 mg/kg/day or 0.04 
mg/kg/day. There has been one serious adverse event (seizures) which was 
deemed unrelated to trametinib in a patient with a brain tumor and pre-existing 
seizure disorder. There have been no dose limiting toxicities in these 5 patients, 2 
years of age or younger or adverse events not previously seen in older patients 
(personal communication, Novartis).  
 
2.4.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
This data is not yet available from the ongoing pediatric phase 1 study in children 
with solid tumors. 
 
2.5 
Overview of Proposed Pediatric Phase 2 Trial 
This trial will enroll children with relapsed/refractory JMML, and evaluate objective 
response using JMML-specific response criteria37 (see Appendix III). Participants will 
also be evaluated for toxicity using CTCAE v5. Stopping rules for toxicity and response 
are included in the statistical section. Patients will receive oral trametinib daily in 
continuous 28-day cycles at the recommended phase 2 dose (RP2D) established in an 
ongoing industry-sponsored trial (NCT02124772) of trametinib in pediatric patients with 
relapsed/refractory solid tumors. The RP2D is 0.032 mg/kg per day for children one 
month to < six years of age and is 0.025 mg/kg per day for children six years of age and 
older. A single dose reduction (see section 5.0 and dosing nomogram in Appendix II) will 
be permitted in individual patients who experience DLT and have evidence of clinical 
benefit and is assessed per the investigator (i.e., improvement in leukemia-related 
symptoms, reduction in transfusion frequency, reduction or clearance of peripheral 
blasts). Minimal residual disease (MRD) testing using mutant allele frequency will be 
performed at baseline and after the first cycles of therapy and every odd other cycle 
thereafter (3, 5, 7, etc.). Pharmacokinetics will be obtained on Days 1 and 15 at hours 0 
and 4. Optional correlative pharmacodynamic studies (see Section 7.0) will be conducted 
to determine the effect of single-agent trametinib on Ras signaling. In the absence of 
toxicity, patients who do not experience clinical or genetic progressive disease (cPD or 
gPD) as defined in Table 2 of Appendix III, can be treated for up to 12 cycles 
(approximately 1 year). Ten to twenty-four participants will be enrolled on this trial. 
 
2.6 
Rationale for Amendment #1- Dosing and Reduced Age Range 
With Amendment #1, the protocol has been updated to include a lower age range 
eligibility from 2 years to 1 month. The lower age limit is based on safety data from a 
phase 1 pediatric study (NCT02124772) using trametinib in children with solid tumors.  
Additionally, patients under six years of age will be dosed at 0.032 mg/kg per day. The 
higher dose for children under six years is based on pharmacokinetic data from the same 
study (NCT02124772) indicating that children under six years of age require higher doses 
to achieve therapeutic levels. Therefore, the RP2D is 0.032 mg/kg per day for children 
one month to < six years of age and is 0.025 mg/kg per day for children six years of age 
and older. 

  
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2.7 
Rationale for Amendment #3  
Historically, the period for determination of best response in phase 2 studies of acute 
leukemia has been 2-4 cycles. When the protocol for ADVL1521, the first trial in COG 
for relapsed JMML, was originally written, the 4 cycle period was used by default. 
However, recognizing that JMML is an overlapping myelodysplastic / myeloproliferative 
disorder of childhood and not an acute leukemia, we now believe that 12 cycles (the 
maximum number of cycles permitted on this study) is the most appropriate time frame to 
assess for responses in this chronic condition. The only other study assessing for 
responses in relapsed JMML is a retrospective analysis of azacitidine. All three of the 
patients that achieved a complete response to azacitidine required at least 6 cycles of 
therapy reflecting the chronic nature of the disease and the treatment.1 Any patients 
enrolled at the time this amendment is approved would be affected by this change in the 
statistical design. 
 
3.0 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol. 
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
NOTE: In order for an institution to maintain COG membership requirements, 
every patient with a known or suspected neoplasm needs to be offered participation 
in APEC14B1, Project:EveryChild A Registry, Eligibility Screening, Biology and 
Outcome Study. 
 
3.1.2 
IRB Approval 
Sites must obtain IRB/REB approval for this protocol and submit IRB/REB 
approval and supporting documentation to the CTSU Regulatory Office before 
they can be approved to enroll patients. Allow 3 business days for processing. 
The submission must include a fax coversheet (or optional CTSU IRB 

  
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Transmittal Sheet) and the IRB approval document(s). The CTSU IRB 
Certification Form may be submitted in lieu of the signed IRB approval letter. 
All CTSU forms can be located on the CTSU web page (https://www.ctsu.org). 
Any other regulatory documents needed for access to the study enrollment 
screens will be listed for the study on the CTSU Member’s Website under the 
RSS Tab. 
 
IRB/REB approval documents may be submitted to the CTSU Regulatory Office 
via the Regulatory Submission Portal, where they will be entered and tracked in 
the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory 
Tab →Regulatory Submission  
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU 
members’ web site by entering credentials at https://www.ctsu.org. For sites 
under the CIRB initiative, IRB data will automatically load to RSS. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. However, these 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 a given 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. 
 
3.1.3 
Reservation Requirements 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps below. Reservations may be obtained 24 hours a day 
through the Oncology Patient Enrollment Network (OPEN) system. Patients must 
be enrolled within 5 calendar days of making a reservation. 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system in OPEN. Prior to discussing 
protocol entry with the patient, site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available for the 
patient. Once a slot-reservation confirmation is obtained, site staff may then 
proceed to enroll the patient to this study.  

  
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If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and 
password.  
2) In order to make a reservation, the patient must have an OPEN patient 
number. Click on the ‘Slot Reservation’ tab to create an OPEN patient 
number, under ‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient.  
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the 
COG Patient ID, and choose the required stratum (if applicable) in order to 
obtain a reservation. 
 
Refer to the ‘SITE – Slot Reservation Quick Reference’ guide posted under 
the ‘Help’ tab in OPEN for detailed instructions:  
https://www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_Q
uickReference_SiteUserGuide_102612.pdf&ftype=PDF 
 
3.1.4 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role 
on either the lead protocol organization (LPO) or participating organization 
roster. 
 
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. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated 
timeframes. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.1.5 
Timing 

  
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Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than 7 business days after the date of study 
enrollment. Patients who are started on protocol therapy prior to study 
enrollment will be considered ineligible and will not be able to receive 
further protocol therapy. 
 
See Section 3.2 for timing requirements for eligibility studies and for timing 
requirements for baseline studies to be obtained prior to start of therapy. Note: 
Repeat laboratory and imaging studies may be required if enrollment and 
start of therapy do not occur on the same day. 
 
Institutions are advised to plan ahead to ensure adequate and timely delivery of 
the investigational agent (see Section 6.1 for details). 
 
3.1.6 
Institutional Pathology Report 
Immediately following enrollment, the institutional pathology report for the 
diagnosis under which the patient is being enrolled must be uploaded into Rave. 
The report must include the associated study number and COG patient 
registration and accession numbers. Personal identifiers, including the patient’s 
name and initials must be removed from the institutional pathology report prior 
to submission.  
 
3.2 
Eligibility: Inclusion Criteria  
Important note: The inclusion 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/research record. These source documents must be available for verification 
at the time of audit.  
 
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 > 7 days old, 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. Bone marrow aspirate (and biopsy, if 
applicable), must be obtained within 2 weeks prior to start of protocol therapy. If a 
bone marrow aspirate cannot be obtained, the patient is not eligible for enrollment. 
 
3.2.1 
Age: Patients must be ≥ 1 month and < 22 years of age at the time of study entry. 
 
3.2.2 
Diagnosis: Patients must have had histologic verification of juvenile 
myelomonocytic leukemia (JMML) at original diagnosis and currently have 
relapsed or refractory disease. The diagnosis is made based on the following 
criteria. 
 

  
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3.2.2.1 JMML Category 1 (all of the following):* 
- 
Splenomegaly 
- 
> 1000 (1x109/μL) circulating monocytes 
- 
< 20% Blasts in the bone marrow or peripheral blood 
- 
Absence of the t(9;22) or BCR/ABL fusion gene 
 
*The diagnostic criteria must include all features in category 1 and 
EITHER (i) one of the features in Category 2 OR (ii) two features from 
Category 3 to make the diagnosis. 
 
3.2.2.2 JMML Category 2 (at least one of the following if at least two Category 
3 criteria are not present): 
- 
Somatic mutation in RAS or PTPN11 
- 
Clinical diagnosis of NF1 or NF1 gene mutation 
- 
Homozygous mutation in CBL 
- 
Monosomy 7 
 
3.2.2.3 JMML Category 3 (at least two of the following if no Category 2 criteria 
are met): 
- 
Circulating myeloid precursors 
- 
White blood cell count, >10 000 (10x109/ μL) 
- 
Increased Hemoglobin F for age 
- 
Clonal cytogenetic abnormality 
- 
GM-CSF hypersensitivity 
 
3.2.3 
Disease Status for Juvenile Myelomonocytic Leukemia (JMML) Patients: 
3.2.3.1 Patients with refractory or relapsed JMML must have had at least one 
cycle of intensive frontline therapy or at least 2 cycles of a DNA 
demethylating agent with persistence of disease, defined by clinical 
symptoms or the presence of a clonal abnormality. Frontline therapy is 
defined as one cycle of intravenous chemotherapy that includes of any of 
the following agents: fludarabine, cytarabine, or any anthracycline but 
specifically excludes oral 6-mercaptopurine. Frontline therapy will also 
include any conditioning regimen as part of a stem cell transplant. 
Patients who transform to AML at any point with more than 20% blasts 
are not eligible for this trial. 
 
3.2.3.2 Performance Level  
Patients must have a Lansky or Karnofsky performance status score of 
≥ 50, corresponding to ECOG categories 0, 1 or 2. Use Karnofsky for 
patients > 16 years of age and Lansky for patients ≤ 16 years of age. 
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. 
(See https://members.childrensoncologygroup.org/prot/reference_materials.asp ) 
 
3.2.4 
Prior Therapy 
Patients must have fully recovered from the acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to study enrollment. 

  
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a. Myelosuppressive chemotherapy: 
Patients must have completely recovered from all acute toxic effects of 
chemotherapy, immunotherapy or radiotherapy prior to study enrollment. At 
least 14 days must have elapsed since the completion of cytotoxic therapy, 
with the exception of hydroxyurea. 
 
Note: Cytoreduction with hydroxyurea can be initiated and continued for up 
to 24 hours prior to the start of protocol therapy. 
b. Hematopoietic growth factors: At least 14 days after the last dose of a long-
acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth 
factor. For agents that have known adverse events occurring beyond 7 days 
after administration, this period must be extended beyond the time during 
which adverse events are known to occur. 
c. Biologic (anti-neoplastic agent): At least 7 days must have elapsed since 
completion of therapy with a biologic agent. For agents that have known 
adverse events occurring beyond 7 days after administration, this period prior 
to enrollment must be extended beyond the time during which adverse events 
are known to occur.  
d. Monoclonal antibodies: 
i. 
At least 30 days after the completion of any type of immunotherapy, 
e.g. tumor vaccines.  
ii. 
At least 3 half-lives must have elapsed since prior therapy that 
included a monoclonal antibody. (See posting of half-lives for 
commonly used monoclonal antibodies on the DVL homepage 
(https://members.childrensoncologygroup.org/Disc/devtherapeutics/default.
asp). 
e. Radiotherapy: 
i. 
≥ 2 weeks must have elapsed since local palliative XRT (small port) 
ii. 
≥ 6 months must have elapsed if prior craniospinal XRT was 
received, if ≥ 50% of the pelvis was irradiated, or if TBI was 
received 
iii. 
≥ 4 weeks must have elapsed if other substantial bone marrow 
irradiation was given. 
f. Stem Cell Transplant or Rescue without TBI: No evidence of active graft vs. 
host disease and ≥ 3 months must have elapsed since transplant. ≥ 4 weeks 
must have elapsed since any donor lymphocyte infusion. 
 

  
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3.2.5 
Organ Function Requirements 
3.2.5.1 Adequate Bone Marrow Function Defined As: 
 
-  Patients must not be known to be refractory to red blood cell or 
platelet transfusions. 
 
3.2.5.2 Adequate Renal Function Defined As: 
- Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or a 
serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
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 utilizing child length and stature data published 
by the CDC. 38 
 
3.2.5.3 Adequate Liver Function Defined As: 
- Total bilirubin  1.5 x upper limit of normal (ULN) for age 
- SGPT (ALT) ≤ 3 x ULN (135 U/L (for the purpose of this study, the 
ULN for SGPT is 45 U/L) 
- Serum albumin ≥ 2 g/dL. 
 
3.2.5.4 Adequate Cardiac Function Defined As: 
- Shortening fraction of ≥ 27% by echocardiogram OR Ejection 
fraction of ≥ 50% by MUGA 
- Corrected QT (QTcB) interval <450 msecs 
 
3.2.6  Patients must be able to swallow tablets or liquid; use of a nasogastric or G tube 
is also allowed. 
 
3.3 
Eligibility: Exclusion Criteria 
 
Important note: The exclusion 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/research record. These source documents must be available for verification 
at the time of audit. 
 
3.3.1 
Pregnancy or Breast-Feeding 
Patients who are pregnant or breast-feeding are not eligible for this study as there 
is yet no available information regarding human fetal or teratogenic toxicities. 
Negative pregnancy tests must be obtained in girls who are post-menarchal. 
Patients of reproductive potential may not participate unless they have agreed to 

  
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use an effective contraceptive method for the duration of study therapy. Women 
of childbearing potential should be advised to use effective contraception for 4 
months after the last dose of trametinib. Trametinib may also potentially be 
secreted in milk and therefore breastfeeding women are excluded. Female 
patients should not breastfeed during treatment with trametinib, and for 4 months 
following the last dose. Male patients must use a condom during intercourse and 
agree not to father a child during therapy and for 4 months following 
discontinuation of trametinib to avoid unnecessary exposure of trametinib to the 
fetus. 
 
3.3.2 
Concomitant Medications (Please see Section 4.1 for the concomitant therapy 
restrictions for patients during the study).3.3.2.1 Corticosteroids: 
Patients 
requiring corticosteroids who have not been on a stable or decreasing 
dose of corticosteroid for the 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. 
 
Note: hydrocortisone used as a pre-medication to prevent transfusion 
related reactions is not considered a concomitant corticosteroid. 
 
3.3.2.2 Investigational Drugs: Patients who are currently receiving another 
investigational drug are not eligible. 
 
3.3.2.3 Anti-cancer Agents: Patients who are currently receiving other anti-
cancer agents are not eligible [except patients receiving hydroxyurea, 
which may be continued until 24 hours prior to start of protocol therapy]. 
 
3.3.2.4 Anti-GVHD or agents to prevent organ rejection post-transplant: 
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent either graft-versus-host disease post bone marrow transplant or 
organ rejection post-transplant are not eligible for this trial. 
 
3.3.2.5 Cardiac Medications: Any medications for treatment of left ventricular 
systolic dysfunction. 
 
3.3.3 
Infection:Patients who have an uncontrolled infection are not eligible. 
 
3.3.4 
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. 
3.3.5 
Veno-occlusive Disease: Patients with a history of hepatic sinusoid obstructive 
syndrome (veno-occlusive disease) within the prior 3 months are not eligible. 
3.3.6 
Patients with a history of or current evidence/risk of retinal vein occlusion (RVO) 
or central serous retinopathy (CSR) are not eligible. 
3.3.6.1 Ocular Conditions: Patients with a history of RVO or CSR, or 
predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or 
ocular hypertension. 
 
 
3.3.7 
Systemic Diseases: Patients with uncontrolled systemic disease(s) such as 
hypertension or diabetes mellitus are not eligible. Blood pressure must be ≤ the 
95th percentile for age, height, and gender (Appendix IX) measured as described 

  
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in Section 5.4.9.1. 
 
3.3.8 
Allergic Reactions: Patients with a history of allergic reaction attributed to 
compounds of similar chemical or biologic composition to the MEK inhibitor, 
trametinib are not eligible. 
 
3.3.9 
Noonan Syndrome: Patients with a clinical diagnosis of Noonan syndrome are 
not eligible. Note: patients with Casitas B-lineage lymphoma (CBL) syndrome, 
also known as Noonan-like syndrome, are eligible to enroll. 
 
3.4 
Regulatory 
 
3.4.1 
All patients and/or their parents or legal guardians must sign a written informed 
consent. 
 
3.4.2 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
 
 
4.0 
TREATMENT PROGRAM 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
A single-arm open label study, with trametinib administered at 0.032 mg/kg/dose (< 6 
years of age) and 0.025 mg/kg/dose (≥ 6 years of age) with a maximum of 2 mg orally 
once daily on a continuous 28-day cycle, for up to 12 total cycles. Dosing will be 
performed based on weight in kilograms (kg) obtained within 7 days of starting each 
cycle. For patients (< 6 years of age) who receive 0.032 mg/kg/dose, in the absence of 
dose limiting toxicity, their dose will remain 0.032 mg/kg/dose for up to 12 cycles even if 
they become 6 years of age during protocol therapy. 
 
4.1.1 
Dose Reduction 
A single dose reduction (25% dose reduction for patients receiving oral solution 
and see Appendix II for tablet formulation dose reductions) will be allowed for 
toxicities as outlined in Section 5.0 for patients who recover to starting criteria as 
outlined in Section 3.2 within 7 days following planned administration. 
 
4.1.2 
Dose Escalation 
There will be no drug dose escalation. 
 
4.1.3 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient does not meet criteria for 
progressive disease (PD) (See Section 10.2 and Appendix III), and  required pre-
cycle assessments (see Therapy Delivery Maps Sections 4.2, 4.3 and 4.4) have 

  
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again met laboratory parameters defined in the eligibility section, Section 3.2.5. 
Note: albumin is not required for starting subsequent cycles. 
 
4.1.4 
Concomitant Therapy 
4.1.1.1 No other cancer chemotherapy, radiotherapy, or immunomodulating 
agents will be used. 
 
4.1.1.2 Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes 
and general supportive care are to be used as necessary. Nausea and 
vomiting has been observed commonly in adult patients treated with 
trametinib. It is recommended to provide all patients a 5-HT₃-receptor 
antagonist (e.g., ondansetron or granisetron) at the start of treatment to be 
used as needed or prophylactically.  In the event of breakthrough 
nausea/vomiting, additional antiemetics may be added as needed. 
 
4.1.5 
Study Specific Supportive Care: 
Prophylactic Treatment for prevention of dermatologic toxicity is: 
1. Broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a 
skin protection factor (SPF) ≥15 at least twice daily. 
2. Thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol cream) 
on dry areas of the body at least twice daily. 
3. Mild strength topical steroid (e.g., hydrocortisone 1% cream) and topical 
antibiotics (e.g., clindamycin) applied at least twice daily starting on Day 1 
of study treatment, to body areas such as face, chest and upper back with 
escalation to higher strength and/or oral steroid as detailed in Section 5.4. 
4. Triamcinolone acetonide 0.1% dental paste for oral sores that arise while 
receiving study medication. 
5. Non-alcohol containing mouth rinse (e.g. Biotene, Peridex, or biosimilars) 
for patients experiencing mouth sores related to swallowing study drug. 
 
For COG Supportive Care Guidelines see:  
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard 
Sections for Protocols. 
 
4.1.6 
Study Specific Ophthalmologic Exams 
An age-appropriate ophthalmologic examination that avoids any sedation should 
be performed by an ophthalmologist at baseline, at the end of Cycle 1, and every 
12 weeks thereafter, while on study. This includes a Snellen examination (if age 
appropriate as determined by the investigator). The examination must include a 
funduscopic evaluation to rule out retinal vein occlusion (RVO) and retinal 
pigment epithelial detachment (RPED), can be dilated or non-dilated at 
discretion of ophthalmologist and can be accomplished using imaging with a 
non-mydriatic fundus camera. 
 
 
 

  
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Cycle 1 
4.2 
Cycle 1 
4.2.1 
Therapy Delivery Map – Cycle 1 
This therapy Delivery Map (TDM) relates to Cycle 1. Each 
cycle lasts 28 days. 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Criteria to start each cycle are listed in Section 3.2.5. Treatment details are provided in Section 4.2.3. 
This treatment delivery map is two (2) pages in length. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Trametinib 
Do not use 
commercial supply 
PO 
Age-based dosing: 
< 6 years= 0.032 mg/kg/dose 
> 6 years = 0.025 mg/kg/dose 
Max dose= 2 mg 
Daily 
See Appendix II for tablet 
formulation dosing nomogram. 
 
Enter Cycle #: _____ Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Trametinib 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_____________mg 
a-f, (g-p)*, q, r% 
 
 
2 
_____________mg 
 
 
 
3 
_____________mg 
 
 
 
4 
_____________mg 
d 
 
 
5 
_____________mg 
 
 
 
6 
_____________mg 
 
 
 
7 
_____________mg 
 
 
 
8 
_____________mg 
a, d, e 
 
 
9 
_____________mg 
 
 
 
10 
_____________mg 
 
 
 
11 
_____________mg 
d 
 
 
12 
_____________mg 
 
 
 
13 
_____________mg 
 
 
 
14 
_____________mg 
 
 
 
15 
_____________mg 
a, d, e, q 
 
 
16 
_____________mg 
 
 
 
17 
_____________mg 
 
 
 
18 
_____________mg 
d  
 
 
19 
_____________mg 
 
 
 
20 
_____________mg 
 
 
 
21 
_____________mg 
 
 
 
22 
_____________mg 
a, d, e 
 
 
23 
_____________mg 
 
 
 
24 
_____________mg 
 
 
 
25 
_____________mg 
d 
 
 
26 
_____________mg 
 
 
 
27 
_____________mg 
 
 
 
28 
______________mg 
(a, d, e, g-m, r )# 
 
 
29 
#Following the completion of Cycle 1 therapy, perform the disease evaluations a, d, e, g-m, 
and r within 3 days, and prior to the start of the next cycle. 
 
Please continue onto the next cycle no later than 14 days from the end of the previous cycle. 
The next cycle starts on Day 29 or when starting criteria are met (see Section 3.2.5), 
whichever occurs later. 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
 
Page 1 of 3 

  
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Cycle 1 
4.2.2 
Required Observations in Cycle 1 
All baseline observations must be collected prior to starting protocol therapy 
unless otherwise indicated below. All other observations can be collected 
within ± 1 day of their prescribed due date. 
 
*For Day 1 observations, g- p samples may be collected up to 14 days prior 
the start of therapy. 
%JMML panel for mutant allele burden may be collected up to 14 days prior 
to the start of therapy if sent as a correlative biology study on this trial or up 
to 30 days prior to the start of therapy if the same test was ordered as fee-
for-service and processed at UCSF. 
 
a. 
Physical exam (including VS with triplicate BPs), and adverse events 
b. Concomitant medications 
c. 
Performance status 
d. CBC, differential, platelets (see Section 7.2 for details regarding Central Review). 
e. 
Electrolytes including Ca2+, Mg2+, and PO4, BUN and creatinine, creatine kinase 
bilirubin (total and direct), AST, and ALT 
f. 
Dermatologic exam. Performed by the treating physician (or dermatologist, at the 
discretion of the investigator). If possible, the same physician should perform each 
exam throughout the study. Photographs of suspect lesions at baseline are 
recommended. Photographs and/or biopsies of any new or changing lesions 
recommended at subsequent on-study visits 
g. An age-appropriate ophthalmologic examination with a funduscopic evaluation that 
avoids any sedation to be performed by an ophthalmologist at baseline. This 
includes a Snellen examination (if age appropriate as determined by the 
investigator). See Section 4.1.6 
h. Peripheral blood smear (See Section 7.2 for details regarding Central Review) 
i. 
BMA/clot section or biopsy and aspirate smear (see Section 7.2 for details regarding 
Central Review) 
j. 
BMA cytogenetics and FISH (It is recommended that cytogenetics/FISH be 
performed by a COG-approved laboratory) 
k. For patients that consent, collect bone marrow for Genomic, Epigenomic, and 
Functional assays (see Section 7.3.3) 
l. 
Echocardiogram or MUGA 
m. ECG  
n. CSF for cell count, cytospin (lumbar puncture only required if clinical suspicion of 
CNS involvement) 
o. Pregnancy test. Female patients of childbearing potential require a negative pregnancy 
test 
p. Imaging (CT or MRI) of chloroma (if present) 
q. For patients that consent, collect peripheral blood for Pharmacokinetic and 
Pharmacodynamic studies (see Section 7.4.1) 
r. 
Peripheral blood sample for the JMML panel using mutant allele burden (see 
Section 7.3.1) 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
 
 
 
 
Page 2 of 3 

  
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Cycle 1 
 
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
Page 3 of 3 

  
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Cycle 1 
 
 
4.2.3 
Treatment Details: Cycle 1 
 
Trametinib: PO daily 
Days: 1-28 
Age-based Dosing:  
< 6 years of age = 0.032 mg/kg/dose (Maximum dose = 2 mg/day) 
NOTE: All patients less than 26.6 kg must receive oral solution. Patients 
≥ 26.6 kg may receive oral solution OR tablets; however, tablets are 
preferred if possible.  
 
≥ 6 years = 0.025 mg/kg/dose (Maximum dose = 2 mg/day) 
NOTE: All patients less than 35 kg must receive oral solution. Patients ≥ 
35 kg may receive oral solution OR tablets; however, tablets are 
preferred if possible. 
 
Trametinib should be taken by mouth on an empty stomach, at least 1 hour 
before or 2 hours after a meal. Nasogastric or G-tube administration of trametinib 
oral solution is permitted. Do not take a missed dose of trametinib within 
12 hours of the next scheduled dose. If vomiting occurs after taking oral solution 
formulation, the dose should NOT be repeated and the next dose should be 
administered at the regularly scheduled time. If vomiting occurs within 
30 minutes of taking the tablet formulation, the dose of trametinib can be 
repeated once. 
 
See Appendix II for tablet formulation dosing nomogram. Doses of tablet 
formulation should be rounded to the nearest 0.5 mg.  
 
Trametinib is available is 0.05 mg/mL reconstituted oral solution. Doses of 
trametinib oral solution should be rounded to the nearest 0.1 mL (0.005 mg) for 
doses ≤  0.11 mg (in oral syringes ≤ 3 mL), to the nearest 0.2 mL (0.01 mg) for 
doses > 0.11 mg (in oral syringes 5-10 mL volume), and to the nearest 1 mL 
(0.05 mg) for doses > 0.375 mg. Since trametinib is a hazardous agent, it is 
recommended that oral dosing syringes should be filled up to 75% of the 
maximum volume. 
Trametinib is distributed by CTEP, DCTD, NCI. Do not use commercial supply. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Complete the end of cycle disease evaluations within three days of the last dose 
of trametinib on Day 28. 
 
Following completion of Cycle 1, the next cycle starts on Day 29 or when 
starting criteria are met (see Section 3.2.5), whichever occurs later. Please 
continue onto the next cycle no later than 14 days from the end of the previous 
cycle. Results of the JMML mutant allele burden test collected at the end of the 
cycle are not required to proceed to the next cycle. 
 

  
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Cycle 2 
4.3 
Cycle 2 
4.3.1 
Therapy Delivery Map – Cycle 2 
This therapy Delivery Map (TDM) relates to Cycle 2. Each 
cycle lasts 28 days. 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Criteria to start each cycle are listed in Section 3.2.5. Extensive treatment details are in Section 4.3.3. 
This treatment delivery map is two (2) pages in length. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Trametinib 
Do not use 
commercial supply 
PO 
Age-based dosing: 
< 6 years= 0.032 
mg/kg/dose 
> 6 years = 
0.025 mg/kg/dose 
Max dose= 2 mg 
Daily 
See Appendix II for tablet 
formulation dosing nomogram. 
 
Enter Cycle #: _____ 
Ht _________cm 
 
Wt _________kg 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Trametinib 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
______________mg 
a-f 
 
 
2 
_____________mg 
 
 
 
3 
_____________mg 
 
 
 
4 
_____________mg 
 
 
 
5 
_____________mg 
 
 
 
6 
_____________mg 
 
 
 
7 
_____________mg 
 
 
 
8 
_____________mg 
d 
 
 
9 
_____________mg 
 
 
 
10 
_____________mg 
 
 
 
11 
_____________mg 
 
 
 
12 
_____________mg 
 
 
 
13 
_____________mg 
 
 
 
14 
_____________mg 
 
 
 
15 
_____________mg 
a, d, e 
 
 
16 
_____________mg 
 
 
 
17 
_____________mg 
 
 
 
18 
_____________mg 
 
 
 
19 
_____________mg 
 
 
 
20 
_____________mg 
 
 
 
21 
_____________mg 
 
 
 
22 
_____________mg 
d 
 
 
23 
_____________mg 
 
 
 
24 
_____________mg 
 
 
 
25 
_____________mg 
 
 
 
26 
_____________mg 
 
 
 
27 
_____________mg 
 
 
 
28 
______________mg 
(d, e, g-l)# 
 
 
29 
#Following the completion of Cycle 2 therapy, complete observations d, e, g-l within 3 days, 
and prior to the start of the next cycle. 
 
The next cycle starts on Day 29 or when starting criteria are met (see Section 3.2.5), whichever 
occurs later. Please continue onto the next cycle no later than 14 days from the end of the 
previous cycle.  
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
Page 1 of 2 

  
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Cycle 2 
4.3.2 
Required Observations in Cycle 2 
 
 
a. 
Physical exam (including VS) and adverse events 
b. Concomitant medications 
c. 
Performance status 
d. CBC, differential, platelets (see Section 7.2 for details regarding Central Review) 
e. 
Electrolytes including Ca2+, Mg2+, and PO4, BUN and creatinine, creatine kinase, 
Total and direct bilirubin, AST, and ALT 
f. 
Dermatologic exam. Performed by the investigator (or dermatologist, at the 
discretion of the investigator). If possible, the same physician should perform each 
exam throughout the study. Photographs of suspect lesions at baseline are 
recommended with photographs and/or biopsies of any new or changing lesions 
recommended at subsequent on-study visits 
g. Peripheral blood smear (see Section 7.2 for details regarding Central Review) 
h. BMA/clot section or biopsy and aspirate smear (see Section 7.2 for details 
regarding Central Review) 
i. 
BMA cytogenetics and FISH (It is recommended that cytogenetics/FISH be 
performed by a COG-approved laboratory) 
j. 
For patients that consent, collect bone marrow for Genomic, Epigenomic, and 
Functional assays (see Section 7.3.3) 
k. Echocardiogram or MUGA 
l. 
ECG 
 
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) 
 
 
 
Page 2 of 2 

  
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Cycle 2 
 
4.3.3 
Treatment Details: Cycle 2 
 
Trametinib: PO daily 
Days: 1-28 
Age-based Dosing:  
< 6 years of age = 0.032 mg/kg/dose  (Maximum dose = 2 mg/day) 
NOTE: All patients less than 26.6 kg must receive oral solution. Patients 
≥ 26.6 kg may receive oral solution OR tablets; however, tablets are 
preferred if possible.  
 
> 6 years of age = 0.025 mg/kg/dose (Maximum dose = 2 mg/day) 
NOTE: All patients less than 35 kg must receive oral solution. Patients ≥ 
35 kg may receive oral solution OR tablets; however, tablets are 
preferred if possible. 
 
Trametinib should be taken by mouth on an empty stomach, at least 1 hour 
before or 2 hours after a meal. Nasogastric or G-tube administration of trametinib 
oral solution is permitted. Do not take a missed dose of trametinib within 
12 hours of the next scheduled dose. If vomiting occurs after taking oral solution 
formulation, the dose should NOT be repeated and the next dose should be 
administered at the regularly scheduled time. If vomiting occurs within 
30 minutes of taking the tablet formulation, the dose of trametinib can be 
repeated once. 
 
See Appendix II for tablet formulation dosing nomogram. Doses of tablet 
formulation should be rounded to the nearest 0.5 mg.  
 
Trametinib is available is 0.05 mg/mL reconstituted oral solution. Doses of 
trametinib oral solution should be rounded to the nearest 0.1 mL (0.005 mg) for 
doses ≤  0.11 mg (in oral syringes ≤ 3 mL), to the nearest 0.2 mL (0.01 mg) for 
doses > 0.11 mg (in oral syringes 5-10 mL volume), and to the nearest 1 mL 
(0.05 mg) for doses > 0.375 mg. Since trametinib is a hazardous agent, it is 
recommended that oral dosing syringes should be filled up to 75% of the 
maximum volume. 
Trametinib is distributed by CTEP, DCTD, NCI. Do not use commercial supply. 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Complete the end of cycle disease evaluations within three days of the last dose 
of trametinib on Day 28. 
 
Following completion of Cycle 2, the next cycle starts on Day 29 or when 
starting criteria are met (see Section 3.2.5), whichever occurs later. Please 
continue onto the next cycle no later than 14 days from the end of the previous 
cycle. 
 
 

  
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All Subsequent Cycles 
4.4 
Cycle 3 and All Subsequent Cycles 
4.4.1 
Therapy Delivery Map – All Subsequent Cycles 
This therapy Delivery Map (TDM) relates to all subsequent 
cycles. Each cycle lasts 28 days. Use a copy of this page once 
for each cycle (please note cycle number below). 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Criteria to start each cycle are listed in Section 3.2.5. Treatment details are in Section 4.4.3. 
This therapy delivery map is two (2) pages in length. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Trametinib 
Do not use 
commercial supply 
PO 
Age-based dosing: 
< 6 years= 0.032 
mg/kg/dose 
> 6 years = 
0.025 mg/kg/dose 
Max dose= 2 mg 
Daily 
See Appendix II for tablet 
formulation dosing 
nomogram. 
 
Enter Cycle #: _____ 
Ht _________cm 
 
Wt _________kg 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Trametinib 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
______________mg 
a-g 
 
 
2 
_____________mg 
 
 
 
3 
_____________mg 
 
 
 
4 
_____________mg 
 
 
 
5 
_____________mg 
 
 
 
6 
_____________mg 
 
 
 
7 
_____________mg 
 
 
 
8 
_____________mg 
 
 
 
9 
_____________mg 
 
 
 
10 
_____________mg 
 
 
 
11 
_____________mg 
 
 
 
12 
_____________mg 
 
 
 
13 
_____________mg 
 
 
 
14 
_____________mg 
 
 
 
15 
_____________mg 
 
 
 
16 
_____________mg 
 
 
 
17 
_____________mg 
 
 
 
18 
_____________mg 
 
 
 
19 
_____________mg 
 
 
 
20 
_____________mg 
 
 
 
21 
_____________mg 
 
 
 
22 
_____________mg 
 
 
 
23 
_____________mg 
 
 
 
24 
_____________mg 
 
 
 
25 
_____________mg 
 
 
 
26 
_____________mg 
 
 
 
27 
_____________mg 
 
 
 
28 
_____________mg 
h, i#, j, k 
 
 
29 
#See note on page 2 of TDM regarding observation i. 
 
Following completion of the cycle, the next cycle starts on Day 29 or when starting criteria are 
met (see Section 3.2.5), whichever occurs later. Please continue onto the next cycle no later 
than 14 days from the end of the previous cycle. 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
Page 1 of 2 

  
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All Subsequent Cycles 
 
 
4.4.2 
Required Observations in All Subsequent Cycles 
 
 
Collect observations beginning in Cycle 3. 
 
a. 
Physical exam (including VS) and adverse events 
b. Concomitant medications 
c. 
Performance status 
d. CBC, differential, platelets 
e. 
Electrolytes including Ca2+, Mg2+, and PO4, BUN and creatinine, creatinine kinase, 
Total and direct bilirubin, AST, and ALT 
f. 
Dermatologic exam. Performed by the investigator (or dermatologist, at the 
discretion of the investigator). If possible, the same physician should perform each 
exam throughout the study. Photographs of suspect lesions at baseline are 
recommended with photographs and/or biopsies of any new or changing lesions 
recommended at subsequent on-study visits 
g. Collect a peripheral blood sample for the JMML panel using mutant allele burden. 
(see Section 7.3.1) 
h. Complete an age-appropriate ophthalmologic examination with a funduscopic 
evaluation that avoids any sedation to be performed by an ophthalmologist at the 
end of Cycle 4 and every 12 weeks after while on study. Snellen examination (if 
age appropriate as determined by the investigator). See Section 4.1.6. 
i. 
Bone marrow; to be collected on every odd numbered cycle only (i.e. cycle 3, 5, 7 
etc.). Note: Only obtain if the bone marrow blast percentage and karyotype are the 
only remaining variables required to determine response classification as 
documented in Appendix III Tables 1 and 2 
j. 
ECG to be collected every 3 cycles after Cycle 2 (i.e. cycle 5, cycle 8, cycle 11) 
k. ECHO/MUGA: every 3 cycles after Cycle 2 (i.e. cycle 5, cycle 8, cycle 11) 
 
 
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) 
 
 
Page 2 of 2 

  
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Version Date: 07/22/2022 
All Subsequent Cycles 
 
 
4.4.3 
Treatment Details: All Subsequent Cycles 
 
Trametinib: PO daily 
Days: 1-28 
Age-based Dosing:  
< 6 years of age = 0.032 mg/kg/dose (Maximum dose = 2 mg/day) 
NOTE: All patients less than 26.6 kg must receive oral solution. Patients 
≥ 26.6 kg may receive oral solution OR tablets; however, tablets are 
preferred if possible.  
 
≥ 6 years of age = 0.025 mg/kg/dose (Maximum dose = 2 mg/day) 
NOTE: All patients less than 35 kg must receive oral solution. Patients ≥ 
35 kg may receive oral solution OR tablets; however, tablets are 
preferred if possible. 
 
Trametinib should be taken by mouth on an empty stomach, at least 1 hour 
before or 2 hours after a meal. Nasogastric or G-tube administration of trametinib 
oral solution is permitted. Do not take a missed dose of trametinib within 
12 hours of the next scheduled dose. If vomiting occurs after taking oral solution 
formulation, the dose should NOT be repeated and the next dose should be 
administered at the regularly scheduled time. If vomiting occurs within 
30 minutes of taking the tablet formulation, the dose of trametinib can be 
repeated once. 
 
See Appendix II for tablet formulation dosing nomogram. Doses of tablet 
formulation should be rounded to the nearest 0.5 mg.  
 
Trametinib is available is 0.05 mg/mL reconstituted oral solution. Doses of 
trametinib oral solution should be rounded to the nearest 0.1 mL (0.005 mg) for 
doses ≤  0.11 mg (in oral syringes ≤ 3 mL), to the nearest 0.2 mL (0.01 mg) for 
doses > 0.11 mg (in oral syringes 5-10 mL volume), and to the nearest 1 mL 
(0.05 mg) for doses > 0.375 mg. Since trametinib is a hazardous agent, it is 
recommended that oral dosing syringes should be filled up to 75% of the 
maximum volume. 
Trametinib is distributed by CTEP, DCTD, NCI. Do not use commercial supply. 
See Section 5.0 for Dose Modifications based on Toxicities. 
 
Complete the end of cycle disease evaluations within three days of the last dose 
of trametinib on Day 28. 
 
Following completion of the cycle, the next cycle starts on Day 29 or when 
starting criteria are met (see Section 3.2.5), whichever occurs later. Please 
continue onto the next cycle no later than 14 days from the end of the previous 
cycle. Results of the JMML mutant allele burden test collected at the end of odd 
numbered cycle are not required to proceed to the next cycle. 
 
 

  
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5.0 
DEFINITIONS AND DOSE MODIFICATION FOR TOXICITY 
 
All dose modifications should be based on the worst preceding toxicity. 
 
5.1 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or 
definitely attributable to trametinib. 
 
Dose limiting hematological and non-hematological toxicities are defined differently.   
 
5.1.1 
Non-Hematological Dose-Limiting Toxicity 
• 
See Section 5.4 for management guidelines for toxicities of special interest, 
note that dose modification or discontinuation of trametinib for toxicity is 
considered a dose limiting toxicity. 
• 
Any Grade 4 non-hematological toxicity with specific exclusion of: 
- 
Grade 4 fever/pyrexia that resolves to Grade < 2 within 72 hours with 
supportive care (anti-pyretics) 
• 
Dose-limiting hypertension will be considered as the following: 
- 
Grade 4 hypertension, 
- 
A blood pressure > 25 mm Hg above the 95th percentile for age, height, 
and gender, confirmed by repeated measurement 
Note: if elevated, take 3 serial blood pressure readings from the same 
extremity with the patient in the same position, separated by at least 5 
minutes. Avoid using the lower extremity if possible. Use the mean 
average of the 3 measurements. 
• 
Any Grade 3 non-hematological toxicity with the specific exception of: 
- 
Grade 3 nausea and vomiting of less < 3 days duration 
- 
Grade 3 fever or infection < 7 days duration. 
- 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia and/or 
hypomagnesemia responsive to oral supplementation within 7 days 
• 
Grade 2 allergic reactions that necessitate discontinuation of study drug will 
not be considered a dose-limiting toxicity 
• 
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 
• 
Grade 2 left ventricular ejection fraction disease 
• 
Grade 2 cardiac valvular toxicity (mitral/aortic/tricuspid) 
• 
Grade 2 pneumonitis 
• 
Treatment interruption longer than 14 days due to delayed recovery from 
toxicity will be dose limiting 
 
5.1.2 
Hematological dose limiting toxicity 
a) Hematologic DLT will be defined as failure to recover a peripheral ANC > 
500/µL and platelets > 20,000/µL by 42 days after the first treatment day, not 
due to malignant infiltration. 
 
Note: Grade 4 febrile neutropenia will not be considered a dose-limiting toxicity. 

  
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5.2 
Dose Modifications for Hematological Toxicity 
 
There are no modifications for patients with persistent JMML who have never 
experienced recovery of normal hematologic parameters. If a patient does have recovery 
of normal hematologic parameters and then experiences Grade 4 neutropenia or Grade 4 
thrombocytopenia, the treatment will be held. Counts should be checked twice weekly 
during this time. If the toxicity resolves to peripheral absolute neutrophil count (ANC) ≥ 
1000/µL and platelet count ≥ 75,000/µL within 14 days of drug discontinuation, the 
patient may resume treatment with 25% dose reduction in patients receiving oral solution 
or the specified dose reduction in patients receiving tablets (See Appendix II). Doses 
reduced for toxicity will not be re-escalated, even if there is minimal or no toxicity with 
the reduced dose. 
 
If toxicity does not resolve to peripheral absolute neutrophil count (ANC) ≥ 1000/µL and 
platelet count ≥ 75,000/µL within 14 days of drug discontinuation, the patient must be 
removed from protocol therapy. 
 
If dose-limiting toxicity recurs in a patient who has resumed treatment at the reduced 
dose, the patient must be removed from protocol therapy. 
 
5.3 
Dose Modifications for Non-Hematological Toxicity 
 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.1.1, 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 with 25% dose reduction in patients receiving oral solution or the specified 
dose reduction in patients receiving tablets (See Appendix II). Doses reduced for toxicity 
will not be re-escalated, even if there is minimal or no toxicity with the reduced dose. 
 
If toxicity does not resolve to meet eligibility or baseline parameters within 14 days of 
drug discontinuation, the patient must be removed from protocol therapy. 
 
If any dose-limiting toxicity recurs in a patient who has resumed treatment at the reduced 
dose level, the patient must be removed from protocol therapy. 
 
5.4 
Guidelines and Dose Modifications for Trametinib Events of Special Interest 
 
Dose modification and adverse event (AE) guidelines are outlined in the sections below 
for AEs that are deemed possibly related to trametinib: 
 
• 
AEs not otherwise specified 
• 
Rash 
• 
Visual changes 
• 
Diarrhea  
• 
Liver chemistry elevation 

  
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• 
Ejection fraction changes 
• 
Hypertension 
• 
Prolonged QTc 
• 
Pneumonitis 
 
 
5.4.1 
Trametinib Dose Modification for Toxicities Not Specified in Subsequent 
Sections: 
 
Trametinib Treatment Modification for Clinically Significant Toxicities Deemed Related to Trametinib 
(This section is not for specific AEs such as hypertension, rash, ejection fraction changes, pneumonitis, diarrhea, 
liver chemistry, QTc prolongation, or visual changes.  Refer to other sections for these specific AEs). 
CTCAE v5 Grade 
Dose Modification 
Grade 1 and tolerable 
Grade 2  
• Continue trametinib at current dose level 
• Monitor closely 
• Provide supportive care according to institutional standards 
Intolerable Grade 2 
and Grade 3 
• Interrupt treatment until resolution to Grade 1 or baseline 
• Upon resolution to baseline or Grade 1, restart with 25% dose reduction in patients 
receiving oral solution or the specified dose reduction in patients receiving tablets (See 
Appendix II) 
• If the intolerable Grade 2 or Grade 3 toxicity recurs, permanently discontinue trametinib 
Grade 4 
• Interrupt treatment 
• Monitor closely 
• Provide supportive care according to institutional standards 
• If event resolves to Grade 1 or baseline discuss potential continuation of trametinib with 
study chair; if continuation of treatment agreed, then restart trametinib with 25% dose 
reduction in patients receiving oral solution or at specified dose reduction in patients 
receiving tablets (See Appendix II) 
• If event does not resolve, permanently discontinue trametinib 
 
5.4.2 
Trametinib Dose Modifications for Rash: 
Dermatologic complications are frequent adverse events in subjects receiving 
trametinib and a proactive approach should be taken. All subjects should avoid 
unnecessary sunlight and use sunscreen whenever there is possible exposure. See 
Section 4.1.5 for prophylactic treatment for prevention of dermatologic toxicity 
 
Reactive Management: 
It is strongly recommended that subjects who develop rash/skin toxicities receive 
evaluations by a dermatologist for management of the specific side effect. 
 
For pruritic lesions, the use of cool compresses and oral antihistamine agents 
may be helpful. 
 
For fissuring, the use of Monsel’s solution, silver nitrate or zinc oxide cream is 
advised. 
 
For desquamation, thick emollients and mild soap are recommended. 
 

  
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For paronychia, antiseptic bath and local potent corticosteroids in addition to oral 
antibiotics are recommended, and if no improvement is seen, a dermatology or 
surgery consultation is recommended. 
 
For infected lesions, bacterial and fungal culturing followed by the appropriate 
culture-driven systemic or topical antibiotics is indicated. 
 
 
 
Management and Trametinib Dose Modification for Rash 
Event 
CTCAE Grade 
Management Guideline 
Action and Dose Modification 
Grade 1 
Initiate prophylactic and symptomatic treatment 
measures.a Use moderate strength topical 
steroid.b Reassess after 2 weeks. 
Continue trametinib. 
Grade 2 
Initiate prophylactic and symptomatic treatment 
measures.a Use moderate strength topical 
steroid.b Reassess after 2 weeks. 
Continue trametinib 
If rash does not recover to ≤ Grade 
1 within 2 weeks, interrupt 
trametinib until recovery to ≤ 
Grade 1, restart trametinib at 
reduced dose (25% dose reduction 
in patients receiving oral solution 
or at specified dose reduction in 
patients receiving tablets (See 
Appendix II)) 
Grade ≥3 
Use moderate strength topical steroidsb (PLUS) 
methylprednisolone dose pack. 
Consult dermatologist. 
Interrupt trametinib until rash 
recovers to Grade ≤1. 
Restart with trametinib at reduced 
dose (25% dose reduction in 
patients receiving oral solution or 
at specified dose reduction in 
patients receiving tablets (See 
Appendix II) 
If no recovery to Grade ≤ 2 within 
2 weeks, permanently discontinue 
trametinib. 
a. Rash prophylaxis is recommended for the first 6 weeks of study treatment 
b. Moderate-strength topical steroids hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream 
c. Notify the study chair. 
 
5.4.3 
Trametinib Dose Modifications for Visual Changes (Eye Disorders) 
Trametinib is known to be associated with visual adverse events. An age-
appropriate ophthalmologic examination should be performed by an 
ophthalmologist (without sedation) at screening, may be performed without 
dilation at discretion of ophthalmologist and can be accomplished using imaging 
with a non-mydriatic fundus camera. During the study, ophthalmologic exams 
will be repeated by an ophthalmologist at the end of cycle 1 and every 12 weeks 
thereafter. If the child or parent report visual problems they will be referred 
promptly for an ophthalmology assessment. 
 

  
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If visual changes are clearly unrelated to study treatment (e.g., allergic 
conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic 
examination. Special attention will be given to retinal findings (e.g., retinal 
pigment epithelial detachment (RPED) or retinovascular abnormalities (i.e., 
branch or central retinal vein occlusions [RVO]). For subjects with clinical 
suspicion of RPED or RVO, fundus photography, and optical coherence 
tomography will be performed. 
 
The ophthalmology exam can include best corrected visual acuity, visual field 
examination, tonometry, slit lamp biomicroscopic examination, and indirect 
ophthalmoscopy as indicated. Optical coherence tomography will be performed if 
retinal abnormalities are suspected. Other types of ancillary testing including 
visual field examination, fundus photography, and fluorescein angiography may 
also be indicated as determined by clinical exam. 
 
Guidelines regarding event management and dose reduction for visual changes 
considered to be related to study treatment are provided in the table below. 
 
Management and Trametinib Dose Modification for Visual Changes 
and/or Ophthalmic Examination Findings 
Event 
CTCAE Grade 
Management Guideline 
Dose Modification 
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only * 
• Consult ophthalmologist within 
7 days of onset. 
• If dilated fundus examination cannot be performed 
within 7 days of onset, hold trametinib until RPED and 
RVO can be excluded by retina 
specialist/ophthalmologist. 
• If RPED and RVO excluded, continue/or restart 
trametinib at same dose. 
• If RPED suspected/diagnosed: See RPED dose 
modification table below (following this table); report 
as SAE. 
• If RVO diagnosed:  Permanently discontinue 
trametinib and report as SAE. 
Symptomatic 
with 
mild 
to 
moderate 
decrease 
in 
visual 
acuity; 
limiting 
instrumental 
ADL 
• 
Consult ophthalmologist 
immediately. 
• Hold trametinib 
• If RPED or RVO excluded, restart trametinib at same 
dose. 
• If RPED diagnosed: See RPED dose modification table 
below; report as SAE. 
• If RVO:  Permanently discontinue trametinib and 
report as SAE. 
Sight-
threatening 
consequences; 
urgent 
intervention 
indicated; 
best 
corrected visual 
acuity of 20/200 
or worse in the 
affected eye 
• 
Consult ophthalmologist 
immediately. 
• 
Report as SAE. 
• Hold Trametinib 
• If RPED/RVO excluded, may restart trametinib at same 
or reduced dose after discussion with the study chair. 
• If RVO or RPED, permanently discontinue 
trametinib. 

  
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Management and Trametinib Dose Modification for Visual Changes 
and/or Ophthalmic Examination Findings 
Event 
CTCAE Grade 
Management Guideline 
Dose Modification 
Abbreviations: RPED = retinal pigment epithelial detachments; RVO = retinal vein occlusion; SAE = serious 
adverse event 
*If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required. 
 
 
Trametinib Dose Modification for RPED 
Event 
CTCAE Grade 
Action and Dose Modification 
RPED (Asymptomatic; clinical or 
diagnostic observations only) 
• Continue treatment with retinal evaluation monthly until resolution. If 
RPED worsens, follow instructions below. 
RPED (Symptomatic with mild to 
moderate decrease in visual acuity; 
limiting instrumental ADL) 
• Interrupt trametinib. 
• Retinal evaluation monthly. 
• If improved to ≤ Grade 1, restart trametinib with a reduced dose (25% 
dose reduction in patients receiving oral solution or at specified dose 
reduction in patients receiving tablets (See  Appendix II) 
• If no recovery within 4 weeks permanently discontinue trametinib 
 
5.4.4. Trametinib Dose Modification for Diarrhea 
Etiology and attribution. Consider evaluation for an alternative etiology of 
diarrhea as clinically indicated. These include medications (e.g., stool softeners, 
laxatives, antacids, etc.), infection by C. difficile, partial bowel obstruction, 
malabsorption/lactose intolerance, fecal impaction, or diets high in fiber or 
lactose. 
 
For Grade ≤ 2 diarrhea: 
Dietary modifications may include: stop all lactose-containing products and eat 
small meals. A bananas, rice, apples, toast (BRAT) diet can be helpful. 
 
Encourage oral hydration according to institutional weight oral hydration 
guidelines as clinically appropriate. 
 
For all subjects consider administration of loperamide (Table 5.4.4.1) with dosing 
per institutional guidelines or as suggested below. Continuation of loperamide is 
suggested until the subject is diarrhea-free for at least 12 hr. 
 
If diarrhea resolves to Grade ≤ 1 within 72 hr of anti-diarrheal measures or 
supportive care measures, continue study treatment without interruption or dose 
reduction. 
 
If Grade 2 diarrhea persists after 72 hr total treatment with loperamide or 
supportive measures in children < 2 years, hold study treatment and consider start 
of second-line agents (octreotide) as clinically indicated. If diarrhea resolves to 
Grade ≤ 1 or baseline within 7 days resume study treatment with dose reduction. If 
Grade > 2 diarrhea does not resolve in ≤ 7 days without study treatment, 
discontinue protocol therapy. 
 

  
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Table 5.4.4.1 Loperamide Dosing 
Age  
Weight 
(kg) 
Initial Dose (start after first 
loose bowel movement) 
Subsequent Doses 
Maximum 
daily dose 
> 1 mo to  
≤ 12 years 
<13 
0.5 mg 
0.5 mg every 3 hr while 
awake, every 4 hr during 
sleep  
4 mg/day 
  
13 to < 20 
 
1 mg 
1 mg every 4 hr  
6 mg/day 
 
20 to < 30 
2 mg 
1 mg every 3 hr while awake, 
every 4 hr during sleep  
8 mg/day 
  
30 to < 43 
 
2 mg 
 
1 mg every 2 hr while awake, 
every 4 hr during sleep  
12 mg/day 
≥ 13 years 
≥ 43 
 
4 mg 
 
2 mg every 2 hr while awake, 
every 4 hr during sleep 
16 mg/day 
 
For Grade 3 or 4 diarrhea: 
Hold study treatment until symptoms resolve to ≤ Grade 1 or baseline then may 
resume study treatment with a dose reduction (25% dose reduction in patients 
receiving oral solution or specified dose reduction in patients receiving tablets 
(See Appendix II). 
 
If loperamide has not been initiated, initiate loperamide immediately using 
institutional or protocol guidelines for dosing. 
 
For dehydration, use intravenous fluids as appropriate; if severe dehydration, 
consider administration of octreotide. 
 
5.4.5. Trametinib Dose Modification for Liver Chemistry Changes: 
Liver chemistry threshold stopping criteria have been designed to assure subject 
safety and to evaluate liver event etiology during administration of study 
treatment(s) and the follow-up period. Upper limit of normal (ULN) for ALT in 
this study will be 45 U/L and ULN for AST is 50 U/L. Adverse event grades will 
be based on increases above the upper limit of normal, regardless of the subject’s 
baseline. See Appendix X for toxicity grading table. Study treatment(s) will be 
stopped if any of the following liver chemistry stopping criteria is/are met: 
 
1. ALT ≥3 times upper limit of normal (ULN) and bilirubin ≥2 times ULN 
(or ALT ≥3 times ULN and international normalization ratio [INR] >1.5) 
 
i. NOTE: Serum bilirubin fractionation should be performed if testing is available. 
If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a 
measurement of direct bilirubin, which would suggest liver injury). 
 
2. ALT ≥5 times ULN. 
 
3. ALT ≥3 times ULN if associated with the appearance or worsening of rash 
or hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, or jaundice) or hypersensitivity (such as fever, rash or 
eosinophilia). 
 

  
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4. ALT ≥3 times ULN persists for ≥4 weeks. 
 
5. ALT ≥3 times ULN and cannot be monitored weekly for 4 weeks. 
 
Subjects with ALT ≥3 times ULN and <5 times ULN and bilirubin <2 times ULN, 
who do not exhibit hepatitis symptoms or rash, can continue study treatment(s) as 
long as they can be monitored weekly for 4 weeks. See following section for 
details on weekly follow-up procedures for these subjects. 
 
5.4.5.1.  Liver Chemistry Follow-up Procedures 
The procedures listed below are to be followed if a subject meets the liver 
chemistry stopping criteria 1 through 5 defined in Section 5.4.5: 
 
• 
Immediately discontinue study treatment. 
• 
Notify the study chair within 24 hr of learning of the abnormality 
to confirm the subject’s study treatment(s) cessation and follow-
up. 
• 
Complete the “Safety Follow-Up Procedures” listed below. 
• 
If the event also meets the criteria of a SAE (see Section 11.2), 
the SAE data collection tool will be completed separately with 
the relevant details. 
• 
Upon completion of the safety follow-up permanently withdraw 
the subject from the study and do not re-challenge with study 
treatment(s). 
 
Safety Follow-Up Procedures for subjects with ALT ≥3 times ULN: 
 
• 
Monitor subjects weekly until liver chemistries (ALT, aspartate 
aminotransferase [AST], alkaline phosphatase [ALP], and 
bilirubin) resolve, stabilize or return to within baseline values. 
 
Safety Follow-Up Procedures for subjects meeting stopping criterion 1 
(ALT ≥3 times ULN and bilirubin ≥2 times ULN [or ALT ≥3 times ULN 
and INR >1.5]): 
 
• 
This event is considered an SAE (see Section 11.2). Serum 
bilirubin fractionation should be performed if testing is available. 
If fractionation is unavailable, urinary bilirubin is to be measured 
via dipstick (a measurement of direct bilirubin, which would 
suggest liver injury). 
• 
Make every reasonable attempt to have subjects return to the 
clinic within 24 hr for repeat liver chemistries, additional testing, 
and close monitoring (with specialist or hepatology consultation 
recommended). 
• 
Monitor subjects twice weekly until liver chemistries (ALT, 
AST, ALP, and bilirubin) resolve, stabilize or return to within 
baseline values. 
• 
In addition, every attempt should be made to carry out the liver 
event follow-up assessments described in Section 5.4.5.2. 
 

  
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5.4.5.2. Liver Chemistry Testing Procedures 
For subjects meeting any of the liver chemistry stopping criteria in 
Section 5.4.5 make every attempt to carry out the liver event follow-up 
assessments described below: 
• 
Viral hepatitis serology, including: 
▪ 
Hepatitis A IgM antibody 
▪ 
Hepatitis B surface antigen and Hepatitis B Core Antibody 
(IgM) 
▪ 
Hepatitis C RNA 
▪ 
Cytomegalovirus IgM antibody 
▪ 
Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, then obtain heterophile antibody or monospot 
testing) 
• 
Serum creatine kinase (CK) and lactate dehydrogenase (LDH). 
Fractionate bilirubin, if total bilirubin ≥2 X upper limit of normal 
(ULN). Obtain a complete blood count (CBC) with differential 
to assess eosinophilia. 
• 
Record the appearance or worsening of clinical symptoms 
indicative of hepatitis or hypersensitivity, such as fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash or eosinophilia as relevant on the AE CRF. 
• 
Record the use of concomitant medications, including 
acetaminophen, herbal remedies or any other over the counter 
(OTC) medications, or any putative hepatotoxins, on the 
concomitant medication CRF. 
 
Every attempt should be made to obtain the following assessments for 
subjects with ALT ≥3 X ULN and bilirubin ≥2X ULN (>35% direct). 
These assessments are optional for other abnormal liver chemistries: 
 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 
anti-liver kidney microsomal antibodies. 
• 
Liver imaging (ultrasound, MRI or CT) to evaluate liver disease. 
• 
Serum acetaminophen adduct High Performance Liquid 
Chromatography 
(HPLC) 
assay 
(quantifies 
potential 
acetaminophen contribution to liver injury in subjects with 
definite or likely acetaminophen use in the preceding week. 
 
5.4.6.   Trametinib Dose Modification for Pneumonitis 
Pneumonitis has been observed in patients receiving trametinib.  To reduce the 
risk of pneumonitis, patients will be monitored closely for symptoms and 
evaluated with imaging and functional tests.  Dose modification and supportive 
care guidelines for pneumonitis are described in the tables below. 

  
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Pneumonitis Guidelines for Trametinib Monotherapy 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• 
CT scan (high-resolution with lung windows) 
recommended. 
• 
Work-up for infection  
• 
Monitoring of oxygenation via pulse-oximetry 
recommended 
• 
Consultation with pulmonologist recommended 
• 
Continue trametinib at current 
dose 
Grade 2 
• 
CT scan (high-resolution with lung windows) 
recommended. 
• 
Work-up for infection  
• 
Consult pulmonologist 
• 
Pulmonary function tests – if < normal, repeat 
every 8 weeks until ≥ normal 
• 
Bronchoscopy with biopsy and/or BAL 
recommended 
• 
Symptomatic therapy including corticosteroids if 
clinically indicated 
• 
Interrupt trametinib until recovery 
to Grade ≤1 
• 
Restart treatment with trametinib 
dose reduction (25% dose 
reduction in patients receiving 
oral solution or specified dose 
reduction in patients receiving 
tablets (See Appendix II)) 
• 
Escalation to previous dose level 
after 4 weeks may be considered 
after consultation with the study 
chair  
• 
If no recovery to Grade ≤1 within 
4 weeks, permanently 
discontinue trametinib 
Grade 3 
• 
Same as Grade 2 
• 
Interrupt trametinib until recovery 
to Grade ≤1 
• 
After consultation with the study 
chair, trametinib may be restarted 
with a dose reduction (25% dose 
reduction in patients receiving 
oral solution or specified dose 
reduction in patients receiving 
tablets (See Appendix II)) 
• 
If no recovery to Grade ≤1 within 
4 weeks, permanently 
discontinue trametinib 
Grade 4 
• 
Same as Grade 2 
• 
Permanently discontinue 
trametinib 
 
5.4.7  Trametinib Dose Modification for Reduced Left Ventricular Ejection Fraction 
Decreases of the left ventricular ejection fraction (LVEF) have been observed in 
patients receiving trametinib.  Therefore, ECHO/MUGAs must be performed at 
baseline, at the end of cycle 1 and at the end of cycle 2. Any ECHO/MUGAs 
thereafter should be done only if clinically indicated. The same procedure (either 
ECHO or MUGA, although ECHO is preferred) should be performed at baseline 
and at follow-up visit(s). 

  
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Trametinib Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose 
Modification 
Asymptomatic 
Absolute 
decrease 
of 
>10% in LVEF compared 
to baseline and ejection 
fraction 
below 
the 
institution’s LLN. 
• Interrupt trametinib and repeat ECHO/MUGA 
within 2 weeks.a 
• If the LVEF recovers within 4 weeks 
(defined as LVEF ≥LLN and absolute 
decrease ≤10% compared to baseline): 
• 
Consult with the study chair and 
request approval for restart. 
• 
Restart treatment with trametinib at 
reduced dose by one dose level.b 
• 
Repeat ECHO/MUGA 2, 4, 8, and 12 
weeks after re-start; continue in 
intervals of 12 weeks thereafter. 
• If LVEF does not recover within 4 weeks: 
• Consult with cardiologist. 
• Permanently discontinue trametinib. 
• Report as SAE 
• Repeat ECHO/MUGA after 2, 4, 8, 12, and 
16 weeks or until resolution. 
• Consult with the study chair.c 
Symptomaticb 
 
• 
Grade 3:  resting 
LVEF 39-20% or≥20% 
absolute reduction from 
baseline 
• 
Grade 4:  Resting 
LVEF ≤20%. 
• 
Permanently discontinue trametinib. 
• 
Report as SAE. 
• 
Consult with cardiologist. 
• 
Repeat ECHO/MUGA after 2, 4, 8, 12, 
and 16 weeks or until resolution. 
a If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later. 
b Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 weeks after 
restarting of trametinib.  Approval from the study chair is required. 
c Symptoms may include:  dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema. 
 

  
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5.4.8.  Trametinib Dose Modification for QTc Prolongation 
 
Trametinib Withholding and Stopping Criteria for QTc Prolongation 
QTc Prolongationa 
Action and Dose Modification 
• 
QTcB >500 msec 
 
• Interrupt study treatment until QTcB prolongation resolves to Grade 1 or 
baseline. 
• Test serum potassium, calcium, phosphorus, and magnesium.  If 
abnormal, correct per routine clinical practice to within normal limits. 
• Review concomitant medication usage for a prolonged QTc. 
• Restart at current dose.b 
• If the event recurs after restarting, permanently discontinue study 
treatment. 
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using Bazett’s formula 
a Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT interval, 
obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to 
determine if study treatments should be interrupted or discontinued. 
b if the QTc prolongation resolves to Grade 1 or baseline, the subject may resume study treatment if the 
investigator determines that the subject will benefit from further treatment. 
 
5.4.9.  Trametinib Dose Modification for Hypertension 
Increases in blood pressure (BP) have been observed in patients receiving 
trametinib. 
 
Should initiation of anti-hypertensive therapy be required, single agent therapy 
(commonly including the calcium channel blockers amlodipine or nifedipine) 
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 
Appendix IX. 
 
If patient is already on an anti-hypertensive medication at study enrollment, then 
their anti-hypertensive therapy should be adjusted (by either adjusting the dose of 
their current anti-hypertensive medication or by adding another anti-hypertensive 
agent) according to the algorithm in Section 5.4.9.3. 
 
5.4.9.1. Baseline Blood Pressure 
 
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: 
• 
Obtain 3 serial blood pressures from the same extremity with the 
patient in the same position that are separated by at least 5 minutes. 
Avoid using the lower extremity if possible.    
• 
The baseline BP is the mean average of the systolic and the mean 
average of the diastolic measurements. 

  
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5.4.9.2 Management of Hypertension 
• 
The upper limit of normal (ULN) is defined as a BP equal to the 95th 
percentile for age, height, and gender. (Appendix IX) 
• 
The NCI CTCAE 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. Patients with an elevated BP should have BP 
measurements performed at least twice weekly until BP is ≤ ULN. 
• 
The algorithm below will be used to manage trametinib 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. 
 
5.4.9.3 Algorithm For Management of Trametinib-Related Hypertension 
 
Elevations in BP are based on systolic or diastolic pressures.  
†Elevated blood pressure 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 is a BP equal to the 95th percentile for age, height, and gender-appropriate normal values (Appendix IX). 
*If BP > 25 mm Hg above ULN for age (verified) or Grade 4 hypertension at any time, hold drug. Study drug should also be held 
for BP ≥ 25 mm Hg above the ULN for 14 days or ≥ 35 mm Hg above baseline for > 14 days. Antihypertensive agents can be 
used to control hypertension as clinically indicated after study drug is held. 
^Antihypertensive therapy should be prescribed as clinically indicated, including use of multiple anti-hypertensive agents.  
#Baseline BP as defined in Section 5.4.9.1 
 
Arm 1 of algorithm: 
• 
If blood pressure (BP) ≤ 95%ile for age, height, and gender: continue trametinib at the same dose. 

  
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Arm 2 of algorithm: 
• 
If BP ≤ 10 mm Hg above the ULN: continue trametinib at the same dose and recheck the BP 
within 72 hours. 
o If the BP is ≤ ULN on recheck, continue trametinib at the same dose.  
o If the BP remains above the ULN on recheck, then start/adjust antihypertensive therapy 
and follow Arm 3 of the algorithm from the point that anti-hypertensive therapy is 
started/adjusted. 
 
Arm 3 of algorithm: 
• 
If BP is 11 to 25 mm Hg above the ULN on ≥ 2 of 3 measurements or > 35 mmHg above 
baseline on ≥ 2 of 3 measurements, start/adjust anti- hypertensive therapy and continue trametinib 
at the same dose. Monitor BP at least twice weekly. 
o If the BP returns to ≤ULN within 14 days, continue trametinib at the same dose and 
continue anti-hypertensive therapy. 
o If the BP remains elevated ≥25 mmHg above the ULN or >35 mmHg above baseline for 
more than 14 days after the institution/adjustment of anti-hypertensive therapy, hold 
trametinib, monitor BP at least every 3 days, and follow Arm 4 of the algorithm from 
the point that trametinib is held. The anti-hypertensive therapy should be continued until 
the BP is less than the ULN. 
• 
If the BP returns to ≤ ULN within 14 days, restart trametinib at reduced dose (25% dose reduction 
in patients receiving oral solution or at specified dose reduction in patients receiving 
tablets (See Appendix II). 
• 
If the BP remains > ULN for more than 14 days, patient must be removed from protocol therapy. 
o If the BP increases to > 25 mm Hg above the ULN despite anti-hypertensive therapy, 
hold trametinib, but continue the anti-hypertensive agent(s). Monitor the BP as clinically 
indicated and follow Arm 4 of the algorithm from the point that trametinib is held. 
 
Arm 4 of algorithm: 
• 
If BP is > 25 mm Hg above the ULN hold trametinib, monitor BP, and administer/adjust anti-
hypertensive therapy as clinically indicated.  
o If the BP returns to ≤ ULN within 14 days, trametinib may be restarted at a reduced 
dose.  
o If the BP is > ULN for >14 days, the patient must be removed from protocol therapy 
 
Arm 5 of algorithm: 
If the participant develops Grade 4 hypertension, discontinue trametinib, monitor 
BP and administer anti-hypertensive therapy as clinically indicated. The patient 
is Off Protocol Therapy. 
 
 
 

  
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6.0 
DRUG INFORMATION 
 
6.1 
Trametinib  
 
 
 
 
 
 
 
(06/09/22) 
(Mekinist, GSK1120212, TMT212-NXA, JTP-74057, JTP-78296, JTP-75303, NSC 
763093) 
Source and Pharmacology: 
Trametinib dimethyl sulfoxide is a kinase inhibitor. The chemical name is acetamide, N-
[3-[3-cyclopropyl-5- [(2-fluoro-4- iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl- 
2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)- 
yl]phenyl]-, 
compound 
with 
1,1’-
sulfinylbis[methane] (1:1). It has a molecular mass of 693.53. Trametinib dimethyl 
sulfoxide is a white to almost white powder. It is practically insoluble in the pH range of 
2 to 8 in aqueous media. 
 
Trametinib is an orally bioavailable, reversible, highly selective allosteric inhibitor of 
MEK1/2 that is active in inhibition of pERK and growth of BRAF and Ras mutant cancer 
cell lines and hematopoietic cancer cells from acute myeloid leukemia (AML) and 
chronic myeloid leukemia (CML) origins. Tumor cells commonly have hyperactivated 
extracellular signal-related kinase (ERK) pathways in which MEK is a critical 
component. Trametinib dimethyl sulfoxide inhibits activation of MEK by RAF kinases 
and MEK kinases. Through inhibition of MEK 1 and 2 kinase activity, trametinib causes 
decreased cellular proliferation, Gap-1 (G1) cell cycle arrest, and increased apoptosis in 
vivo following oral dosing. Trametinib is FDA-approved for the treatment of adults with 
advanced melanoma with a BRAF V600E or V600K mutation. 
 
Pharmacokinetics (PK): 
In patients with solid tumors trametinib is absorbed rapidly with median time to 
maximum plasma concentration (Tmax) occurring 1.5 hours after single oral 
administration of trametinib under fasting conditions. It has a moderate to high absolute 
oral bioavailability (72%) relative to a co-administered intravenous (IV) microdose. 
Single-dose administration of trametinib with a high-fat, high-calorie meal resulted in a 
70% decrease in Cmax, a 24% decrease in area under the concentration-time curve from 
time zero (pre-dose) to last time point (AUC[0-t]) and a 10% decrease in AUC 
extrapolated to infinity (AUC[0-∞]) compared to fasted conditions. 
Following repeat-dosing the mean AUC [0-tτ] and Cmax increased in an approximately 
dose proportional manner. Trametinib accumulates with repeat dosing and has a terminal 
half-life (T1/2) of 5.3 days determined after single dose administration. Steady state 
appears to be achieved by Day 15, with little difference in pre-dose (trough) 
concentration at the end of the dosing interval (C-tτ), Cmax and AUC [0-24]) between 
Days 15 and 21. 
Trametinib is a low extraction ratio drug based on plasma IV clearance of 3.21 L/hr and 
has a high volume of distribution (Vd) of 1060 L. Following a single dose of [14C]-
trametinib, approximately 50% of circulating radioactivity is represented as the parent 
compound. The fecal route was the major excretion pathway of radioactivity after a 
single [14C] trametinib oral dose, while urinary excretion accounted for up to 19% of 
excreted radioactivity recovered.  

  
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Potential Drug Interactions: 
In vitro and in vivo data suggest that trametinib is unlikely to affect the PK of other drugs 
and that the PK of trametinib is unlikely to be affected by other drugs. . In vitro studies 
suggest that trametinib is not a substrate of CYP enzymes or of human BCRP, MRP2, 
OATP1B1, OATP1B3, OATP2B1, OCT1 or MATE1 transporters. It is eliminated 
predominantly via deacetylation to metabolite M5, which is mediated by 
caroboxylesterases (CES1b, CES1c, CES2). There is little evidence from clinical studies 
for drug interactions mediated by carboxylesterases. Trametinib is a substrate for P-gp 
and BSEP, but this is not expected to be clinically relevant. 
 
Trametinib dimethyl sulfoxide is an in vitro inhibitor of CYP 2C8 and is anticipated to 
have overall low potential for drug interactions as a perpetrator. It is also a weak CYP 
2B6 and 3A4 inducer and expected to have little clinical effect on sensitive substrates. 
Trametinib is not an inhibitor of CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4 and not 
an inhibitor of MRP2 or BSEP, but an in vitro inhibitor of P-gp, BCRP, OATP1B1, 
OATP1B3, OAT1, OAT3, OCT2 and MATE1 at systemic concentrations that are not 
clinically relevant. No clinically relevant inhibition by trametinib is predicted in the liver 
or kidney and a low risk of intestinal drug-drug interaction is possible with BCRP.  
 
Trametinib is highly bound to plasma proteins (97.3%) and has the potential to interfere 
with other highly protein-bound drugs. Use caution in patients taking concomitant drugs 
that are highly protein-bound and have narrow therapeutic ranges.  
 
Pregnancy and lactation: 
Trametinib may impair female fertility in humans based on the reduction of corpora lutea 
in rats. Trametinib is unlikely to affect male fertility. Based on findings from animal 
studies and its mechanism of action, trametinib can cause fetal harm when administered 
to a pregnant woman. There are no adequate and well-controlled studies of trametinib in 
pregnant women. Women of childbearing potential should be advised to use effective 
contraception during treatment with trametinib and for 4 months after the last dose. Male 
patients must use a condom during intercourse and not to father a child during therapy 
and for 4 months following discontinuation of trametinib to avoid unnecessary exposure 
of trametinib to the fetus. It is not known if trametinib is excreted in milk. Women should 
not breastfeed during treatment with trametinib and for 4 months following the last dose.  
 
Toxicity: 
Comprehensive Adverse Events and Potential Risks list (CAEPR)  
for 
Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below). Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguideli
nes.pdf for further clarification. Frequency is provided based on 1111 patients. 
Below is the CAEPR for Trametinib (GSK1120212B). 

  
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NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER. If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
Version 2.6, October 10, 20191 
 
 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 
 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) 
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
 
Left 
ventricular 
systolic 
dysfunction 
  
 
Sinus bradycardia 
 
  
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Dry eye 
 
  
 
 
Eye 
disorders 
- 
Other 
(chorioretinopathy also known 
as retinal pigment epithelial 
detachment) 
  
 
 
Eye disorders - Other (retinal 
vein occlusion) 
  
 
Eye disorders - Other (visual 
disorders)2 
 
  
 
 
Papilledema 
  
 
Periorbital edema 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colitis 
  
 
 
Colonic perforation 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema face 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
Generalized edema3 
 
 
 Generalized edema3 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction4 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Folliculitis 
 
 Folliculitis (Gr 2) 
 
Lung infection 
 
  

  
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 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Paronychia 
 
 Paronychia (Gr 2) 
 
Skin infection 
 
 Skin infection (Gr 2) 
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine 
aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased  
 Alkaline 
phosphatase 
increased (Gr 2) 
 
Aspartate 
aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 3) 
 
CPK increased 
 
  
 
Ejection fraction decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypoalbuminemia 
 
  
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
 Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Nail changes 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (drug reaction 
with eosinophilia and systemic 
symptoms [DRESS]) 
  
Skin and subcutaneous tissue 
disorders - Other (rash)5 
  
 
 Skin 
and 
subcutaneous 
tissue 
disorders 
- 
Other 
(rash)5 (Gr 3) 
 
 
Stevens-Johnson syndrome6 
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic 
event 
(venous) 
  
 
Vascular 
disorders 
- 
Other 
(hemorrhage)7 
 
  

  
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1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed 
to all Principal Investigators at the time of revision.  The current version can be obtained by 
contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and 
the agent should be included in the e-mail. 
 
2Visual disorders include visual disturbance that can be associated with conjunctival hemorrhage, 
corneal graft rejection, cyclitis, eye nevus, halo vision, iritis, macular edema, retinal hemorrhage, 
visual acuity reduced, visual impairment, and vitreous detachment. 
 
3Generalized edema includes edema, lymphedema, and edema limbs. 
 
4Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased 
liver function tests, and visual disturbances. 
 
5Skin and subcutaneous tissue disorders - Other (rash) may include rash, rosacea, rash acneiform, 
erythematous rash, genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash 
papular, seborrhoeic dermatitis, dermatitis psoriasiform, rash follicular, skin fissures, and skin 
chapped. 
 
6Stevens-Johnson syndrome has been observed in patients treated with trametinib and dabrafenib 
combination. 
 
7The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding in a 
critical area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), and 
fatal intracranial hemorrhages have been reported. 
 
 
 
Adverse events reported on trametinib dimethyl sulfoxide (GSK1120212B) trials, but for 
which there is insufficient evidence to suggest that there was a reasonable possibility that 
trametinib dimethyl sulfoxide (GSK1120212B) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular coagulation; 
Febrile neutropenia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Myocardial infarction; Restrictive 
cardiomyopathy; Sinus tachycardia 
EYE DISORDERS - Corneal ulcer; Eyelid function disorder; Flashing lights; Floaters; Glaucoma; 
Photophobia 
GASTROINTESTINAL DISORDERS - Ascites; Duodenal ulcer; Esophageal necrosis; Esophageal 
ulcer; Esophagitis; Gastric hemorrhage7; Gastric ulcer; Gastritis; Gastrointestinal disorders - Other 
(intestinal 
obstruction); 
Gastrointestinal 
disorders 
- 
Other 
(pneumatosis 
intestinalis); 
Gastrointestinal fistula; Gingival pain; Hemorrhoidal hemorrhage7; Ileus; Obstruction gastric; 
Pancreatitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; 
General disorders and administration site conditions - Other (axillary pain); Localized edema; 
Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatic pain; Hepatobiliary 
disorders - Other (hepatic encephalopathy) 
INFECTIONS AND INFESTATIONS - Biliary tract infection; Catheter related infection; Device 
related infection; Endocarditis infective; Enterocolitis infectious; Hepatitis viral; Infections and 
infestations - Other (abscess limb); Infections and infestations - Other (necrotizing fasciitis); 
Infections and infestations - Other (oral infection); Pharyngitis; Sepsis; Upper respiratory infection; 
Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Blood bilirubin increased; Blood lactate dehydrogenase increased; Creatinine 
increased; Electrocardiogram QT corrected interval prolonged; GGT increased; Lipase increased; 

  
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Lymphocyte count decreased; Platelet count decreased; Serum amylase increased; White blood 
cell decreased 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Hyperglycemia; 
Hyperkalemia; 
Hyperphosphatemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness; Muscle cramp; Musculoskeletal and connective tissue disorder - Other (compression 
fracture); Myalgia; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor 
hemorrhage7; Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial hemorrhage7; 
Lethargy; Nervous system disorders - Other (diplopia); Seizure; Somnolence; Stroke; Syncope; 
Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; 
Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Dysuria; 
Hematuria; Proteinuria; Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal fistula; Vaginal hemorrhage7 
RESPIRATORY, 
THORACIC 
AND 
MEDIASTINAL 
DISORDERS 
- 
Bronchopulmonary 
hemorrhage7; Hypoxia; Laryngeal edema; Oropharyngeal pain; Pleural effusion; Pneumothorax; 
Productive cough; Pulmonary hypertension; Respiratory failure; Sinus disorder 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Photosensitivity; 
Purpura; Skin and subcutaneous tissue disorders - Other (erythema nodosum); Skin ulceration; 
Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension 
 
 
Note: Trametinib (GSK1120212B) 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. 
 
Formulation and Stability: 
Trametinib will be supplied as 0.5 mg and 2 mg (as free base) tablets and powder for oral 
solution. Tablets may be provided in investigationally-labeled bottles or commercially-
labeled bottles.  
 
The 
tablet 
core 
contains 
mannitol, 
microcrystalline 
cellulose, 
hypromellose, 
croscarmellose sodium, magnesium stearate (vegetable source), colloidal silicon dioxide 
and sodium lauryl sulfate. 
 
The aqueous film coating consists of hypromellose, titanium dioxide, polyethylene glycol, 
iron oxide yellow (0.5 mg tablet), iron oxide red (2 mg tablet) and polysorbate 80 (2 mg 
tablet). 
 
Each investigationally-labeled bottle contains 32 tablets with a desiccant: 
 
• 
0.5 mg tablets are yellow, modified oval, biconvex and film-coated.  
• 
2 mg tablets are pink, round, biconvex and film-coated.  
 
Each commercially-labeled bottle contains 30 tablets with a desiccant: 
 
• 
0.5 mg tablets are yellow, modified oval, biconvex, film-coated tablets with ‘GS’ 
debossed on one face and ‘TFC’ on the opposing face.  
 

  
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2 mg tablets are pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one 
face and ‘HMJ’ on the opposing face. 
 
Trametinib tablets are immediate release for oral administration containing trametinib 
dimethyl sulfoxide equivalent to 0.5 mg or 2 mg of trametinib as free base.  
 
Trametinib powder for oral solution: each bottle of powder for solution contains 5 mg 
supplied as a multi-dose formulation in amber glass (USP Type III) bottles with child-
resistant, high-density polypropylene closures. The powder for oral solution is uniform 
white to slightly colored and contains 5 mg of trametinib in addition to beta-cyclodextrin 
sulfobutylether, sucralose, citric acid, sodium phosphate (dibasic, anhydrous), strawberry 
flavor, potassium sorbate and methylparaben. The oral solution is stable for 35 days after 
reconstitution.  
Storage:  
Store tablets at 2°C -8°C (36° F to 46° F) in the original bottle and dispense unopened 
bottles. Do not open bottles or repackage tablets or remove desiccant. Bottles should be 
protected from light and moisture. Refer to the package label for expiration. Stability 
studies are ongoing. Tablets are only stable for 32 days once bottle has been opened. If 
multiple bottles are dispensed to a patient in the same visit, please advise the patient to 
open only one bottle at a time. 
 
Store 5 mg powder for oral solution up to 2°C - 8°C (36°F - 46°F). The oral solution 
(0.05 mg/mL) is stable for 35 days after reconstitution when stored up to 25°C and 
protected from light. Do not freeze. 
 
If a storage temperature excursion is identified, promptly return trametinib to 2°C -8°C 
and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
Trametinib should be taken by mouth on an empty stomach, at least 1 hour before or 
2 hours after a meal. Trametinib solution can be administered via NG or G-tube, if oral 
administration is not feasible. Do not take a missed dose of trametinib within 12 hours of 
the next scheduled dose. If vomiting occurs after taking oral solution formulation, the 
dose of trametinib should NOT be repeated and the next dose should be administered at 
the regularly scheduled time. If vomiting occurs within 30 minutes of taking the tablet 
formulation, the dose of trametinib can be repeated once.  
Reconstitution and administration of powder for oral solution: 
1. Tap the sides of the Powder-in-Bottle to loosen the powder, and then remove the cap. 
Add 90 mL room-temperature water for irrigation, bottled still drinking water, Sterile 
Water for Injection or Purified Water to the bottle. Replace the cap tightly. 
Reconstituted solution is 0.05 mg/mL. 
  
2. Shake vigorously by inversion for at least two minutes to ensure complete powder 
reconstitution to a solution. Then place the bottle on a bench top or flat surface 
undisturbed for 5-10 minutes for any foam to dissipate. 

  
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3. Insert a 28 mm "Press-In-Bottle Adapter (PIBA®)” into the neck of the bottle. 
Please ensure that the lip of the Adapter fits snugly with the top of the bottle. 
Replace the cap tightly. 
  
4. Immediately prior to the removal of dose for administration swirl the bottle of solution 
gently 2-3 times, if any foam appears allow the bottle to sit for at least 1 minute for the 
foam to dissipate. 
 
5. Remove the required dose using a suitable graduated syringe: 
a. Ensure that the syringe plunger is fully pushed into the barrel. 
b. Insert the syringe tip into the Adapter, then invert the bottle and dispense at least 5 
mL of solution into the syringe and then pump the entire solution back into the bottle 
to purge the syringe of any air bubbles. Repeat this step until the syringe is free from 
air bubbles. 
c. Withdraw the required dosing volume. Then re-invert the bottle and remove the 
syringe from the Adapter and administer the dose to the patient as soon as possible. 
Supplier: Trametinib is supplied by Novartis and distributed by CTEP, DCTD, NCI. Do 
not use commercial supply. 
Obtaining the Agent 
Agent Ordering 
NCI supplied agent may be requested by the eligible participating investigator (or their 
authorized designee) at each participating institution. The CTEP assigned protocol number 
must be used for ordering all CTEP supplied investigational agents. The responsible 
investigator at each participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA form 1572 (Statement of Investigator), NIH 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. Patients must be enrolled prior to ordering study agent since no starter 
supplies are being provided. If expedited ordering is required, sites should provide 
express courier information through the Online Agent Order Processing (OAOP) 
application. 
 
Note: No starter supplies will be provided. Drug orders of trametinib should be 
placed with CTEP after enrollment on ADVL1521 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. 
 
Submit agent requests 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 any time.  Refer to the PMB’s 
website for specific policies and guidelines related to agent management.   
 

  
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Agent Accountability 
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. 
 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP IAM account and the 
maintenance of an “active” account status, a “current” password and active person 
registration status. Questions about IB access may be directed to the PMB IB coordinator 
via email. 
 
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://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• 
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) 
• 
IB Coordinator: Ibcoordinator@mail.nih.gov 
 
 
 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed 
therapy and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient 
and family logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable 
(except where explicitly prohibited within the protocol). 
 
7.1 
End of Therapy& Follow-up 
 
STUDIES TO BE OBTAINED 
End of Therapy 
Progressive 
Disease 
History 
X 
 
Physical exam with VS 
X 
 
Ht, Wt, BSA 
X 
 

  
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Performance status 
X 
 
Pregnancy test 
X 
 
CBC, differential, platelets 
X 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
 
Creatinine, SGPT (ALT), bilirubin 
X 
 
Total protein/albumin 
X 
 
Bone marrow evaluation 
X 
 
JMML panel using mutation allele burden 
X 
X 
Genomic, Epigenomic and Functional assays* 
X 
X 
*if the patient consented 
 
See COG Late Effects Guidelines for recommended post treatment follow-up: 
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. 
 
 
7.2 
Retrospective Central Pathology Review 
 
7.2.1 
Requested Materials 
Please send the following materials for retrospective pathology review at baseline 
collection, at the end of Cycles 1 and 2, and when subsequent bone marrows are 
collected for review: 
 
• 
Bone marrow biopsy (if unavailable; submit a bone marrow aspirate 
clot): 1 H& E stained glass slide 
• 
Bone marrow aspirate smear: 1 or 2 stained (e.g. Wright’s Giemsa) 
aspirate smears 
• 
Peripheral blood smear: 1 stained smear 
• 
A copy of the CBC report from the date of marrow collection 
 
7.2.3 
Specimen Labeling and Shipping Information 
All material submitted for central review should be labeled with the patient’s 
COG I.D., study number (ADVL1521), and the date and time the sample was 
drawn. Data should be recorded on the Central Pathology Review Specimen 
Transmittal Form, which must accompany the samples. Please ship within three 
days of obtaining all samples via FedEx priority overnight to the following 
address: 
 
FedEx Shipping account number: 331909297 
 
UCSF Hematopathology 
Attn: Iryna Yarova & Scott C. Kogan M.D. 
505 Parnassus Ave 
Room M569, Box 0100 
San Francisco, CA 94143 
 
Lab Contact: 
Scott C. Kogan M.D. 
Phone: (415) 353-1672 

  
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7.2.5 
Cytologic Slides- Storage/Return 
Cytologic slides will be retained at the UCSF Hematopathology lab indefinitely, 
unless the institution requests their return. 
 
7.3 
Mutant Allele Burden Measurement REQUIRED 
The mutant allele burden assay encompasses the DNA sequencing of all exons in each of 
the following genes: NRAS, KRAS, RRAS2, PTPN11, CBL, NF1, SETBP1, SH2B3, 
ASXL1, and JAK3. The assay is quantitative and is intended to monitor the allele burden 
of one or more previously uncovered mutations in a patient to assess for minimal residual 
disease. See Appendix V for details regarding the determination of pathogenicity.  
 
When a patient enrolls on study, send an email to ADVL1521@ucsf.edu with a copy to 
the COG assigned Study Research Coordinator, to receive a specimen collection kit. 
 
7.3.1 
Sample Collection and Handling Instructions 
A peripheral blood sample will be collected at the time points described 
below. Each sample will be utilized for the purpose of mutant allele 
burden measurement. 
 
Sampling Schedule and Collection 
Peripheral blood samples will be obtained at the following time points: 
 
• 
A single sample collected at any time between Day -14 through 
Day 0, before Cycle 1 (if sent as fee-for-service, can be collected 
up to 30 days prior to treatment) 
• Day 28 of Cycle 1 
• Day 1 of every odd Cycle (3, 5, 7, etc.…) 
• Progressive disease (when applicable)  
• End of Treatment 
 
Sample Processing and Labeling 
Collect peripheral blood samples of approximately 2-4 mL in Sodium 
(Na) Heparin green top tubes. Invert 5 times to ensure mixing of the 
anticoagulant and blood. Peripheral blood should be collected at every 
Mutant Allele Burden Measurement timepoint listed above. 
 
Collect 4 buccal swabs for each cheek (8 total) by gently rolling the swab 
along the inside of each cheek 10 times. Place each swab inside a 
separate tube making sure not to touch the tips. Patient should not have 
any food inside the mouth at the time of collection. Buccal swabs will 
only be collected at the initial time point (Day -14 through Day 0, before 
Cycle 1).  
 
Each tube and swab must be labeled with the patient’s COG I.D., study 
number (ADVL1521), and the date and time the sample was drawn. Data 
should be recorded on the Mutant Allele Burden Measurement Specimen 
Transmittal Form, which must accompany the sample(s). 
 
7.3.2  Sample Shipping Instructions 
The samples should be shipped to the UCSF Molecular Diagnostics 

  
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(CLIA) laboratory. Samples should be shipped between Monday and 
Thursday for overnight delivery to ensure delivery by Friday. Samples 
collected on Friday should be shipped on Monday. The sodium heparin 
tubes and buccal swabs (swabs only collected at first time point) should 
be shipped at room temperature. Please notify the laboratory prior to 
shipment, and send tracking information to the following email address: 
 
Erik.Samayoa@ucsf.edu 
 
Samples should be shipped to the following address: 
 
UCSF Clinical Laboratories 
Attn: Molecular Diagnostics Lab 
185 Berry Street, Suite 100 
San Francisco, CA 94107 
 
Lab Contact: Erik Samayoa 
Phone: (415) 353-4845 
 
7.4 
Correlative Biology Studies 
Please note that no more than 3 mL/kg of blood or bone marrow should be drawn on any 
one day for patients <1 year of age. For patients >1 year of age, no more than 2 mL/kg of 
blood or bone marrow should be drawn on any one day. 
 
 
7.4.1 
Pharmacodynamic (PD) and Pharmacokinetic (PK) Studies OPTIONAL 
For patients who consent, peripheral blood samples will be collected for the 
purpose of determining trametinib concentration. When a patient is being 
considered for PD and PK studies, send an email to ADVL1521@ucsf.edu to 
receive a kit with supplies for blood collection with a copy to the COG assigned 
Study Research Coordinator. 
 
Pharmacodynamic Studies: Plasma inhibitory assays will be performed to 
indirectly assess levels of MEK inhibition in patient samples. Phospho-flow 
cytometry will also be performed on samples to assess changes in intracellular 
and extracellular signaling after exposure to trametinib. 
 
Pharmacokinetic Studies Trametinib will be extracted from plasma and will be 
quantified by internal standardization and HPLC-MS/MS methodology. Peak 
areas will be generated and peak area ratios will be used to calculate trametinib 
concentrations in each sample. 
 
7.4.1.1 Sample Collection and Handling Instructions 
 
Sampling Schedule and Collection 
Blood samples will be obtained at the following time points during 
Cycle 1: 
 
• Day 1, hours 0 and 4 
• Day 15, hours 0 and 4 
 

  
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Sample Processing and Labeling 
Collect blood samples of approximately 4 mL in a K2 EDTA Vacutainer 
and invert to ensure mixing of the anticoagulant and blood. Store the 
blood samples on wet ice for approximately 10 minutes. Centrifuge 
(refrigerated centrifuge) at approximately 2000g for 10 minutes at 4◦C. 
Transfer the plasma immediately after centrifugation to an appropriately 
labeled 1.8 mL NUNC storage tube and store at -80◦C. Plasma samples 
on day 1 and 15 can be stored at -80◦C, and batched for shipment on dry 
ice at the end of cycle 1 on day 28 along with smart tubes (see section 
7.4.2.1). Any remaining blood in the EDTA tubes after removing the 
plasma should be shipped room temperature on the day of collection. 
 
Each tube must be labeled with the patient’s COG I.D., study number 
(ADVL1521), and the date and time the sample was drawn. Data should 
be recorded on the PD and PK Specimen Transmittal Form, which must 
accompany the sample(s). 
 
7.4.1.2 Sample Shipping Instructions 
Ship samples to the Loh laboratory. Samples should be shipped between 
Monday and Thursday for overnight delivery to ensure delivery by 
Friday. Samples collected on Friday should be shipped on Monday. 
NUNC storage tubes should be shipped on dry ice. The EDTA tubes 
should be shipped at room temperature. 
 
Please contact the laboratory prior to shipment, and send tracking 
information to the following email address: 
 
ADVL1521@ucsf.edu with a copy to the COG assigned Study 
Research Coordinator. 
 
FedEx Shipping account number: 331909297; select priority overnight 
 
Samples should be shipped to the following address: 
 
Elliot Stieglitz, MD 
HDFCCC, Loh Lab 1450 3rd St, Room 230  
San Francisco, CA 94158 
 
Lab Contact: Alex Chao 
Phone: (415) 514-9389 
Email: ADVL1521@ucsf.edu 
 
Subsequent Processing by Dr. Jones’s Laboratory- Pharmacokinetic 
Studies 
Samples will be processed by the Loh laboratory. A fraction of the 
plasma will be stored at -80◦C and shipped to Dr. David Jones laboratory 
at the University of Indiana. Plasma samples will be utilized for 
pharmacokinetic analysis, and the determination of blood trametinib 
concentrations. 
 
Specimens will be batched and sent to the Jones laboratory with copies 
of the completed Specimen Transmittal Forms. 

  
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7.4.2 
Genomic, Epigenomic and Functional Studies OPTIONAL 
We will perform exome sequencing, RNA seq, methylation profiling, and CG-
CSF hypersensitivity assays at diagnosis, at the end of Cycles 1 and 2, and 
disease progression (if applicable). We aim to determine whether genomic, 
transcriptomic, or epigenetic changes occur as a result of treatment with 
trametinib. 
 
When a patient is being considered for these optional studies, send an email to 
ADVL1521@ucsf.edu with a copy to the COG assigned Study Research 
Coordinator, to receive a kit with supplies for bone marrow collection. 
 
7.4.2.1 Sample Collection and Handling Instructions 
For patients who consent, bone marrow and peripheral blood samples 
will be collected at the time points described below. Samples will be 
used to determine whether genomic, transcriptome, or epigenetic changes 
occur as a result of trametinib treatment. 
 
If available, please send bone marrow slides (unstained aspirate smears or 5 
unstained FFPE recuts) from the original diagnosis of JMML. DNA will be 
extracted for the purpose of mutation analysis and paired sequencing with 
relapse samples. 
 
If a patient consents to optional studies, leftover DNA from buccal swabs 
collected as part of the mandatory Mutant Allele Burden Measurement test 
will be used as a germline control for next generation sequencing for 
research. 
 
Sampling Schedule and Collection 
Bone marrow and peripheral blood samples will be obtained at each of 
the following time points: 
• Any time point between Day -14 through Day 0 before Cycle 1 
therapy 
• Day 28 of Cycle 1 
• Day 28 of Cycle 2 
• Progressive disease (when applicable) 
 
Sample Processing and Labeling 
Collect bone marrow samples of approximately 5-10 mL in Sodium (Na) 
Heparin green top tubes. Invert 5 times to ensure mixing of the 
anticoagulant and bone marrow. 
 
Collect peripheral blood samples of approximately 5-10 ml in Sodium 
(Na) Heparin green top tubes and invert to ensure mixing of the 
anticoagulant and blood. Transfer 1ml from the Sodium Heparin tube(s) 
into three separate Smart Tubes (1ml in each of the three Smart Tubes). 
Smart Tubes collected before and during cycle 1 should be stored at -
80°C and batched for shipment at the end of cycle 1 on day 28 along 
with NUNC tubes (see section 7.4.1.1). Any remaining blood in the 
Sodium Heparin tubes should be shipped same day at room temperature. 

  
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Smart tubes collected during cycle 2 and at progression (if applicable) 
should be stored at -80°C and shipped on dry ice as soon as possible. 
 
Please see the ADVL1521 protocol page for additional Smart Tubes 
instructions. 
 
Each tube must be labeled with the patient’s COG I.D., study number 
(ADVL1521), and the date and time the sample was drawn. Data should 
be recorded on the Biologic Studies Specimen Transmittal Form, which 
must accompany the sample(s). 
 
7.4.2.2 Sample Shipping Instructions 
The samples should be shipped to the Loh laboratory. Samples should be 
shipped between Monday and Thursday for overnight delivery to ensure 
delivery by Friday. The sodium heparin tubes should be shipped at room 
temperature. The Smart Tubes should be sent on dry ice. Please contact 
the laboratory prior to shipment, and send tracking information to the 
following email address: 
 
ADVL1521@ucsf.edu; with a copy to the COG assigned Study 
Research Coordinator 
 
FedEx Shipping account number: 331909297; select priority overnight 
 
Samples should be shipped to the following address: 
 
Elliot Stieglitz, MD 
HDFCCC, Loh Lab 1450 3rd St, Room 230 
San Francisco, CA 94158 
 
Lab Contact: Alex Chao 
Phone: (415) 514-9389 
Email: ADVL1521@ucsf.edu 
 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
8.1 
Criteria for Removal From Protocol Therapy 
a) Progressive disease. 
b) Adverse Events requiring removal from protocol therapy, as stated in Section 5.0. 
c) Patients who receive concurrent anticancer or investigational therapy, as stated in 
Section 4.1.4. 
d) Refusal of further protocol therapy by patient/parent/guardian. 
e) Completion of 12 cycles of therapy. 
f) Physician determines it is in patient’s best interest. 
g) Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
h) Patients who develop a second malignant neoplasm. 

  
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Patients who are removed from protocol therapy (except for 8.1.g) are to be followed until 
they meet the criteria for Off Study (see below). Follow-up data will be required unless 
consent was withdrawn.   
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Entry into another COG study with tumor therapeutic intent (e.g., at recurrence). 
d) Withdrawal of consent for any further data submission. 
e) The fifth anniversary of the date the patient was enrolled on this study. 
f) Patient did not receive protocol treatment after study enrollment 
 
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
Sample Size and Study Duration 
COG study AAML0122 (for newly diagnosed JMML) accrued at an average annual rate 
of 15 patients/year in the US. Assuming roughly half of these newly-diagnosed patients 
relapse or are refractory to chemotherapy, we can expect an accrual rate of 
7.5 relapsed/refractory patients/year. With these entry rates, the probability of accruing 
10 patients to complete the initial stage of evaluation within 20 months is 80% and within 
24.5 months is 90%. The corresponding probability for enrolling 20 patients in 38 months 
is 80% and within 43 months is 90%. Allowing for a 20% inevaluability rate, a minimum 
of 10 patients and a maximum of 24 patients are anticipated. The study will likely require 
2.5 to 3.5 years for sufficient patient enrollments to evaluate trametinib in 
relapsed/refractory JMML. 
 
9.2 
Study Design 
The primary endpoint will be objective response by the criteria listed in Section 10.2. The 
following Simon two-stage design will be used. 
 
 
Cumulative Number 
of Responses 
Decision 
Stage 1: Enter 10 patients 
0 
Terminate the trial: agent ineffective 
 
1 or more 
Inconclusive result, continue trial  
 
 
(proceed to Stage 2) 
Stage 2: Enter 10 additional 
patients 
2 or less      
Terminate the trial: agent ineffective 
 
3 or more 
Terminate the trial: agent effective 
 
We will consider trametinib not of sufficient interest for further evaluation in a disease 
category if the true response rate is 5% and of sufficient interest if the true response rate 
is 25%. If the agent has a true response rate of 5%, the rule described above will identify 
it of sufficient interest for further study with probability 0.069 (type I error), and the trial 
will have an expected sample size of 14.01 with 59.9% probability of early termination. 

  
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If the agent has a true response rate of 25%, the rule described above will identify it of 
sufficient interest for further study with probability 0.882 (power against the alternative 
hypothesis p = 0.25). An expanded table of possible true response rates is below: 
 
True 
response 
rate 
Probability of 
stopping early for 
lack of activity 
Probability of 
identifying agent 
as effective 
Expected 
number of 
patients accrued 
  5% 
0.599 
0.069 
14.01 
10% 
0.349 
0.299 
16.51 
15% 
0.197 
0.560 
18.03 
20% 
0.107 
0.759 
18.93 
25% 
0.056 
0.882 
19.44 
30% 
0.028 
0.947 
19.72 
35% 
0.013 
0.978 
19.87 
 
 
 
9.3 
Methods of Analysis 
Response criteria are described in Appendix III. A responder is defined as a patient who 
achieves a best response (as defined in Section 10.2) of PR or CR on the study prior to 
having an overall response of PD (as defined in Section 10.2); all others will be 
considered non-responders. The evaluation period for determination of the best response 
will be 12 treatment cycles. Response rates will be calculated as the percent of evaluable 
patients who are responders, and confidence intervals will be constructed accounting for 
the two-stage design. 
 
Duration of response (Aim 1.2.5) will be defined as the time from first occurrence of PR 
or CR until the first occurrence of PD, death, or going off study. Patients who progress 
will be considered to have had an event, patients who die prior to progressing will be 
considered to have a competing event, and patients who go off study prior to progressing 
will be censored at time of last contact. The analysis will be done using the method of 
Gray. 45 
 
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. 
 
The analytic unit for monitoring for protocol-specific toxicities will be the patient-course: 
Each course where the patient receives the agent and either 1) has a protocol-specific 
toxicity event, or 2) receives at least 85% of their assigned dose during the cycle will be 
considered in the analysis. If there is strong evidence (posterior probability of at least 
70% with at least 2 observed toxicities) that there is a per course protocol-specific 
toxicity probability of more than 20%, such information will be presented to the DSMC. 
 
We will use a Bayesian rule to monitor for protocol-specific toxicities. We will assume a 
beta prior distribution with α = 0.52 and β = 2.08. At least once per month, we will 
calculate the posterior probability (given the data) that the probability of protocol-specific 
toxicity exceeds the 20% threshold: 
 

  
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( )
( )
0.48
1.08
1
protocol-specific toxicities
0.2
0.48
1.08
1
0
(2.6)
(1
)
(1
)
(0.52) (2.08)
P(
20% Data)
(2.6)
(1
)
(1
)
(0.52) (2.08)
x
n x
x
n x
p
p
p
p
dp
q
q
q
d
n
n
q
p
x
q
x
−
−
−
−

−


−



=

−


−




∣
 
 
Here n is the number of protocol-specific toxicity-evaluable cycles and x is the number of 
such cycles on which a protocol-specific toxicity event is observed. Examples of 
situations in which this rule will indicate protocol-specific toxicities have been noted and 
are presented below: 
 
Number of failures Number of patient-cycles 
2 
6 
3 
10 
4 
14 
5 
19 
6 
23 
7 
28 
8 
32 
9 
37 
10 
41 
11 
46 
12 
51 
13 
55 
14 
60 
 
Protocol-specific toxicities of interest include rash, diarrhea, ejection fraction changes, 
hypertension, prolonged QTc, pneumonitis, visual changes, ALT increase, AST increase, 
and bilirubin increase. 
 
If there is strong evidence (posterior probability of at least 70% with at least 2 observed 
toxicities) that there is a per course protocol-specific toxicity probability of more than 
20%, such information will be presented to the DSMC. 
 
9.4 
Evaluability for Response 
Any patient who is enrolled and receives at least one dose of trametinib will be 
considered evaluable for response. 
 
9.5 
Evaluability for Toxicity 
All patients who either (1) receive one dose of trametinib and have a toxicity, or (2) 
receive at least 85% of the total dose of trametinib according to protocol guidelines 
during the first cycle of therapy will be considered in the evaluation of toxicity. 
 
9.6 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
 

  
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DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian or 
Other Pacific Islander 
0 
1 
0 
0 
1 
Black or African 
American 
1 
1 
0 
0 
2 
White 
4 
11 
2 
2 
19 
More Than One Race 
0 
0 
0 
0 
0 
Total 
6 
14 
2 
2 
24 
 
This distribution was derived from AAML0122. 
 
9.7 
Analysis of the Pharmacokinetic Parameters 
A descriptive analysis of pharmacokinetic (PK) parameters of trametinib will be 
performed to define systemic exposure, drug clearance, and other pharmacokinetic 
parameters. The PK parameters will be summarized with simple summary statistics, 
including means, medians, ranges, and standard deviations (if numbers and distribution 
permit). 
 
9.8 
Analysis of Biological and Correlative Endpoints 
Mutant allele burden (as percentages) and trametinib concentrations as measured by mass 
spectrometry will be analyzed descriptively. Values will be summarized with means, 
standard deviations, and 95% confidence intervals. 
 
 
10.0 
EVALUATION CRITERIA 
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize the CTCAE of the National Cancer Institute (NCI) for toxicity and 
performance reporting. The descriptions and grading scales found in the revised CTCAE 
version 5.0 will be utilized for reporting. All appropriate treatment areas should have 

  
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access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
10.2 
Response Criteria  
Response and progression will be evaluated using the tables found in Appendix III. These 
criteria were developed by an international consensus panel. 46 
 
The overall response will be defined in terms of the genetic and clinical responses defined in 
Appendix III according to the following table: 
 
Genetic 
Response 
Clinical Response 
cCR 
cPR 
cSD 
cPD 
gCR 
CR 
CR 
CR 
PD 
gSD 
PR 
PR 
SD 
PD 
gPD 
PD 
PD 
PD 
PD 
 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
11.1 
Purpose 
Adverse event (AE) 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. Certain adverse events must 
be reported in an expedited manner to allow for timelier monitoring of patient safety and 
care. The following sections provide information about expedited reporting. 
 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI 
requires that AEs be submitted according to the timeframes in the AE reporting table 
assigned to the protocol, using the CTEP Adverse Event Reporting System (CTEP-
AERS). 
 
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. 
 
11.3 
Specific Examples for Expedited Reporting  
11.3.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of 
a possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting table in this protocol.  
 
11.3.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it occurs 
at any time following treatment with an agent under a NCI IND/IDE since these are 
considered serious AEs. 
 
11.3.3 Death 
 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: Newborn death occurring during the first 28 days after 
birth. 
o 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 term associated with Grade 5. 
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
o Death due to progressive disease should be reported as Grade 5 Disease 
Progression under the system organ class (SOC) “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 occurring greater than 30 days after the last dose of the 
investigational agent/intervention requires expedited reporting within 24 hours 
only if it is possibly, probably, or definitely related to the investigational 
agent/intervention. 
 

  
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11.3.4 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 metastasis of the initial neoplasm is not considered a 
secondary malignancy.  
The NCI 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:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
must also be reported via the routine reporting mechanisms outlined in this 
protocol. 
 
11.3.5 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. 
 
11.3.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: 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) 897-7404. The potential risk of exposure of the 
fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section of the CTEP-AERS report. 
 
11.3.6.1 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 is known. If the 
baby is born with a birth defect or anomaly, then a second CTEP-AERS 
report is required. 
 
11.3.6.2 Pregnancy Loss (Fetal Death) 
• Pregnancy loss is defined in CTCAE as “Death in utero.” 
• Any pregnancy loss should be reported expeditiously, as Grade 
4 “Pregnancy loss” under the “Pregnancy, puerperium and 
perinatal conditions” SOC. Do NOT report a pregnancy loss 
as a Grade 5 event since CTEP-AERS recognizes any Grade 5 
event as a patient death. 
 

  
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11.3.6.3 Death Neonatal  
• 
Neonatal death, defined in CTCAE as “Newborn deaths occurring 
during the first 28 days after birth” that is felt by the investigator to be 
at least possibly due to the investigational agent/intervention, should be 
reported expeditiously. 
 
• 
A neonatal death should be reported expeditiously as Grade 4 ”Death 
neonatal” under the “General disorders and administration” SOC when 
the death is the result of a patient pregnancy or pregnancy in 
partners of men on study 
 
• 
Do NOT report a neonatal death resulting from a patient pregnancy or 
pregnancy in partners of men  as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death.  
 
Pregnancy should be followed up until the outcome of the pregnancy is known at 
intervals deemed appropriate by her physicians. The “Pregnancy Information 
Form” should be used for all necessary follow-ups. This form is available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf.  
 
11.4 
Reporting Requirements for Specialized AEs  
11.4.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (e.g., elevated laboratory 
value, diarrhea). The baseline AE must be re-assessed throughout the study and 
reported if it fulfills expedited AE reporting guidelines. 
a. If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the 
event to determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.4.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses. 
 
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 
 
11.4.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
 

  
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ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.5 
Exceptions to Expedited Reporting 
11.5.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and 
Potential Risks (CAEPR) that contains a list of events that are considered 
expected for CTEP-AERS reporting purposes. (Formerly referred to as the Agent 
Specific Adverse Event List (ASAEL)). 
 
AEs listed on the SPEER should be reported expeditiously by investigators to the 
NCI via CTEP-AERS ONLY if they exceed the grade of the event listed in 
parentheses after the event. If the CAEPR is part of a combination IND using 
multiple investigational agents and has an SAE listed on different SPEERs, use 
the lower of the grades to determine if expedited reporting is required. 
 
11.5.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed under the 
CTEP-AERS reporting table for this protocol. 
 
11.6 
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. 
 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP web site  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted 
electronically 
to 
NCI 
via 
CTEP-AERS 
at: 
https://eapps-
ctep.nci.nih.gov/ctepaers 

  
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In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to 
be made to the NCI for agents supplied under a CTEP IND by telephone call to (301) 
897-7497. 
 
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of 
the report at the site. 
 
• 
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 event, 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 the investigator learning of the event.  
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth defect, 
or is an IME, which based upon the medical judgment of the investigator may 
jeopardize the patient and require intervention to prevent a serious AE, must be 
reported via CTEP-AERS if the event occurs following investigational agent 
administration.  
 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 
24 hours. 
• 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE 
requires expedited reporting within 24 hours. 
 
CTEP-AERS Medical Reporting includes the following requirements as part of the 
report: 1) whether the patient has received at least one dose of an investigational agent on 
this study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not 
hospitalization or prolongation of hospitalization was associated with the event. 
 
Any medical documentation supporting an expedited report (e.g., H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to 
the NCI. NOTE: English is required for supporting documentation submitted to the 
numbers listed below in order for the NCI to meet the regulatory reporting 
timelines. 
 
Fax supporting documentation for AEs related to investigational agents supplied 
under a CTEP IND to: (301) 230-0159 (back-up: (301) 897-7404). 
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax# (310) 
640-9193; email: COGAERS@childrensoncologygroup.org; Attention: COG AERS 
Coordinator).  
 

  
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• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
11.8 
Reporting Table for Late Phase 2 and Phase 3 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 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse event.  
3) Any AE that results 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.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6.)  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below.   
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
7 Calendar Days 
 
 
24-Hour 
Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 Calendar 
Days 
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. Additional Special 
Situations as Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“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 
notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of 
learning of the AE.  
 
1SAEs 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 4, and Grade 5 AEs  

  
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Expedited 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events  

  
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11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
• 
Grades 1-4 hematologic toxicity (anemia, neutropenia, and thrombocytopenia) 
do not require expedited reporting.  
• 
Grade 1-2 non-hematologic toxicities do not need to be reported unless they 
otherwise meet criteria for a serious adverse event as defined above. 
 
11.10 Routine Reporting of Adverse Events 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting will include all CTEP-AERS 
reportable events and Grade 3 and higher Adverse Events. 
 
Hematologic Toxicity: Routine reporting of all grade 1-4 hematologic toxicities is not 
required in RAVE. 
 
Non-Hematologic Toxicities: Please also report the following via the RAVE AE CRFs: 
• 
All Grade 3 and higher non-hematologic toxicities should be reported. 
• 
The following Grade 1 and 2 events should be reported: 
o Ejection fraction decreased 
o Pneumonitis 
o Eye disorders 
o Paronychia 
o Skin and subcutaneous tissue disorders 
o Palmar-plantar erythrodysesthesia syndrome 
o Diarrhea 
 
 
Please see section 11.4 for more information regarding routine reporting requirements. 
 
12.0 
STUDY REPORTING AND MONITORING 
 
The Case Report Forms and the submission schedule are posted on the COG website with each 
protocol under “Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31 and October 31. This is not a responsibility of institutions 
participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses. 
 

  
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Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. 
The study statistician is responsible for the monitoring of the interim results and is 
expected to request DSMC review of any protocol issues s/he feels require special 
review. Any COG member may bring specific study concerns to the attention of the 
DSMC. 
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (e.g., termination, dropping an arm based on toxicity results or other 
trials reported, increasing target sample size, etc.). The DSMC determines whether and to 
whom outcome results may be released prior to the release of study results at the time 
specified in the protocol document. 
 
 
12.3 
CRADA/CTA 
 
NCI/ DCTD Standard Language to Be Incorporated into All Protocols Involving 
Agent(s) Covered by a Clinical Trials Agreement (CTA), a Cooperative Research and 
Development Agreement (CRADA) or a Clinical Supply Agreement, hereinafter 
referred to as Collaborative 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 Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other 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 NCI, 
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 

  
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other Collaborator to develop, obtain regulatory approval or commercialize its 
own 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 Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for 
advisory review and comment prior to submission for publication. Collaborator(s) 
will have 30 days from the date of receipt for review. Collaborator shall have the 
right to request that publication be delayed for up to an additional 30 days in order to 
ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must 
be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as 
possible and preferably at least three (3) days prior to submission, but in any case, 
prior to presentation at the meeting 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. 
 
 

  
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APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
 
INVESTIGATOR AND RESEARCH ASSOCIATE REGISTRATION WITH CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the  Roster Update Management System (RUMS), OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
 
 
 
 
 
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 Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 

  
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In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must 
be rostered at the enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at https://ctep.cancer.gov/
investigatorResources/default.htm. For questions, please contact the RCR Help Desk by email at 
RCRHelpDesk@nih.gov. 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Protocol Organization 
(PO) on the protocol. One way to search for a protocol is listed below.  
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select COG, and 
protocol number (*insert study number*). 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load 
automatically to the CTSU.) 
 
Protocol-Specific Requirements For 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) 
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 

  
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Checking Your Site’s Registration Status 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory  at the top of the screen; 
• 
Click on Site Registration; and  
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
Data Submission / Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) 
or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (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 staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff 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. If an eLearning is required 
and has not yet been taken, the link to the eLearning will appear under the study name in 
iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section 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.   

  
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APPENDIX II: DOSING NOMOGRAM 
 
Consistent with dose levels defined in the pediatric solid tumor study, trametinib dosing will be weight 
based. The drug is supplied in tablet form or in or solution form, with dosing nomogram for tablet 
formulation below. The maximum dose is 2 mg per day. 
Note: If switching from trametinib solution to trametinib tablets or vice versa in patients 
requiring dose reduction, match up the patient’s starting dose to ensure the proper dose reduction 
is being made. 
 
Dose Level: 
 
0.025 mg/kg/dose PO once daily (age ≥ 6 years) 
Subject Weight: 
 
≥ 35 kg 
Formulation:  
Trametinib Tablets 0.5 and 2 mg 
Actual 
Weight*(kg) 
Dose 
(mg) 
Number of 
0.5 mg tablets 
Number of 
2 mg tablets 
Dose 
Reduction 
(mg) 
Number of 
0.5 mg tablets 
Number of 
2 mg tablets 
35 – 50 
1 mg 
2 
0 
Oral solution only 
0.75 mg (15 mL) 
50.1 – 70 
1.5 mg 
3 
0 
1 mg 
2 
0 
≥ 70.1 
2 mg 
0 
1 
1.5 mg 
3 
0 
*weight measured within 7 days of the start of the cycle 
 
 
*weight measured within 7 days of the start of the cycle 
Dose Level: 
 
0.032 mg/kg/dose PO once daily (age 1 month to < 6 years) 
Subject Weight: 
 
≥ 26.6 kg 
Formulation:  
Trametinib Tablets 0.5 and 2 mg 
Actual 
Weight*(kg) 
Dose 
(mg) 
Number of 
0.5 mg tablets 
Number of 
2 mg tablets 
Dose 
Reduction 
(mg) 
Number of 
0.5 mg tablets 
Number of 
2 mg tablets 
26.6 – 39 
1 mg 
2 
0 
Oral solution only 
0.75 mg (15 mL) 
39.1 – 54.6 
1.5 mg 
3 
0 
1 mg 
2 
0 
≥54.7 
2 mg 
0 
1 
1.5 mg 
3 
0 

  
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APPENDIX III: RESPONSE CRITERIA FOR PATIENTS WITH JMML 
 
Table 1: Variables for evaluation of response to therapy in JMML 
 
CR: complete response, PR: partial response, PD: progressive disease, WBC: white blood cell, PB: peripheral blood, BM: bone 
marrow 
*Myeloid precursors include promyelocytes, myelocytes, and metamyelocytes. The myeloid and erythroid precursors and blasts 
in PB are given as % of the total nucleated cells in PB (WBC including erythroblasts).  
**in NF-1, PTPN11, NRAS, KRAS, RRAS2, or CBL, thus the mutation are thought to be initiating. In patients with germ-line NF-
1, PTPN11 or CBL mutation, only acquired mutations can be evaluated for response and relapse after therapy. The germ-line 
mutation remains even if patients achieved complete molecular response. The molecular response will be determined using the 
“JMML Mutant Allele Burden” assay. 
Criteria for progression including WBC, platelet count and spleen size cannot be used in the setting of an active infection. 
#Extramedullary disease includes infiltration of skin, lung, and very rarely cranial nerves or central nervous system. 

  
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Table 2: Definition of response following therapy other than HSCT in JMML 
 
 
**In patients with germ-line NF-1, PTPN11 or CBL mutation, the germ-line mutation remains even if 
patients achieved a genetic complete remission. 
 
 

  
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APPENDIX IV: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ADVL1521 
(For children from 7 through 12 years of age) 
A study of the drug trametinib in children and young adults 
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. We will do this by trying a new medicine to treat your cancer.  
 
3. Children who are part of this study will be treated with a cancer-fighting medicine called 
trametinib. You will also have regular tests and exams done more often while you are in this 
study. The doctors want to see if trametinib will make children with your type of cancer get 
better. We don’t know if trametinib will work well to get rid of your cancer. That is why we are 
doing this study.  
 
4. 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 
trametinib 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. 
 
5. 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 more problems, or side 
effects, from trametinib than other treatments. Other things may happen to you that we don’t yet 
know about. 
 
6. Your family can choose for you to be part of this study or not. Your family can also decide for 
you 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. 
 
7. As part of your regular care, your doctor may have removed some bone marrow and/or blood to 
see if you have cancer. If you take part in this study, we will keep some of the tissue that is left 
over to do special tests. These tests may help us learn more about how trametinib works.  
 

  
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INFORMATION SHEET REGARDING RESEARCH STUDY ADVL1521 
(For teens from 13 through 17 years of age) 
A study of the drug trametinib 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 been diagnosed with Juvenile 
Myelomonocytic Leukemia. 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. Children and teens who are part of this study will be given a cancer-fighting medicine called 
trametinib. We are using trametinib in this study because it seems to work against certain types of 
cancer cells in test tubes and animals. Trametinib is considered experimental because the Food and 
Drug Administration (FDA) has not approved this drug for JMML. The dose of trametinib used in 
this study was found to be well-tolerated in adults. 
 
4. You will get trametinib by mouth, once a day, on Days 1 through 28 of a 28-day period. This entire 
28-day period is called a cycle. You may continue to receive trametinib for up to about 12 months (up 
to 12 cycles) as long as you do not have bad effects from it and your cancer does not get any worse. 
You will also have exams and tests done that are part of normal cancer care. But, the exams and tests 
will be done more often while you are being treated with trametinib. The doctors want to see if 
trametinib will make children with your type of cancer get better. We don’t know if trametinib is 
better than other medicines. That is why we are doing this 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 trametinib 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 more problems, or side effects, 
from trametinib than other treatments. Other things may happen to you that we don’t yet 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 illness that your doctor 
can tell you about. Make sure to ask your doctors any questions that you have.  
 
8. As part of your regular care, your doctor may have removed some bone marrow and/or blood to see if 
you have cancer. If you take part in this study, we will keep some of the tissue that is left over to do 
special research tests. These tests may help us learn more about how trametinib works. The samples 
will come from leftover tissue so there would be no extra procedures. 
 

  
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APPENDIX V: DETERMINATION OF PATHOGENICITY 
 
Variants will be determined as pathogenic, likely pathogenic, variants of uncertain significance, likely 
benign or benign. A combination of assessments are used to determine the classification of each variant in 
accordance with the “Standards and guidelines for the interpretation of sequence variants: a joint 
consensus recommendation of the American College of Medical Genetics and Genomics and the 
Association for Molecular Pathology”. 47 
 
Single nucleotide polymorphisms (SNPs):  Variants are cross referenced in databases including: 
 
dbSNP https://www.ncbi.nlm.nih.gov/projects/SNP/ 
ExAC http://exac.broadinstitute.org/ 
1000 genomes project. http://www.internationalgenome.org/  
 
In silico prediction: Variants are assessed for pathogenicity using: 
Mutation Assessor http://mutationassessor.org/r3/ 
SIFT http://sift.jcvi.org/ 
Polyphen. http://genetics.bwh.harvard.edu/pph/data/  
 
Conservation: Variants are assessed using GERP (http://mendel.stanford.edu/SidowLab/downloads/gerp/) 
to assess for conservation amongst species. 
 
Cancer Databases: Variants are cross-referenced in COSMIC (http://cancer.sanger.ac.uk/cosmic), and 
cBioPortal (http://www.cbioportal.org/ ) and assessed for prior evidence of pathogenicity. 
 
Tumor-Normal: The allelic frequency for each variant is determined in both a tumor and a normal sample. 
 
 

  
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APPENDIX VI: TRAMETINIB MEDICATION DIARY (TABLET) 
COG Patient ID:___________   ACC # : _____     Institution :________________________________  
Please do not write patient names on this form. 
 
Complete each day with the date, time and number of trametinib tablets taken. Make note of other drugs 
and supplements taken. Your doctor will tell you what foods you should avoid. Trametinib should be 
taken by mouth on an empty stomach once a day, at least 1 hour before or 2 hours after a meal. Do not 
take a missed dose of trametinib within 12 hours of the next scheduled dose. If vomiting occurs within 
30 minutes of taking the tablet formulation, the dose of trametinib can be repeated once. Return the 
completed diary to your institution at the end of each treatment cycle. Please return all unused tablets at 
the end of each cycle. Store tablets in the refrigerator. 
 
Sites will fill out the day of the week and number of prescribed tablets per day according to the dosing 
nomogram in Appendix II. 
 
EXAMPLE 
 
Number of Tablets taken 
Comments 
WEEK 1 
Date 
Time 
0.5 mg 
2 mg 
. 
Day 1: 
Monday 
1/15/
12 
8:30 
AM 
# prescribed:__3__ 
# taken: __3___ 
# prescribed:__0__ 
# taken: __0__ 
He felt nauseated an 
hour after taking the 
drug but did not vomit 
 
 
Cycle #: _____              Start Date: |__/__|__/__|__/__|              End Date: |__/__|__/__|__/__|  
 
kg _____   Dose: ________mg/kg     Total Daily Dose per Nomogram: ___________ mg 
 
WEEK 1 
Date 
Time 
0.5 mg 
2 mg 
Comments 
Day 1: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 2: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 3: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 4: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 5: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 6: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 7: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
 
 
 

  
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WEEK 2 
Date 
Time 
0.5 mg 
2 mg 
Comments 
Day 8: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 9: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 10: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 11: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 12: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 13: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 14: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
 
 
 
  
WEEK 3 
Date 
Time 
0.5 mg 
2 mg 
Comments 
Day 15: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 16: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 17: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 18: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 19: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 20: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 21: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
 

  
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WEEK 4 
Date 
Time 
0.5 mg 
2 mg 
Comments 
Day 22: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 23: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 24: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 25: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 26: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 27: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 28: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
 
 
 
Comments: 
 

  
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APPENDIX VII: TRAMETINIB MEDICATION DIARY (ORAL SOLUTION) 
 
COG Patient ID:___________   ACC # : _____     Institution :________________________________  
Please do not write patient names on this form. 
 
Complete each day with the date, time and volume in mL of trametinib oral solution taken. Make note of 
other drugs and supplements taken. Your doctor will tell you what foods you should avoid. Trametinib 
should be taken by mouth on an empty stomach once a day, at least 1 hour before or 2 hours after a meal. 
Do not take a missed dose of trametinib within 12 hours of the next scheduled dose. If vomiting occurs 
after taking oral solution formulation, the dose should NOT be repeated and the next dose should be 
administered at the regularly scheduled time. Return the completed diary to your institution at the end of 
each treatment cycle. Please return all unused solution at the end of each cycle. Store the solution at room 
temperature (25°C or 77°F). 
 
Immediately prior to the removal of dose for administration swirl the bottle of solution gently 2-3 times, 
if any foam appears allow the bottle to sit for at least 1 minute for the foam to dissipate. Remove the 
required dose using a suitable graduated syringe: 
a. Ensure that the syringe plunger is fully pushed into the barrel. 
b. Insert the syringe tip into the Adapter, then invert the bottle and dispense at least 5 mL of 
solution into the syringe and then pump the entire solution back into the bottle to purge the 
syringe of any air bubbles. Repeat this step until the syringe is free from air bubbles. 
c. Withdraw the required dosing volume. Then re-invert the bottle and remove the syringe from 
the Adapter and administer the dose to the patient as soon as possible. 
 
Sites will fill out the day of the week and the volume of prescribed solution per day. 
 
 
EXAMPLE 
 
 
Amount of 
oral solution 
taken 
Comments 
WEEK 1 
Date 
Time 
(total mL per 
dose) 
 
Day 1 
1/15/09 
8:30 
AM 
2 
He felt nauseated an hour after taking the drug but 
did not vomit. 
  
Cycle #: _____              Start Date: |__/__|__/__|__/__|              End Date: |__/__|__/__|__/__|  
 
kg: _____   Dose: ________mg/kg     Total Daily Dose per Nomogram: ___________ mg 
 
WEEK 1 
Date 
Time 
Amount of solution 
taken (total mL per 
dose) 
Comments 
Day 1: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 2: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 3: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 

  
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Day 4: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 5: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 6: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 7: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
 
 
 
WEEK 2 
Date 
Time 
Amount of solution 
taken (total mL per 
dose) 
Comments 
Day 8: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 9: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 10: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 11: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 12: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 13: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 14: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
 
 
 
  
WEEK 3 
Date 
Time 
Amount of solution 
taken (total mL per 
dose) 
Comments 
Day 15: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 16: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 

  
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Day 17: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 18: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 19: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 20: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 21: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
 
WEEK 4 
Date 
Time 
Amount of solution 
taken (total mL per 
dose) 
Comments 
Day 22: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 23: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 24: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 25: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 26: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 27: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
Day 28: 
__________ 
 
 
AM / PM 
# mL prescribed:_____ 
 
# mL taken: _____ 
 
 
 
 
Comments: 

  
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APPENDIX VIII: WALLET CARD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of your 
healthcare providers and keep it 
with you in case you go to the 
emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:  ADV1521 
Study Drug(S):  Trametinib 
 
 
 
 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 

  
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APPENDIX IX: BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT 
PERCENTILE 
 
Blood pressure (BP) levels for BOYS: 
 
Instructions for using this BP Chart: 
1. Measure the patient’s blood pressure using an appropriate size cuff. 
2. Select appropriate chart for female or male patient. 
3. Using the “age” row and “height” column determine if the BP is within the ULN. 
4. See Section 5.1.1 for definition of dose limiting hypertension. See Section 5.4.9.2 for management and grading of 
hypertension. 
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High 
BloodPressure in Children and Adolescents” PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576.  
 
Note: For patients ≥ 18 yrs, ULN BP is 140/90 mmHg. 

  
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Blood pressure (BP) levels for GIRLS: 
 
 
Instructions for using this BP Chart: 
1. Measure the patient’s blood pressure using an appropriate size cuff. 
2. Select appropriate chart for female or male patient. 
3. Using the “age” row and “height” column determine if the BP is within the ULN. 
4. See Section 5.1.1 for definition of dose limiting hypertension. See Section 5.4.9.2 for management and grading of 
hypertension. 
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High 
BloodPressure in Children and Adolescents” PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576.  
 
Note: For patients ≥ 18 yrs, ULN BP is 140/90 mmHg. 
 

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

  
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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.,  

  
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Version Date: 07/22/2022 
40. 
Visual disorders include visual disturbance that can be associated with conjunctival hemorrhage, 
corneal graft rejection, cyclitis, eye nevus, halo vision, iritis, macular edema, retinal hemorrhage, 
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Generalized edema includes edema, lymphedema, and edema limbs.,  
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Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased 
liver function tests, and visual disturbances.,  
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Skin and subcutaneous tissue disorders - Other (rash) may include rash, rosacea, erythematous 
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seborrhoeic dermatitis, dermatitis psoriasiform, rash follicular, skin fissures, and skin chapped.,  
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fatal intracranial hemorrhages have been reported.,  
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