Clinical trial NCT03213665
Conditions: Advanced Malignant Solid Neoplasm Ann Arbor Stage III Hodgkin Lymphoma Ann Arbor Stage III Non-Hodgkin Lymphoma Ann Arbor Stage IV Hodgkin Lymphoma Ann Arbor Stage IV Non-Hodgkin Lymphoma Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor Low Grade Glioma Recurrent Ependymoma Recurrent Ewing Sarcoma Recurrent Glioma Recurrent Hepatoblastoma Recurrent Hodgkin Lymphoma Recurrent Langerhans Cell Histiocytosis Recurrent Malignant Germ Cell Tumor Recurrent Malignant Glioma Recurrent Malignant Solid Neoplasm Recurrent Medulloblastoma Recurrent Neuroblastoma Recurrent Non-Hodgkin Lymphoma Recurrent Osteosarcoma Recurrent Peripheral Primitive Neuroectodermal Tumor Recurrent Primary Central Nervous System Neoplasm Recurrent Rhabdoid Tumor Recurrent Rhabdomyosarcoma Recurrent Soft Tissue Sarcoma Refractory Hodgkin Lymphoma Refractory Langerhans Cell Histiocytosis Refractory Malignant Germ Cell Tumor Refractory Malignant Glioma Refractory Malignant Solid Neoplasm Refractory Medulloblastoma Refractory Neuroblastoma Refractory Non-Hodgkin Lymphoma Refractory Osteosarcoma Refractory Peripheral Primitive Neuroectodermal Tumor Refractory Rhabdoid Tumor Refractory Soft Tissue Sarcoma Rhabdoid Tumor Stage III Soft Tissue Sarcoma AJCC v7 Stage IV Soft Tissue Sarcoma AJCC v7 Wilms Tumor
Sponsor: National Cancer Institute (NCI)
Start date: 2017-11-13; Completion date: 2024-12-31
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II Pediatric MATCH trial studies how well tazemetostat works in treating patients with brain tumors, solid tumors, non-Hodgkin lymphoma, or histiocytic disorders that have come back (relapsed) or do not respond to treatment (refractory) and have EZH2, SMARCB1, or SMARCA4 gene mutations. Tazemetostat may stop the growth of tumor cells by blocking EZH2 and its relation to some of the pathways needed for cell proliferation.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with tazemetostat with advanced solid tumors (including central nervous system \[CNS\] tumors), non-Hodgkin lymphoma or histiocytic disorders that harbor gain of function mutations in EZH2, or loss of function mutations in the SWI/SNF complex subunits SMARCB1 or SMARCA4 at a dose of 520 mg/m\^2/dose twice daily for patients without any CNS involvement or 1200 mg/m\^2/dose orally twice daily for patients with CNS involvement.

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival in pediatric patients treated with tazemetostat that harbor gain of function mutations in EZH2, or loss of function mutations in the SWI/SNF complex subunits SMARCB1 or SMARCA4.

II. To obtain information about the tolerability of tazemetostat in children with relapsed or refractory cancer.

EXPLORATORY OBJECTIVES:

I. To evaluate other biomarkers as predictors of response to tazemetostat and specifically, whether tumors that harbor different missense mutations or fusions will demonstrate differential response to tazemetostat treatment.

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

OUTLINE:

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

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

Arms: arm 1: Patients receive tazemetostat PO BID on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Tazemetostat
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
  
 
 
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 
 
Executive Director of 
Administration and Finance 
Jennifer Bandich, MBA 
jbandich@childrensoncology 
group.org 
 
Group Operations Center  
and 
Statistics & Data Center  
(SDC) Headquarters 
800 Royal Oaks Drive 
Suite 210 
Monrovia, CA 91016 
P 626 241 1500 
F 626 445 4334 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A National Cancer Institute- 
funded group member of the  
National Clinical Trials Network 
June 15, 2021 
 
 
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, 
 
Please find attached Amendment #5 to APEC1621C, NCI-COG Pediatric MATCH 
(Molecular Analysis for Therapy Choice) - Phase 2 subprotocol of tazemetostat for patients 
with tumors harboring alterations in EZH2 or members of the SWI/SNF complex 
 
Amendment #5 provides a response to a Request for Amendment (RA) from CTEP, dated 
May 11, 2021. The CAEPR within the protocol and associated risk information 
contained within the consent document for Tazemetostat, NSC 791066 have 
been modified to satisfy the RA received. Additionally, minor administrative changes have 
been included in to the protocol. CRFs have been updated to include changes to the 
language of the inclusion criteria. No changes have been made to the training module 
Please contact us if you have any further questions. 
 
Sincerely, 
 
Samuel Baird, MPH, Protocol Coordinator for 
Susan Chi, M.D., APEC1621C Study Chair, and 
Donald Parsons, M.D., PhD, PI, Chair, Molecular Analysis for Therapy Choice 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ii 
 
 
I. 
Protocol Changes: 
Section 
Comment 
Throughout 
Updated amendment number and version dates.  
Table 
of 
Contents 
Updated on repagination. 
Study 
Committee 
Updated PC, RC and MS statistician Information. 
9.1.9 
Updated CAEPR to version 2.4, March 30, 2021, per RA instructions. 
Appendix II 
Updated Appendix to most recent version. 
 
 
 
 


 
 
APEC1621C 
Version Date: 06/15/2021 
 
1 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
APEC1621C 
 
NCI-COG PEDIATRIC MATCH 
(MOLECULAR ANALYSIS FOR THERAPY CHOICE)- 
PHASE 2 SUBPROTOCOL OF TAZEMETOSTAT IN PATIENTS WITH TUMORS 
HARBORING ALTERATIONS IN EZH2 OR MEMBERS OF THE SWI/SNF COMPLEX 
 
Open to COG Member Institutions in the USA  
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED 
OR USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN 
THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY 
ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT 
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL 
HOSPITAL OR HEALTHCARE INSTITUTION. 
 
STUDY CHAIR 
 
 
 
 
 
 
 
 
 
Activated: 
July 24th, 2017 
                 Version Date: 06/15/2021 
Closed: 
05/07/2021 
                 Amendment: 5 
 
 
 
 
 
Susan Chi, MD 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 
Phone: (617) 632-4386 
Fax: (617) 632-4897 
Email: susan_chi@dfci.harvard.edu 


 
 
APEC1621C 
Version Date: 06/15/2021 
 
2 
 
 
TABLE OF CONTENTS
 
SECTION 
 
PAGE 
CHILDREN’S ONCOLOGY GROUP 
1 
STUDY COMMITTEE, CONT. 
4 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Aims 
8 
1.2 
Secondary Aims 
8 
1.3 
Exploratory Aims 
8 
2.0 
BACKGROUND 
8 
2.1 
Introduction/Rationale for Development 
8 
2.2 
Preclinical Studies 
9 
2.3 
Adult Studies 
10 
2.4 
Pediatric Studies 
11 
2.5 
Overview of Proposed Pediatric Study 
12 
2.6 
Rationale for Amendment #1 (Increase in Dose Level) 
13 
2.7 
Rationale for Amendment #3B T-cell Lymphoblastic Lymphoma Monitoring (changes in 
dose level) 
13 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
14 
3.1 
Genetic Screening Procedures for Eligibility 
14 
3.2 
IRB Approval 
14 
3.3 
Informed Consent/Assent 
15 
3.4 
Screening Procedures 
15 
3.5 
Eligibility Checklist 
15 
3.6 
Study Enrollment 
15 
3.7 
Institutional Pathology Report 
16 
3.8 
Dose Assignment 
16 
4.0 
PATIENT ELIGIBILITY 
16 
4.1 
Inclusion Criteria 
16 
4.2 
Exclusion Criteria 
20 
5.0 
TREATMENT PROGRAM 
21 
5.1 
Overview of Treatment Plan 
21 
5.2 
Criteria for Starting Subsequent Cycles 
22 
5.3 
Grading of Adverse Events 
22 
5.4 
Definition of Dose-Limiting Toxicity (DLT) 
22 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
23 
6.1 
Dose Modification for Patients Newly Diagnosed with T-LBL/T-ALL 
23 
6.2 
Dose Modifications for Hematological Toxicity 
24 
6.3 
Dose Modifications for Non-Hematological Toxicity 
24 
6.4 
Dose Modifications for Toxicities Related to Bromide 
24 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
26 
7.1 
Concurrent Anticancer Therapy 
26 
7.2 
Investigational Agents 
26 


                                        
 
     APEC1621C 
 
                                                                                                                      
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3 
7.3 
Supportive Care 
26 
7.4 
Growth Factors 
26 
7.5 
Concomitant Medications 
26 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
27 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
27 
8.2 
Monitoring for Specific Toxicities 
28 
8.3 
Radiology Studies 
29 
8.4 
Circulating Tumor DNA Study (optional) 
31 
9.0 
AGENT INFORMATION 
33 
9.1 
Tazemetostat 
33 
9.2 
Agent Ordering and Agent Accountability 
38 
9.3 
Clinical Drug Request and Investigator Brochure Availability 
38 
9.4 
Agent Inventory Records 
38 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
39 
10.1 
Criteria for Removal from Protocol Therapy 
39 
10.2 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
39 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
40 
11.1 
Sample Size 
40 
11.2 
Dosing Considerations 
40 
11.3 
Study Design 
40 
11.4 
Methods of Analysis 
41 
11.5 
Evaluability for Response 
41 
11.6 
Evaluability for Toxicity 
41 
11.7 
Progression free survival (PFS) 
42 
11.8 
Correlative Studies 
42 
11.9 
Gender and Minority Accrual Estimates 
42 
12.0 
EVALUATION CRITERIA 
42 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
42 
12.2 
Progression-Free Survival 
42 
12.3 
Response Criteria for Patients with Solid Tumors 
43 
12.4 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
46 
12.5 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
48 
12.6 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
50 
12.7 
Response Criteria for Patients with CNS Tumors 
51 
12.8 
Response Criteria for Patients with non-Hodgkin Lymphoma/Histiocytosis 
53 
12.9 
Best Response 
55 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
56 
13.1 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
56 
13.2 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
57 
13. Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements: 58 
13.4 
Definition of Onset and Resolution of Adverse Events 
59 
13.5 
Other Recipients of Adverse Event Reports 
60 
13.6 
Specific Examples for Expedited Reporting 
60 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
62 
14.1 
Categories of Research Records 
62 
14.2 
CDUS 
62 


                                        
 
     APEC1621C 
 
                                                                                                                      
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4 
14.3 
CRADA/CTA/CSA 
62 
14.4 
Data and Safety Monitoring Plan 
64 
REFERENCES 
65 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
66 
APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
67 
APPENDIX III-A:  MEDICATION DIARY FOR TAZEMETOSTAT (ORAL SUSPENSION 
FORMULATION) 
70 
APPENDIX III-B:  
PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
73 
APPENDIX IV: TAZEMETOSTAT DOSING PREPARATION (ORAL SUSPENSION 
FORMULATION) 
75 
APPENDIX V: APEC1621C THERAPY DELIVERY MAP 
77 
Therapy Delivery Map – Cycle 1 
77 
Required Observations in Cycle 1 
78 
All Subsequent Cycles 
80 
APPENDIX VI: TARGET HISTOLOGIES FOR APEC1621C EXPANSION COHORTS 
83 
APPENDIX VII: APEC1621C ACTIONABLE MUTATIONS OF INTEREST 
84 
APPENDIX VIII CORRELATIVE STUDIES GUIDE 
85 
APPENDIX IX YOUTH INFORMATION SHEETS 
86 
APPENDIX X CTEP AND CTSU REGISTRATION PROCEDURES 
88 
APPENDIX XI: TOXICITY-SPECIFIC GRADING 
91 
 


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3 
STUDY COMMITTEE 
STUDY CHAIR 
Nita Seibel, MD 
Susan Chi, MD 
National Cancer Institute 
Dana-Farber Cancer Institute 
9609 Medical Center Drive, MSC 9739 
450 Brookline Ave 
Rockville, MD 20892 
Boston, MA 02215 
Phone:  (240) 276-6560 
Phone: (617) 632-4386 
Fax:  (240) 276-7892 
Fax: (617) 632-4897 
E-mail: seibelnl@mail.nih.gov  
Email: susan_chi@dfci.harvard.edu 
 
 
Peter C. Adamson, MD 
STUDY VICE CHAIR 
Children’s Hospital of Philadelphia 
Joanna Yi, M.D 
3501 Civic Center Blvd CTRB-10060 
Pediatric Hematology/Oncology 
Philadelphia, PA 19104 
Baylor College of Medicine 
Phone:  (215) 590-6359 
1102 Bates, Suite 1220 
Fax:  (215) 590-7544 
Houston, TX 77030 
Email: adamson@email.chop.edu 
Phone: (832) 824-6699 
 
Fax: (832) 825-4039 
Stacey Berg, MD 
Email: jsyi@texaschildrens.org 
Study Design and Logistics 
 
Baylor College of Medicine 
 
Pediatric Oncology  
Will Parsons, MD, PhD  
6621 Fannin Street 
Baylor College of Medicine 
MC3-3320 
1102 Bates, Suite 1030.15 
Houston, TX 77030 
Houston, TX 77030 
Phone: (832) 824-4588 
Phone: (832) 824-4643 
Fax:  (832) 825-4039 
Email: dwparson@txch.org 
Email: sberg@txch.org 
 
 
Todd Alonzo, PhD 
Elizabeth Fox, MD 
Study Statistician  
Study Design and Logistics 
COG Statistics and Data Center- Monrovia 
Children’s Hospital of Philadelphia 
222 East Huntington Dr., Suite 100 
Pediatrics/Division of Oncology 
Monrovia, CA 91016 
3501 Civic Center Blvd CTRB-4016 
Phone: (626) 241-1522 
Philadelphia, PA 19104 
Fax: (626) 445-4334 
Phone: (267) 425-3010 
Email: talonzo@childrensoncologygroup.org 
Fax:  (267) 425-0113 
 
Email: foxe@email.chop.edu 
Joel Reid, PhD. 
 
Study Pharmacologist 
Jin Piao, PhD 
Mayo Clinic 
Study Statistician 
Guggenheim 17-37 
COG Statistics and Data Center- Monrovia 
200 First St SW 
222 East Huntington Dr., Suite 100 
Rochester, MN 55905 
Monrovia, CA 91016 
Phone: (507) 284-0822 
Phone: (626) 241-1572 
Fax: (507) 284-3906 
Fax: (626) 445-4334 
E-mail: reid.joel@mayo.edu  
Email: jpiao@childrensoncologygroup.org 
 
 
 


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Version Date: 06/15/2021 
 
4 
STUDY COMMITTEE, CONT. 
 
 
STUDY CRA 
TBD 
STUDY PHARMACIST  
Sarah Newman, PharmD 
 
Nicklaus Children's Hospital 
COG PEP-CTN PROTOCOL COORDINATOR 
3100 SW 62nd Ave. 
Samuel Baird, MPH 
Miami, FL 33155 
Children's Oncology Group 
Phone: (786) 624-2478 
Phone: (626) 214-1619 
E-mail: sarah.newman@mch.com 
E-mail: sbaird@childrensoncologygroup.org 
 
 
 
COG PEP-CTN RESEARCH COORDINATOR 
 
Nikita Patel, BS 
 
Children's Oncology Group 
 
Phone: (626) 241-1599 
 
E-mail: nipatel@childrensoncologygroup.org 
 
 
 
COG PEP-CTN STATISTICIAN 
For Group Operations (GOC) and 
Lauren Saguilig-Doyle, MS 
Statistics & Data Center (SDC) contacts see: 
Children's Oncology Group 
https://members.childrensoncologygroup.org 
Phone: (626) 241-1547 
 
E-mail: lsaguilig@childrensoncologygroup.org 
AGENT NSC# AND IND#’s 
 
NCI-Supplied Agents: 
Tazemetostat 
 
(NSC# 791066) 
 
IND Sponsor: DCTD, NCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about subjects collected during the course of our covered studies.  The 
researchers involved in the studies cannot be forced to disclose the identity or any information collected in 
the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings.  However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances.  For example, if the subject or his/her 
guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
ABSTRACT 
This subprotocol is a component of the NCI-COG Pediatric MATCH trial APEC1621. The APEC1621SC 
screening protocol details the assay used for the integral genomic profiling which will determine eligibility 
for this subprotocol. Here we will conduct a phase 2 trial of tazemetostat in children with recurrent or 
refractory solid tumors (including non-Hodgkin lymphomas, histiocytoses and CNS tumors) harboring 
specified activating genetic alterations in EZH2 or members of the SWI/SNF complex. EPZ-6438 
(tazemetostat) is a selective small molecule inhibitor of the histone methyltransferase EZH2.1 Tazemetostat 
will be administered orally twice daily at the recommended phase 2 dose (RP2D) as determined by the 
ongoing pediatric phase 1 trial. The primary endpoint will be objective response rate as determined by 
RECIST. Progression-free survival (PFS) will be assessed as a secondary endpoint. 
 
EXPERIMENTAL DESIGN SCHEMA 
For patient(s) enrolled Pre-amendment #3B: 
 
Day 1-28 
Day 28 
Tazemetostat 1200 mg/m2/dose 
 (Orally, twice daily) 
Evaluation 
 
For patient(s) enrolled post-amendment #3B: 
Patients without CNS 
involvement  
Day 1-28 
Day 28 
Tazemetostat 
520mg/m2/dose  
(Orally, twice daily) 
 
Evaluation                
 
Patients with CNS 
involvement  
Tazemetostat 1200 
mg/m2/dose  
(Orally, twice daily)  
 
Evaluation                
 
 
 
Tazemetostat will be administered orally twice daily (based on disease location per above table); a cycle 
will be 28 days.  
 
Tumor evaluations will occur at the end of every other cycle x 3, then every 3 cycles. 
 


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8 
Therapy will be discontinued if there is evidence of progressive disease or drug related dose-limiting 
toxicity that requires removal from therapy (Section 6.0). Therapy may otherwise continue for up to 2 years 
(maximum of 26 cycles) provided the patient meets the criteria for starting subsequent cycles (Section 5.2) 
and does not meet any of the criteria for removal from protocol therapy criteria (Section 10.0).  
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
 
To determine the objective response rate (ORR; complete response + partial 
response) in pediatric patients treated with tazemetostat with advanced solid 
tumors(including CNS tumors), non-Hodgkin lymphoma or histiocytic disorders 
that harbor gain of function mutations in EZH2, or loss of function mutations in 
the SWI/SNF complex subunits SMARCB1 or SMARCA4 at a dose of 520 
mg/m2/dose twice daily for patients without any CNS involvement  or 1200 
mg/m2/dose orally twice daily for patients with CNS involvement.   
 
1.2 
Secondary Aims 
 
 
To estimate the progression-free survival in pediatric patients treated with 
tazemetostat that harbor gain of function mutations in EZH2, or loss of function 
mutations in the SWI/SNF complex subunits SMARCB1 or SMARCA4. 
 
 
To obtain information about the tolerability of tazemetostat in children with 
relapsed or refractory cancer. 
 
1.3 
Exploratory Aims 
 
 
To evaluate other biomarkers as predictors of response to tazemetostat and 
specifically, whether tumors that harbor different missense mutations or fusions 
will demonstrate differential response to tazemetostat treatment. 
 
 
To explore approaches to profiling changes in tumor genomics over time through 
evaluation of circulating tumor DNA. 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
Histone methyltransferases (HMT) play a critical role in the transcriptional control. EZH2 
(Enhancer of zeste homologue-2) is the catalytic subunit of the multi-protein Polycomb 
Repressive Complex 2 (PRC2) and PRC2 is the only human HMT that can methylate 
H3K27 (lysine 27 of histone H3), catalyzing the mono, di and tri-methylation of H3K27.2 
Hyper-trimethylation of H3K27 is transcriptionally repressive, resulting in the silencing of 
tumor suppressor genes.  Aberrant trimethylation of H3K27 has been postulated to be 
oncogenic in a broad spectrum of human cancers including non-Hodgkins lymphoma, INI-
1 deficient tumors, carcinomas, cutaneous melanoma, gliomas, medulloblastoma, and 
ependymoma via mutation, amplification and overexpression.   
 
EZH2 overexpression is mainly found in solid tumors, whereas activating or inactivating 
mutations are identified in hematologic malignancies. EZH2 gain of function mutations 
were initially identified in NHL3, specifically in follicular lymphoma (FL, 7.2%) and 


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diffuse large B-cell lymphoma (DLBCL, 9.7%, exclusively in germinal center B-cell 
[GCB] subtype). Genetic databases suggest that the incidence of EZH2 point mutations is 
15-25% in FL and GCB-DLBCL.  The oncogenic mutations at tyrosine 646 (Y646), A682 
and A692 are those responsible for an excess of H3K27me3 repressive marks, impairing 
gene expression programs in lymphomas. 
 
A natural antagonistic relationship between the SWI/SNF complex and PRC2 complex has 
been demonstrated with regards to stem cell-associated program. Loss of SWI/SNF 
complex members, such as SMARCB1, has been demonstrated to aberrantly activate those 
programs.4 Consistent with the reciprocal relationship of PRC2 and SWI/SNF conditional 
mouse models, genetic inactivation of EZH2 has been shown to block tumor formation 
driven by SMARCB1 loss.  
 
It is not possible to precisely determine the frequency of relevant genetic alterations in 
childhood malignancies eligible for this arm of the pediatric MATCH protocol using 
available databases. Detection of such genetic alterations requires advanced sequencing 
methods yet these methods have not been utilized on a sufficient number or broad diversity 
of samples from recurrent childhood solid tumors and lymphomas, as such data is limited 
to determine an accurate prediction of frequency.  
 
2.2 
Preclinical Studies 
 
 
Antitumor Activity 
Tazemetostat has been shown to induce apoptosis and differentiation in INI1-
negative MRT cell lines.5 In xenograft-bearing mice, treatment with tazemetostat 
resulted in dose-dependent regression of MRTs with correlated diminution of 
intra-tumoral H3K27 methylation and prevention of tumor regrowth after dosing 
cessation. See Section 2.3.3 for further preclinical experience including human 
lymphoma cell lines, SMARCB1-deficient malignant rhabdoid tumor (MRT) cell 
lines, and SMARCA2/A4 negative small cell carcinoma of the ovary, 
hypercalcemic type (SCCOHT) cell lines. 
 
 
Animal Toxicology 
Non-clinical repeated-dose oral toxicity studies in Sprague-Dawley (S-D) rats and 
cynomolgus monkeys, which may be relevant to human safety, revealed the following 
toxicities and target organs in the two species as follows: 
- 
In the gastrointestinal (GI) tract: ulcer/erosion in the stomach, duodenum, jejunum, 
and/or ileum 
- 
In lymphoid tissues: lymphoid depletion 
- 
In a 13-week study in adult S-D rats, T- cell lymphoma o c c ur r ed  in  a non - dose 
and non-concentration related fashion and was observed in 11 of 40 rats at 300 
mg/kg/day (mid-dose) and in 1 of 40 animals at 600 mg/kg/day (high dose) dose 
groups. No cases of lymphoma were observed in the 100 mg/kg/day (low dose) 
tazemetostat dose cohort in adult rats or at any dose cohort (100-600 mg/kg/day) in 
cynomolgus monkeys treated for 4 or 13 weeks. In a 13-week study in juvenile S-D 
rats, thymic lymphoma was observed in male and female animals.  However, the 
incidence of T-cell lymphoma did not increase continuously as systemic exposure to 
tazemetostat increased.  At doses that resulted in steady-state AUC0-24 values less than 
100,000 ng*h/mL, T-cell lymphoma was observed in 2/81 juvenile rats.  However, 
T-cell lymphoma was observed in 24/63 juvenile rats at doses that resulted in AUC0-24 
from 125,000 ng*h/mL to 290,000 ng*h/mL. The greatest tazemetostat AUC0-24 was 


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425,000 ng*h/mL and was observed in female juvenile rats that received 150/600 
mg/kg/day tazemetostat.  T-cell lymphoma was observed in 2/20 female juvenile rats 
in the tazemetostat 150/600 mg/kg/day dose group.  The etiology of the rat lymphoma 
is currently unknown, but does not appear to be related to alterations in the Notch 
signaling pathway or endogenous rat leukemia virus reactivation. Please see Section 
2.7 for relevance to pediatric patients. 
- 
In bone in S-D rats only: there was trabecular bone formation in the femur and 
sternum in the 4- and 13-week studies 
- 
In the serum of monkeys only: increase of chloride due to bromide derived from the 
tazemetostat bromide salt formulation (subsequent Phase 1 studies in humans have 
determined no detectable bromide levels) 
- 
In the liver of monkeys only: hepatocyte and Kupffer cell hypertrophy in the 4-week 
and 13-week studies, which was accompanied by pigmentation of Kupffer cells and 
bile duct hyperplasia in some cases in the 13-week study 
- 
In the kidney of monkeys only: glomerulopathy in the 13-week study 
 
Additional animal toxicology is provided in the Investigator’s Brochure (IB) for 
tazemetostat. 
 
2.3 
Adult Studies 
 
 
Phase 1 Studies 
Epizyme has conducted a Phase 1/2, first-in-human clinical study (E7438-G000-
101, NCT01897571), a multicenter, open-label, dose-escalation study in adult 
patients with advanced solid tumors.  The Phase 1 portion of this study completed 
enrollment in December 2015.  Fifty-eight adult patients (21 B-cell lymphomas, 
37 solid tumors) were enrolled and treated at five dose levels of 100, 200, 400, 
800, and 1600 mg BID. Tazemetostat PK exhibits rapid absorption, Tmax =1-2 hrs 
post-dose, as well as rapid elimination (t1/2 ~ 3-5 hr), justifying twice daily dosing. 
Tazemetostat exposure was linearly dose-proportional with maximal inhibition 
(~40%) at observed at the 800 mg and 1600 mg dose levels.  Correlation between 
dose exposure and target inhibition (decreased H3K27Me3 inhibition by IHC of 
skin) was demonstrated. One DLT of thrombocytopenia was reported at the 1600 
mg dose level. The most frequently occurring adverse events (≥ 15%) were 
asthenia, anemia, decreased appetite, muscle spasms, nausea, vomiting, 
constipation, thrombocytopenia, and dyspnea. All other adverse events occurred 
with a frequency of < 15% of patients.  In the B-cell lymphoma cohort, 3 CR and 
5 PR were observed.  One CR was observed in the solid tumor cohort, this subject 
had malignant rhabdoid tumor.  To date, 8 subjects with INI1-negative tumors have 
been treated.  Two subjects have had objective responses (1 CR and 1 PR) and one 
with SD (with 15% reduction in tumor). Based on the safety, PK, biological 
activity and responses, the RP2D was determined to be 800 mg BID. 
 
The most common treatment-emergent AEs in all studies to date, in descending 
order of frequency, were asthenia, nausea, thrombocytopenia, decreased appetite, 
anemia, constipation, dysgeusia, vomiting, diarrhea, dry skin, dyspnea, muscle 
spasms, and abdominal pain. 
 
The effect of food on the bioavailability of tazemetostat and the drug-drug 
interaction (DDI) potential of tazemetostat has been evaluated in adults. 
Administration of tazemetostat with a high-fat meal resulted in a non-clinically 


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relevant effect on systemic disposition and overall systemic exposure, thus 
tazemetostat may be taken without regard to meals.  Tazemetostat is metabolized 
primarily by CYP3A. It is a weak inducer of CYP3A4/5 isozyme as well as an 
inhibitor of the CYP3A, CYPA2C family, CYP2D6 and P-glycoprotein (P-gp). 
A Phase 2 study is ongoing for subjects with relapsed/refractory DLBCL and FL.    
 
 
Phase 2 Studies 
Currently, Epizyme is conducting a Phase 2 clinical study (NCT02601950) for 
adult subjects with INI1-negative tumors or relapsed/refractory synovial sarcoma 
as well as a Phase 2 clinical study (NCT02860286) in adult subjects with malignant 
mesothelioma with BAP1 loss of function. 
 
 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
EPZ-6438 (tazemetostat) is a selective small molecule inhibitor of the histone 
methyltransferase EZH2.1  Tazemetostat is an inhibitor of both wild type and 
mutated EZH2 containing residues Y646, A682G and A692 with half maximal 
inhibitory concentrations (IC50) ranging from 2-38 nmol/L.  The compound shows 
a 35-fold selectivity over the most closely related HMT, EZH1, and greater than a 
4500-fold selectivity over other HMTs.  It selectively inhibits H3K27 methylation 
in a concentration and time dependent manner leading to selective killing of cell 
lines, specifically, human lymphoma cell lines with mutant or wildtype EZH2, 
SMARCB1-deficient malignant rhabdoid tumor (MRT) cell lines, and 
SMARCA2/A4 negative SCCOHT cell lines with IC50 in the nanomolar range.  
Tazemetostat administered orally has demonstrated antitumor activity in vivo 
against several EZH2 wild type and mutant human lymphoma xenograft murine 
models.6 SMARCB1 mutant MRT xenografts treated for 21-28 days demonstrated 
near elimination of the tumors with no regrowth observed.  The MRT tumors 
demonstrated strong inhibition of H3K27Me3 which correlated with anti-tumor 
activity.5    
 
2.4 
Pediatric Studies 
 
 
Prior Experience in Children  
The first pediatric phase 1 study of tazemetostat (EZH-102, NCT02601937) for 
children with relapsed/refractory malignant rhabdoid tumors, including CNS 
ATRT, and other INI-deficient tumors and synovial sarcoma enrolled its first 
patient in January 2016 and completed the dose escalation phase of the trial (dose 
expansion is ongoing).  As of July 2017, the RP2D was determined to be 1200 
mg/m2/dose twice daily. On this study, a liquid formulation of tazemetostat is 
administered PO BID. Pharmacology, pharmacokinetics and correlative 
biological studies are currently being collected in the ongoing phase 1study.   
 
 
Hydrobromide Salt Formulation 
 
An analysis of chloride levels in subjects on study EZH-102 at the 1200 mg/m2 
dose level showed elevated chloride levels (beyond the ULN) in 5/7 subjects who 
had been treated at this dose level. Reviewing this finding further, subjects at lower 
dose levels (4/6 subjects at 900 mg/m2, 4/6 subjects at 700mg/m2 and 4/6 subjects 
at 520 mg/m2) also demonstrated elevated chloride levels.  
Hyperchloremia is considered an artifact resulting from interference of serum 
bromide with the serum chloride assay (tazemetostat is a bromide salt). The 


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hydrobromide salt of tazemetostat is the form used in clinical studies, including 
the EZH-102 study. Bromide may artificially increase chloride measurements, and 
this phenomenon was noted in non-clinical studies of tazemetostat in which 
artifactually elevated serum chloride was noted in repeat-dose toxicology studies 
of tazemetostat in rats and monkeys at doses up to 1000 mg/kg/day (equivalent 
surface area doses in humans = 142-333 mg/m2).  Ion exchange chromatography 
showed increased serum chloride in these nonclinical studies to be pseudo-
hyperchloremia, representing increased bromide and decreased chloride in serum. 
Due to this nonclinical finding, which could indicate the potential for elevated 
bromide levels in clinical studies, bromide levels were measured in the Phase 1 
study of tazemetostat in adults. Bromide was within normal levels (<6.2 mmol/L) 
for all subjects taking the oral tablet formulation in doses up to 1600 mg BID. 
However, mean tazemetostat AUC(0-24) in children at the 1200 mg/m2 dose level 
exceeded that observed in the 1600 mg BID dose group in adults from Study 
E7438-G000-101.  There is a potential risk of bromide toxicity related to the 
hydrobromide salt used in the formulation of tazemetostat.  Signs of bromide 
toxicity consist of CNS AEs including lethargy, headache, ataxia, and coma. No 
subject on any study as of 20 July 2017 has been reported to have experienced AEs 
consistent with bromide toxicity. 
Although bromide is no longer typically used as an anti-epileptic agent, it has been 
used in the past as a treatment for refractory epilepsy. Thus, there are few current 
published guidelines for therapeutic monitoring and treatment of bromide.  Ryan 
and Baumann (1999) presented an overview of available literature which provides 
therapeutic bromide ranges including levels associated with bromide toxicity. As 
different units of measure have been used at various testing laboratories with no 
clear preferred unit of measure used, the authors recommend the following 
conversion: 1 mEq/L = 8 mg/dL = 0.96 mmol/L.  The central testing laboratory 
(ARUP) being utilized in the EZH-102 study provides results using the mg/dL unit 
of measure.  The authors report therapeutic ranges as being between 10-35 mEq/L 
(80-280 mg/dL) with toxicity occurring in some studies at approximately the 20 
mEq/L range (160 mg/dL).  Elevated bromide levels can cause neurologic toxicity; 
drowsiness is often the first symptom that may occur and has been reported at 
levels of 20 mEq/L (160 mg/dL), with severe neurologic symptoms occurring at 
200 mg/dL or greater.   
To date, no patients on EZH-102 have experienced any adverse events that are 
suggestive or indicative of bromide toxicity.  However, assessment of bromide 
levels was instituted in the Phase 1 study and therefore will be incorporated into 
this subarm protocol. 
2.5 
Overview of Proposed Pediatric Study 
For patients with CNS involvement, Tazemetostat will be administered orally at the MTD 
and recommended phase 2 dose (RP2D) of 1200 mg/m2/dose BID. Patients without any 
CNS involvement will be administered Tazemetostat orally at the lower starting dose of 
520mg/m2/dose BID. For patient(s) enrolled pre-amendment #3B Tazemetostat will be 
administered orally at the MTD and recommended phase 2 dose (RP2D) of 1200 
mg/m2/dose BID. 
 
The primary aim of this trial will be to establish the objective response rate to tazemetostat. 
 


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Key secondary objectives include further evaluation of the tolerability of tazemetostat in 
pediatric patients.  Toxicity will be assessed using CTCAE v5.0.  Imaging for disease 
evaluation will occur every other cycle x 3, then every three cycles.  Disease response will 
be assessed according to RECIST v1.1 for solid tumors and 2-dimensional measurement 
for CNS tumors. 
 
 
2.6 
Rationale for Amendment #1 (Increase in Dose Level) 
The purpose of Amendment #1 is to increase the starting dose level from 900 mg/m2 BID 
to 1200 mg/m2 BID. The most common treatment- emergent adverse events (TEAE) were 
vomiting (41%), pyrexia (28%), headache (24%), and nausea (24%), while the most 
common grade ≥3 TEAEs were death (17%, all unrelated to study drug) and anemia (9%). 
One patient at the 300 mg/m2 dose level had DLTs of dyspnea (grade 4) and hypoxia (grade 
3), however, no other DLT s were noted in any other cohort.   Though the “rolling 6” design 
of the pediatric Phase I clinical trial supported further escalation of the dose level, of special 
note, elevated serum chloride levels were observed in 3/6 evaluable patients at the 1200 
mg/m2 BID dose level as well as in earlier dose levels (retrospective observation). The 
observed hyperchloremia was considered to be factitious and related to the formulation of 
tazemetostat as a bromide salt.  Elevated serum bromide levels were detected in 2/5 active 
patients without any associated clinical signs or symptoms. With these data and on the 
basis of pharmacodynamic activity demonstrating H2K27me3 in peripheral mononuclear 
cells, as of July 2017, the RP2D was determined to be 1200 mg/m2/dose twice daily. 
 
2.7 
Rationale for Amendment #3B T-cell Lymphoblastic Lymphoma Monitoring 
(changes in dose level) 
In the Epizyme-sponsored pediatric phase I trial, one child developed T-cell lymphoblastic 
lymphoma (T-LBL) after receiving tazemetostat for 14 months.  As of 1 May 2018, this is 
the only case of T-cell lymphoma that has occurred out of a total of 79 children enrolled in 
tazemetostat clinical trials. In addition, there have been no cases of T-LBL or related T-
acute lymphoblastic leukemia (T-ALL) in the 702 adult patients treated across multiple 
studies conducted in different types of cancer. All tazemetostat trials were temporarily 
halted while a risk assessment was conducted. Pediatric patients were noted to have higher 
tazemetostat exposures than had been seen in adults (specifically high AUC (0-24h)). In 
the company’s assessment, the risk for T-LBL/T-ALL in tazemetostat clinical trials 
appears to be largely concentrated in pediatric patients based on: 
 
1) The known epidemiology / pathophysiology of T-LBL/ALL.  
2) Age-related intact and active thymus (thymic involution increases over time 
with reduced risk with increasing age) 
3) Higher AUC (0-24h) exposures in pediatric patients   
 
Based on these data, amendment 3B will adjust the dosing for new APEC1621C patients 
based on site of disease (CNS vs. non-CNS) and will allow for increased monitoring of T-
LBL/ALL(see Section 5 and Section 6.2). Based on the pediatric phase I trial of lower 
Tazemetostat exposures in children receiving 520mg/m2, and one patient in this cohort 
receiving prolonged benefit, 520mg/m2 was chosen for patients not requiring higher, CNS-
penetrant doses to limit exposures and potential secondary malignancies. 
 
 
 
 


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3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
Patient enrollment for this study will be facilitated using the Oncology Patient Enrollment Network 
(OPEN), a web-based registration system available on a 24/7 basis. It is integrated with the NCI 
Cancer Trials Support Unit (CTSU) Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient record in the RAVE database. 
 
Access requirements for OPEN:  
Investigators and site staff will need to be registered with CTEP and have a valid and active Cancer 
Therapy Evaluation Program-Identity and Access Management (CTEP-IAM) account (check at < 
https://ctepcore.nci.nih.gov/iam/>). This is the same account (user id and password) used for 
credentialing in the CTSU members' web site. To perform registrations in OPEN, the site user must 
have been assigned the 'Registrar' role on the relevant Group or CTSU roster. OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. Registrars must hold a minimum of an AP registration type.   
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise 
System for regulatory and roster data and, upon enrollment, initializes the patient position in the 
Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in OPEN, the 
IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on the site’s IRB 
approval.  Please see Appendix X for detailed CTEP and CTSU Registration Procedures including: 
registration in Registration and Credential Repository (RCR), requirements for site registration, 
submission of regulatory documents and how to check your site’s registration status. 
 
3.1 
Genetic Screening Procedures for Eligibility  
Patient enrollment onto the APEC1621SC screening protocol is required. Tumor and blood 
samples will be obtained and the results of the evaluation of the tumor specimens will 
determine if the patient's tumor has an actionable Mutation of Interest (aMOI) for which a 
MATCH treatment subprotocol is available. 
 
The treatment assignment to a MATCH subprotocol (if a relevant aMOI is detected) will 
be communicated to the enrolling institution via the COG or MATCHBox treatment 
assignment mechanism at the time the results of MATCH are returned, upon which a 
reservation to APEC1621C will be secured by COG.  Reservations should be withdrawn 
by the institution if at any point the patient indicates they do NOT intend to consent to 
participation or the site investigator indicates the patient will never be eligible for 
APEC1621C. 
 
3.2 
IRB Approval 
In order to participate in Pediatric MATCH, an institution must participate in the NCI 
Pediatric CIRB. NCI Pediatric CIRB approval of this study must be obtained by a site prior 
to enrolling patients.  
 
Submitting Regulatory Documents:  Submit required forms and documents to the CTSU 
Regulatory Office, where they will be entered and tracked in the CTSU RSS.   
 
Online: www.ctsu.org (members’ section) → Regulatory Submission Portal 
 
Email: CTSURegulatory@ctsu.coccg.org (for regulatory document submission 
only) 
 
Fax: 215-569-0206 
 
Mail: 
CTSU Regulatory Office 


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1818 Market Street, Suite 1100 
 
 
Philadelphia, PA 19103 
                             
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, sites must submit a Study 
Specific Worksheet for Local Context (SSW) to the CIRB (via IRBManager) to indicate 
their intention to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office for compliance in the RSS.  The Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study so that the study approval can be applied 
to those institutions.  Other site registration requirements (e.g., laboratory certifications, 
protocol-specific training certifications, or modality credentialing) must be submitted to 
the CTSU Regulatory Office or compliance communicated per protocol instructions. 
 
3.3 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
 
3.4 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent.  This can be accomplished 
through the study-specific protocol.  Documentation of the informed consent for screening 
will be maintained in the patient’s research chart. Studies or procedures that were 
performed for clinical indications (not exclusively to determine eligibility) may be used for 
baseline values even if the studies were done before informed consent was obtained. 
 
3.5 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be uploaded 
into RAVE immediately following enrollment. 
 
3.6 
Study Enrollment 
Following a MATCH treatment assignment to a protocol, patients may be enrolled on the 
study once all eligibility requirements for the study have been met. Before enrolling a 
patient on study, the Study Chair or Vice Chair should be notified. Patients who give 
informed consent for the protocol in order to undergo screening for eligibility are not 
considered enrolled and should not be enrolled until the screening is completed and they 
are determined to meet all eligibility criteria. Study enrollment is accomplished by going 
to the CTSU OPEN (Oncology Patient Enrollment Network) https://open.ctsu.org/open/. 
For questions, please contact the COG Study Research Coordinator, or the CTSU OPEN 
helpdesk at https://www.ctsu.org/CTSUContact.aspx.  Patients must be enrolled before 
treatment begins.  Patients must not receive any protocol therapy prior to enrollment. 
 
Should the Epizyme-sponsored Phase 1/2 protocol for patients with recurrent or refractory 
malignant rhabdoid tumors, including CNS ATRT and other INI-deficient tumors and 
synovial sarcoma (EZH-102, NCT02601937) be open, matching patients may be 
preferentially referred for enrollment on that study if found eligible. 


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Patients must be enrolled within 8 weeks (56 days) of treatment assignment. Protocol 
therapy must start no later than 7 calendar days after the date of enrollment. Patients 
enrolling onto APEC1621C will have a COG ID obtained through their prior enrollment 
onto the screening protocol or from a prior COG study. 
 
Note:  No starter supplies will be provided. Drug orders of tazemetostat should be 
placed with CTEP after enrollment and treatment assignment to APEC1621C with 
consideration for timing of processing and shipping to ensure receipt of drug supply 
prior to start of protocol therapy. 
 
3.7 
Institutional Pathology Report 
The institutional pathology report from the tumor specimen submitted for sequencing will 
have been uploaded into RAVE immediately following enrollment on the APEC1621SC 
screening protocol.  
 
3.8 
Dose Assignment 
The dose will be assigned via OPEN at the time of study enrollment. 
 
4.0 
PATIENT ELIGIBILITY 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy.  Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum  creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging 
studies, bone marrow biopsy and/or aspirate (when applicable) must be obtained within 14 days 
prior to start of protocol therapy (repeat the tumor imaging if necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived.  All clinical and laboratory data required for determining eligibility of a patient 
enrolled on this trial must be available in the patient’s medical or research record which 
will serve as the source document for verification at the time of audit. 
 
4.1 
Inclusion Criteria 
 
 
APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been 
given a treatment assignment to MATCH to APEC1621C based on the presence 
of an actionable mutation as outlined in Appendix VII. 
  
 
Age:  Patients must be  than 12 months and   21 years of age at the time of study 
enrollment. 
 
 
Disease Status: Patients must have radiographically measurable disease (See 


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Section 12) at the time of study enrollment. Patients with neuroblastoma who do 
not have measurable disease but have MIBG+ evaluable disease are eligible. 
Measurable disease in patients with CNS involvement is defined as tumor that is 
measurable in two perpendicular diameters on MRI and visible on more than one 
slice.  
 
Note:  The following do not qualify as measurable disease:  
- 
malignant fluid collections (e.g., ascites, pleural effusions) 
- 
bone marrow infiltration except that detected by MIBG scan for 
neuroblastoma 
- 
lesions only detected by nuclear medicine studies (e.g., bone, gallium or 
PET scans) except as noted for neuroblastoma 
- 
elevated tumor markers in plasma or CSF  
- 
previously radiated lesions that have not demonstrated clear progression 
post radiation  
- 
leptomeningeal lesions that do not meet the measurement requirements for 
RECIST 1.1. 
 
 
Performance Level:  Karnofsky  50% for patients > 16 years of age and Lansky 
 50 for patients  16 years of age (See Appendix I).  Note:  Neurologic deficits in 
patients with CNS tumors must have been stable for at least 7 days prior to study 
enrollment.  Patients who are unable to walk because of paralysis, but who are up 
in a wheelchair, will be considered ambulatory for the purpose of assessing the 
performance score. 
 
 
Prior Therapy 
 
 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the numerical eligibility criteria are met, e.g. blood count 
criteria, the patient is considered to have recovered adequately. 
 
a. Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive.  
See https://www.cogmembers.org/site/disc/devtherapeutics/default.a
spx  for commercial and Phase 1 investigational agent classifications. 
For agents not listed, the duration of this interval must be discussed 
with the study chair and the study-assigned Research Coordinator 
prior to enrollment. 
i. 
 ≥ 21 days after the last dose of cytotoxic or myelosuppressive 
chemotherapy (42 days if prior nitrosourea).  
 
 
 
b. Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥ 7 days after the 
last dose of agent.  
See https://www.cogmembers.org/site/disc/devtherapeutics/default.a
spx for commercial and Phase 1 investigational agent classifications. 
For agents not listed, the duration of this interval must be discussed 
with the study chair and the study-assigned Research Coordinator 


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prior to enrollment.  
 
c.  Antibodies: ≥ 21 days must have elapsed from infusion of last dose 
of antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1. 
 
d. Corticosteroids: See Section 4.2.2.1. If used to modify immune 
adverse events related to prior therapy, ≥ 14 days must have elapsed 
since last dose of corticosteroid. 
 
e.  Hematopoietic growth factors: ≥ 14 days after the last dose of a long-
acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting 
growth factor. For growth factors that have known adverse events 
occurring beyond 7 days after administration, this period must be 
extended beyond the time during which adverse events are known to 
occur.  The duration of this interval must be discussed with the study 
chair and the study-assigned Research Coordinator. 
 
f.  Interleukins, Interferons and Cytokines (other than hematopoietic 
growth factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than hematopoietic growth factors) 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥ 84 
days after infusion and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion:  ≥ 42 
days. 
 
h.  Cellular Therapy: ≥ 42 days after the completion of any type of 
cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.) 
 
i.  XRT/External Beam Irradiation including Protons: ≥ 14 days after 
local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to 
 50% of the pelvis; ≥ 42 days if other substantial BM radiation. 
 
Note: Radiation may not be delivered to “measurable disease” tumor 
site(s) being used to follow response to subprotocol treatment. 
 
j.  Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-
MIBG): ≥ 42 days after systemically administered 
radiopharmaceutical therapy. 
 
k.  Patients must not have had prior exposure to tazemetostat or other 
inhibitor(s) of EZH2. 
 
 
Organ Function Requirements: 
 
 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 


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involvement: 
- 
Peripheral absolute neutrophil count (ANC)  1000/mm3 
- 
Platelet count  100,000/mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
-     Hemoglobin ≥ 8.0 g/dL at baseline (may receive RBC 
transfusions) (See Section 4.2.6) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in 4.1.6.1.a 
(may receive transfusions provided they are not known to be 
refractory to red cell or platelet transfusions). These patients will 
not be evaluable for hematologic toxicity.  
 
 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 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 
 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated)  1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT)  135 U/L.  (For the purpose of this study, the ULN 
for SGPT is 45 U/L.)  
- 
Serum albumin  2 g/dL. 
 
 Adequate Cardiac Function Defined as: 
-  
QTc interval  480 milliseconds 
 
 Adequate Neurologic Function Defined as: 
- 
Patients with seizure disorder may be enrolled if on anticonvulsants 
and well controlled. 
- 
Nervous system disorders (CTCAE v5.0) resulting from prior 
therapy must be  Grade 2, with the exception of decreased tendon 
reflex (DTR). Any grade of DTR is eligible. 
 
 Adequate Coagulation Defined as: 
o INR ≤ 1.5  


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o For subjects with CNS involvement (primary tumor or metastatic 
disease): Subjects must not have any active bleeding, or new 
intratumoral hemorrhage of more than punctate size on screening 
MRI or known bleeding diathesis or treatment with anti-platelet or 
anti-thrombotic agents. 
 
 
Informed Consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional guidelines.  
 
4.2 
Exclusion Criteria 
 
 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study because there 
is currently no available information regarding human fetal or teratogenic 
toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males 
or females of reproductive potential may not participate unless they have agreed 
to use an effective contraceptive method for the duration of study treatment. 
Female subjects of childbearing potential should agree to remain abstinent or use 
adequate contraceptive methods for 30 days after the last dose of tazemetostat. 
Male subjects should agree to remain abstinent or use adequate contraceptive 
methods, and agree to refrain from donating sperm, and for 90 days after the last 
dose of tazemetostat.   
 
 
Concomitant Medications 
 
 Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. If used to modify immune adverse events 
related to prior therapy, ≥ 14 days must have elapsed since last dose of 
corticosteroid (See Section 4.1.6.1.d). 
 
 Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
 
 Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible. 
 
 Anti-GVHD agents post-transplant:  
 
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease post bone marrow transplant are not 
eligible for this trial. 
 
 CYP3A4 Agents:  
Patients who are currently receiving drugs that are strong inducers or 
strong inhibitors of CYP3A4 are not eligible. Strong inducers or inhibitors 
of CYP3A4 are prohibited from 14 days prior to the first dose of 
tazemetostat to the end of the study.  See Appendix II for a list of agents.  
Note: Dexamethasone for CNS tumors or metastases, on a stable dose, is 


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21 
allowed. 
 
 
Infection:  Patients who have an uncontrolled infection are not eligible.  
 
 
On CBC differential, patients must not have any significant morphologic 
abnormalities concerning for MPN/MDS or T- ALL. 
 
 
Patients must not have thrombocytopenia, neutropenia, or anemia of Grade ≥ 3 
(per CTCAE 5.0 criteria) or any prior history of myeloid malignancies, including 
myelodysplastic syndrome (MDS). (See Section 4.1.6.1 for hemoglobin 
eligibility criteria.) 
 
Patients with a history of prior history of T-LBL/T-ALL. 
 
Patients with any prior history of myeloid malignancies, including 
myelodysplastic syndrome (MDS). 
 
 
Patients who have received prior solid organ transplantation are not eligible. 
 
 
Patients who in the opinion of the investigator may not be able to comply with 
the safety monitoring requirements of the study are not eligible. 
  
5.0 
TREATMENT PROGRAM 
 
5.1 
Overview of Treatment Plan 
 
For patient(s) enrolled pre-amendment #3B:  
Day 1-28 
Day 28 
Tazemetostat 1200 mg/m2/dose 
 (Orally, twice daily) 
Evaluation 
 
For patient(s) enrolled post-amendment #3B: 
 
Patients without CNS 
involvement  
Day 1-28 
Day 28 
Tazemetostat 
520mg/m2/dose  
(Orally, twice daily) 
 
Evaluation                
 
Patients with CNS 
involvement  
Tazemetostat 1200 
mg/m2/dose  
(Orally, twice daily)  
 
Evaluation                
 
 
 
Tazemetostat will be administered as a liquid suspension at a dose of 520 mg/m2/dose 
orally, twice daily (for patients without any CNS involvement); or 1200 mg/m2/dose orally 
twice daily (for patients with CNS involvement) (based on disease location per above 
table); without regard to meals with no less than 8 hours between each dose.  For patient(s) 
enrolled pre-amendment #3B Tazemetostat will be administered orally at the MTD and 
recommended phase 2 dose (RP2D) of 1200 mg/m2/dose BID. If vomiting occurs after 
taking oral suspension formulation, the dose should NOT be repeated and the next dose 
should be administered at the regularly scheduled time. See Section 9.1.6 and Appendix 


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22 
IV for additional oral suspension administration and preparation instructions. See 
Appendix V for treatment roadmap. 
 
Therapy will be discontinued if there is evidence of progressive disease or drug related 
dose-limiting toxicity that requires removal from therapy (Section 6.0). Therapy may 
otherwise continue for up to 2 years provided the patient meets the criteria for starting 
subsequent cycles (Section 5.2) and does not meet any of the criteria for removal from 
protocol therapy criteria (Section 10.0).  
 
A cycle of therapy is considered to be 28 days.  A cycle may be repeated up to a total 
duration of therapy of 2 years (maximum 26 cycles). 
 
All patients with CNS involvement enrolled after AMD#3 will be treated at the established 
pediatric MTD/RP2D which is 1200 mg/m2/dose BID. All  patients without any CNS 
involvement patients enrolled after AMD#3 will be treated at the lower starting dose of 
520mg/m2/dose BID.  (See Section 6.1 and Section 6.2). 
 
Drug doses should be adjusted based on the BSA calculated from height and weight 
measured within 7 days prior to the beginning of each cycle, and according to the dosing 
nomogram.  Calculated dosing volumes of tazemetostat oral suspension should be rounded 
to the nearest 1 mL (30 mg) for the actual deliverable dose (Appendix IV). Patients who 
experience dose-limiting toxicity should have their dose reduced by 25% so that patients 
receive 75% of the original administered dose. 
 
 
Therapy Delivery Map 
See Appendix V for APEC1621C Therapy Delivery Map  
 
5.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease and has 
again met laboratory parameters as defined in the eligibility section, Section 4.0 and 
eligible to continue agent administration per the requirements in Section 6.0 and Section 
10.1. 
  
5.3 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to version 5.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE).  All appropriate treatment areas 
should have access to a copy of version 5.0 of the CTCAE.  A copy of the CTCAE v5 can 
be downloaded from the CTEP website (http://ctep.cancer.gov). Any suspected or 
confirmed dose-limiting toxicity should be reported immediately (within 24 hours) to the 
Study Chair. 
 
5.4 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to protocol therapy. Dose limiting hematological and non-hematological 
toxicities are defined differently.  
 
 
Non-Hematological Dose-Limiting Toxicity 
 Any Grade 3 or greater non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
- 
Grade 3 nausea and vomiting of less < 3 days duration 


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- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to 
levels that meet initial eligibility criteria or baseline within 7 days See  
Appendix XI for values that represent thresholds between CTCAE grades.  
Note: For the purposes of this study the ULN for ALT is defined as 45 U/L 
regardless of baseline. 
- 
Grade 3 or 4 fever < 5 days duration. 
- 
Grade 3 infection < 5 days duration. 
- 
Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to supplementation 
 
• 
Toxicity due to bromide elevation/neurological toxicity that requires a dose 
reduction per Section 6.3 will be considered dose-limiting 
• 
Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by 
patients that it requires treatment interruption. 
• 
Note: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
 
 
Hematological dose limiting toxicity  
Hematological dose limiting toxicity is defined as: 
 
In patients evaluable for hematological toxicity (see Section 4.1.7.1),   
• 
Grade 4 thrombocytopenia or neutropenia, not due to malignant 
infiltration. 
• 
Grade 3 thrombocytopenia that persists for ≥ 7 days 
• 
Grade 3 thrombocytopenia requiring a platelet transfusion on two 
separate days, within a 7 day period 
• 
Grade 3 thrombocytopenia with clinically significant bleeding  
• 
Neutropenia or thrombocytopenia that causes a delay of > 14 days 
between treatment cycles" (e.g. platelets <100K or ANC<1000). 
 
Note:   Grade 3 or 4 febrile neutropenia will not be considered a dose-limiting 
toxicity. 
 
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. 
6.1 
Dose Modification for Patients Newly Diagnosed with T-LBL/T-ALL   
• 
If a new case of T-LBL/T-ALL occurs in patients at the dose level > 520 mg/m2 then 
the patient will be discontinued from treatment, a case assessment will be conducted to 
better understand the event, and enrollment will be suspended.  
 
• 
If a new case of T-LBL/T-ALL occurs at  520 mg/m2 or less than 1 year on study 
treatment, the patient will be discontinued from treatment and a case assessment will be 
conducted to better understand the event. Enrollment will be suspended and risk/benefit 
of the drug will be assessed to decide whether to continue the study or not. 
 
 


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6.2 
Dose Modifications for Hematological Toxicity 
 
 
If a patient experiences hematological dose-limiting toxicity as defined in Section 
5.4.2, the treatment will be held.  Counts should be checked every 3-4 days for 
thrombocytopenia and every other day for neutropenia during this time. If the 
toxicity resolves to meet eligibility parameters within 14 days of drug 
discontinuation, the patient may resume treatment at a reduced dose (See Appendix 
IV). Patients who experience dose-limiting toxicity should have their dose reduced 
by 25% so that patients receive 75% of the original administered dose (Patients 
enrolled at 1200mg/m2/dose should dose reduce to 900 mg/m2/dose and patients 
enrolled at 520mg/m2/dose should dose reduce to 390 mg/m2/dose) 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 parameters within 14 days of drug 
discontinuation, the patient must be removed from protocol therapy. 
 
If hematological dose-limiting toxicity recurs in a patient who has resumed 
treatment at the reduced dose, the patient must be removed from protocol therapy. 
 
6.3 
Dose Modifications for Non-Hematological Toxicity 
 
 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.4.1, the treatment will be held. When the toxicity resolves to meet 
eligibility parameters or baseline within 14 days of drug discontinuation, the 
patient may resume treatment at a reduced dose (See Appendix IV). Patients who 
experience dose-limiting toxicity should have their dose reduced by 25% so that 
patients receive 75% of the original administered dose, patients enrolled at 
1200mg/m2/dose should dose reduce to 900 mg/m2/dose and patients enrolled at 
520mg/m2/dose should dose reduce to 390mg/m2/dose.. 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 dose-limiting toxicity recurs in a patient who has resumed treatment, the patient 
must be removed from protocol therapy. 
 
6.4 
Dose Modifications for Toxicities Related to Bromide 
 
 
 
For toxicities determined to be related to bromide, the following table should be 
used for dose modifications. 
 
Bromide 
Level 
Neurologic 
Findingsa 
Dose Adjustmentb,c 
10-50 mg/dL 
None 
Continue 
10-50 mg/dL 
Grade 1 
Discuss with Study Chair possibility of dose reduction  
10-50 mg/dL 
Grade 2 
Reduce by one dose reduction of at least 25% of starting dose.  
• 
1200mg/m2/dose→decrease to 900 mg/m2/dose 
• 
520mg/m2/dose→decrease to 390mg/m2/dose 


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Bromide 
Level 
Neurologic 
Findingsa 
Dose Adjustmentb,c 
10-50 mg/dL 
Grade 3 and above 
• 
Interrupt dosing and discuss with Study Chair increased 
frequency of bromide monitoring and potential for 
restarting treatment   
• 
Treatment may be restarted if approved by the Study Chair 
by one dose reduction of at least 25% of starting dose.  
• 
1200mg/m2/dose→decrease to 900 mg/m2/dose 
• 
520mg/m2/dose→decrease to 390mg/m2/dose 
>50-75 mg/dL 
None 
Continue 
>50-75 mg/dL 
Grade 1 
Discuss with Study Chair possibility of dose reduction 
>50-75 mg/dL 
Grade 2 and above 
• 
Interrupt dosing and discuss with Study Chair increased 
frequency of bromide monitoring and potential for 
restarting treatment   
• 
Treatment may be restarted if approved by the Study Chair 
Reduce by one dose reduction of at least 25% of starting 
dose.  
• 
1200mg/m2/dose→decrease to 900 mg/m2/dose 
• 
520mg/m2/dose→decrease to 390mg/m2/dose  
 
>50-75 mg/dL 
Grade 3 and above 
• 
Interrupt dosing and discuss with Study Chair increased 
frequency of bromide monitoring and potential for 
restarting treatment   
• 
Treatment may be restarted if approved by the Study Chair 
Reduce by one dose reduction of at least 25% of starting 
dose.  
• 
1200mg/m2/dose→decrease to 900 mg/m2/dose 
• 
520mg/m2/dose→decrease to 390mg/m2/dose  
>75 mg/dL 
None 
• 
Discuss with Study Chair increased frequency of bromide 
monitoring and potential need for dose reduction. 
• 
Reduce by one dose reduction of at least 25% of starting 
dose, if deemed appropriate.  
>75 mg/dL 
Grade 1 
• 
Discuss with Study Chair increased frequency of bromide 
monitoring and potential need for dose interruption and 
dose reduction by one dose reduction of at least 25% of 
starting dose.  
>75 mg/dL 
Grade 2 
• 
Interrupt dosing and discuss with Study Chair 
increased frequency of bromide monitoring and 
potential for restarting treatment.   
• 
Treatment may be restarted if approved by the Study 
Chair 
• 
Reduce by one dose reduction of at least 25% of 
starting dose.  
• 
1200mg/m2/dose→decrease to 900 mg/m2/dose 
• 
520mg/m2/dose→decrease to 390mg/m2/dose  
>75 mg/dL 
Grade 3 and above 
• 
Interrupt dosing and discuss with Study Chair 
increased frequency of bromide monitoring and 
potential for restarting treatment   


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Bromide 
Level 
Neurologic 
Findingsa 
Dose Adjustmentb,c 
• 
Treatment may be restarted if approved by the Study 
Chair Reduce by one dose reduction of at least 25% of 
starting dose.  
• 
1200mg/m2/dose→decrease to 900 mg/m2/dose 
• 
520mg/m2/dose→decrease to 390mg/m2/dose  
a. Neurologic signs or symptoms not related to disease under study or concomitant medication 
b. If the Investigator believes a dose modification or interruption is warranted but not specified in the 
table above, the Study Chair should be contacted to discuss the appropriate treatment plan.  
c. If more than 1 dose modification is required, contact Study Chair to discuss risk: benefit ratio of 
continuing on study. 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. Please see COG Supportive Care guidelines at 
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. See Section 
7.5 for drugs that should not be used concomitantly due to potential interactions with 
tazemetostat. 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. The Study Chair 
should be notified before growth factors are initiated. 
 
7.5 
Concomitant Medications 
 
 
CYP3A4/5 inhibitors or inducers: Strong CYP3A4/5 inhibitors or inducers are 
prohibited from 14 days prior to the first dose of tazemetostat to the end of the 
study (See Appendix II for list of agents). Note: Dexamethasone for CNS tumors 
or metastases, on a stable dose, is allowed.  
 
 
Strong inhibitors and inducers of CYP2C8, CYP2D6, and P-glycoprotein (P-gp) 
should be used with caution.  
 
 
Medications that are sensitive or narrow therapeutic range substrates of CYP3A, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6 should be avoided if possible. Other 
substrates of CYP2C8, 2C9, 2C19, 2D6, 3A, P-gp, OATP1B1, OATP1B3, OAT3, 
MATE1, and MATE2K should be used with caution.   
  


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Medications that are sensitive or narrow therapeutic range substrates of P-gp, 
BCRP, CYP3A, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or have a narrow 
therapeutic range should be used with caution. 
 
 
No grapefruit juice, Seville oranges, or grapefruit can be consumed while on 
tazemetostat. 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
 Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) must be no older than seven (7) days at the start of therapy.  Laboratory 
tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess 
eligibility.  If a post-enrollment lab value is outside the limits of eligibility, or laboratory 
values are older than 7 days, then the following laboratory evaluations must be re-checked 
within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) 
and serum creatinine.  If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies, bone 
marrow aspirate and/or biopsy, must be obtained within 14 days prior to start of protocol 
therapy (repeat the tumor imaging if necessary). 
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Prior to Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
Neurologic Exam 
X 
 
X 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
 
Pregnancy Test1 
X 
 
 
CBC, differential10, platelets 
X 
Weekly2,3 
X2,3 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Albumin 
X 
 
X 
Bromide Level 
X 
 
X 
INR 
X 
 
 
EKG 
X 
 
Every 3 cycles 
Tumor Disease Evaluation4-A, 4-B, 4-C 
X 
 
Every other cycle x 3 
then q 3 cycles 4 
Bone Marrow Aspirate and/or biopsy5,6 
X 
 
 
Plain radiograph tibial growth plate 
(Bone X-Ray Tests)9 
X 
 
Prior to cycles 2, 5 
and every 6 months 
Patient Diary7 
 
Weekly 
X 
Circulating Tumor DNA (ctDNA-
optional)8 
 
 
Cycle 5, Day 1 and 
(for patients receiving 
≥  5 cycles only)  at 
end of Protocol 
Therapy OR disease 
progression 
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually 


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active patients must use an acceptable method of birth control.  Abstinence is an acceptable method of 
birth control. 
2 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery 
to Grade 3. 
3 
If patients develop Grade 3 or greater thrombocytopenia then CBCs should be checked every 3 to 4 days 
until recovery to Grade 3, per Section 6.1. 
4 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation 
of either a PR or CR.  Subsequent scans may restart 2 cycles after the confirmatory scan. Please note 
that for solid tumor patients, if the institutional investigator determines that the patient has progressed 
based on clinical or laboratory evidence, he/she may opt not to confirm this finding radiographically. 
4-A     Neurological exam also required for CNS patients.    
4-B  Non- Hodgkin Lymphoma/ Histiocytosis patients are required to have PET scans within 2 weeks prior 
to start of therapy and should also be followed with PET scans if positive at diagnosis. Refer to Section 
12.8   
4-C    Patients with neuroblastoma must have both CT/MRI and MIBG scintigraphy prior to enrollment if the 
patient was enrolled with or has a history of having MIBG avid tumor. Otherwise the patient must have 
both CT/MRI and bone scan prior to enrollment. For patients with neuroblastoma and measurable disease 
by CT or MRI, lesions should be measured and followed using the same modality (CT or MRI) in 
addition to MIBG or bone scan. For patients with neuroblastoma and evaluable disease by MIBG 
scintigraphy or bone scan, use the same modality (MIBG scintigraphy or bone scan) to image and follow 
patients; CT/MRI are not required but may be performed as clinically indicated. Refer to Section 12.5.4 
and Section 12.9. 
5 
Bone marrow aspirate and/or biopsy only required in patients suspected of having bone marrow 
metastasis on the basis of history, symptoms, laboratory evaluation or other clinical data. Should only 
be performed on patients with known bone marrow involvement at baseline. 
6 
Bone marrow aspirate and/or biopsy should be performed only when complete response or partial 
response is identified in target disease or when progression in bone marrow is suspected. 
7.  Patient diary (see Appendix III) should be reviewed weekly during Cycle 1 and then after completion of 
each treatment cycle and uploaded into RAVE. 
8. 
With consent, two samples will be collected on this protocol (Cycle 5 Day 1; and for patients receiving 
≥ 5 cycles, at progression or end of protocol therapy) see Section 8.4 for details of the ctDNA studies. 
Note that a ctDNA sample is scheduled to be obtained on the APEC1621SC screening protocol prior to 
the initiation of treatment on this subprotocol. 
9. 
Plain radiographs of at least one tibial growth plate should be obtained in all patients prior to first dose 
of protocol therapy. In patients with open growth plates, follow-up plain radiographs of the same growth 
plate(s) should be obtained according to Section 8.2.  
10. Patients should get a manual differential if automated differential demonstrates blasts 
 
8.2 
Monitoring for Specific Toxicities  
 
Growth Plate Toxicities:  
Patients will have a plain AP radiograph of a single proximal tibial growth plate 
(bone X-ray tests) obtained prior to the first dose of protocol therapy. 
a. If patients are found to have a closed tibial growth plate, no further radiographs 
will be required.  
b.  If patients are found to have an open tibial growth plate, then repeat plain AP 
radiographs of the same tibial growth plate will be obtained prior to cycles 2, 
5 and every 6 months 
• 
Patients with evidence of growth plate thickening or other changes should 
have a knee MRI performed to further assess the degree of physeal 
pathology and undergo more frequent x-ray follow up. MRI should be 
performed without contrast. 
• 
Patients with knee MRI changes should be managed in an individualized 
manner. Decisions regarding continuation of tazemetostat should be 


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29 
made after discussion with the Study Chair or Study Vice-Chair and 
MATCH Leadership, taking into account the presence of any symptoms 
referable to the knee as well as the patient’s response to tazemetostat. 
Consultation with an orthopedic surgeon may also be indicated. Plans for 
follow-up imaging will also be made on an individualized basis, taking 
into account the presence of symptoms at the knee or other joints as well 
as the decision to continue tazemetostat or not. 
 
8.3 
Radiology Studies 
 
 
Bone Age/Knee MRI 
All tibial radiographs and knee MRIs (if obtained) should be submitted for review. 
 
 
Central Radiology Review for Response:  
Patients who respond (CR, PR) to therapy or have long term stable disease (SD) 
(≥ 6 cycles) on protocol therapy will be centrally reviewed.  The Operations center 
will notify the site when a patient has met the criteria for review. The tumor disease 
evaluations to be submitted for review include baseline (pre-study) evaluations as 
well as all end of cycle tumor disease evaluations which occurred while the patient 
was on the subprotocol therapy study..  
 
 
Technical Details of Submission:  
To ensure an adequate interpretation of FDG-PET and CT with contrast scans, 
scans transferred between the treating institutions and the Imaging and Radiation 
Oncology Core Group IROC RI (QARC) must be submitted in Digital Imaging 
and Communications in Medicine (DICOM) format. BMP ﬁles, JPG ﬁles, or hard 
copies (ﬁlms) are unacceptable for adequate interpretation of PET and CT with 
contrast scans. Imaging studies must be submitted electronically as outlined in the 
following paragraph. The images will be made available to study radiologists and 
nuclear medicine physicians for central review. 
 
Submission of Diagnostic Imaging data in DICOM format is required.  
Submission of the digital files and reports via TRIAD is preferred.  Instructions for 
TRIAD set up are below. 
 
Alternatively, the images and reports may be submitted via sFTP to IROC Rhode 
Island. Digital data submission instructions including instructions for obtaining a 
sFTP account, can be found at http://irocri.qarc.org. Follow the link labeled digital 
data.  Sites using the Dicommunicator software to submit imaging may continue 
to use that application. 
 
Corresponding Radiology reports may be submitted along with the electronic 
submission via TRIAD or sFTP or may be emailed to DataSubmission@QARC.o
rg.  The COG operations center and IROC are available to assist with any queries 
regarding the corresponding radiology reports which should be included when the 
scans are submitted 
 
Questions may be directed to DataSubmission@QARC.org or 401.753.7600. 
  
Digital RT Data Submission Using TRIAD (if TRIAD is available at your site): 
TRIAD is the American College of Radiology’s (ACR) image exchange 


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30 
application.  TRIAD provides sites participating in clinical trials a secure method 
to transmit DICOM and DICOM RT files and other digital objects, such as reports. 
TRIAD de-identifies and validates the images as they are transferred. 
 
TRIAD Access Requirements: 
Site physics staff who will submit images through TRIAD will need to be 
registered with the Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP Identity and Access Management (IAM) account.  Please refer to 
CTEP Registration Procedures of the protocol for instructions on how to request a 
CTEP-IAM account. 
To submit images, the site TRIAD user must be on the site roster and be assigned 
the 'TRIAD site user' role on the CTSU roster.  Users should contact the site’s 
CTSU Administrator or Data Administrator to request assignment of the TRIAD 
site user role.   
 
TRIAD Installations: 
 
When a user applies for a CTEP-IAM account with the proper user role, he/she 
will need to have the TRIAD application installed on his/her workstation to be able 
to submit images. TRIAD installation documentation can be found by following 
this link https://triadinstall.acr.org/triadclient/   
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password. 
 
If you have any questions regarding this information, please send an e-mail to the 
TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
IROC Rhode Island (formerly QARC) will facilitate the central reviews. 
 
For FDG-PET imaging, the transferred imaging data should include uncorrected 
and attenuation-corrected PET projection data, as well as the reconstructed PET or 
PET/CT images used by the institution to achieve a response assessment. If low- 
dose CT was used for attenuation correction, the acquired CT images should also 
be submitted. The imaging data submitted for central review must allow the study 
to be reconstructed and displayed in transaxial, sagittal and coronal formats using 
standard reconstruction techniques. Reconstructed MPEG clips and similar types 
of reconstructions will not be accepted. CT and MRI images similarly should be 
submitted in a format that either includes properly reconstructed multi-planar 
viewing formats in soft tissue and bone windows, or includes the thin-section axial 
acquisition data from which multi-planar reconstructions can be re-created. 
 
Sites not able to submit imaging electronically may submit imaging via CD.   CD’s 
may be sent by courier to:  
 
Address for submission: IROC RI (QARC) 
Building B, Suite 201 
640 George Washington Highway Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax:     (401) 753-7601 
Web:    http://irocri.qarc.org 


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8.4 
Circulating Tumor DNA Study (optional) 
 
 
Sampling Schedule   
An initial sample was previously required at time of enrollment onto the 
APEC1621SC screening protocol. Two additional samples (optional) will be 
collected into Streck Cell-Free DNA BCT tubes at the timepoints: 
(1) Cycle 5 Day 1 
(2) At disease progression or end of protocol therapy (for patients receiving ≥ 5 
cycles of therapy only) 
 
Peripheral blood samples for circulating tumor DNA should be obtained as 
follows:  
• 
For patients ≥ 10 kg collect 20 mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥ 5 kg but < 10 kg collect 10 mL (one tube)  
• 
For patients < 5 kg research samples will not be collected  
 
In all cases, blood draw volumes should strictly adhere to institutional limitations, 
taking other blood draws into consideration. However, if a reduction in volume is 
required, samples should be collected in 10 mL increments (ie. 0, 10, or 20 mL 
should be collected such that each Streck Cell-Free DNA BCT is completely 
filled). 
 
Established institutional guidelines should be followed for blood collection via 
vascular access devices. Heparin should be avoided in pre-collection flush 
procedures. If therapeutic heparin dosing contamination is a possibility, 
venipuncture is recommended as a first choice collection method. If a Streck Cell-
Free DNA BCT tube immediately follows a heparin tube in the draw order, we 
recommend collecting an EDTA tube as a waste tube prior to collection in the 
Streck Cell-Free DNA BCT. 
 
For patients who do not have indwelling catheters, blood should be collected via 
venipuncture. To guard against backflow, observe the following precautions: 
 
• 
Keep patient’s arm in the downward position during the collection 
procedure. 
• 
Hold the tube with the stopper in the uppermost position so that the tube 
contents do not touch the stopper or the end of the needle during sample 
collection. 
• 
Release tourniquet once blood starts to flow in the tube, or within 2 
minutes of application. 
• 
Fill tube completely. 
• 
Remove tube from adapter and immediately mix by gentle inversion 8 to 
10 times. Inadequate or delayed mixing may result in inaccurate test 
results.  
• 
Store blood in Streck tube at room temperature until shipment. 
 
 
Sample Processing 
Samples do not need to be processed at the collection site. 
 


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32 
 
 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D (APEC1621C), and the date and time the sample was drawn.  Data should be 
recorded on the appropriate transmittal form found in RAVE, which must 
accompany the sample(s). 
 
 
Sample Shipping Instructions 
Specimen should be shipped at room temperature to the BPC (address below). 
Upon arrival separation, extraction, and storage of plasma and cellular DNA will 
be performed. Samples should be shipped from Monday through Friday for 
Tuesday through Saturday delivery. If blood is collected over the weekend or on 
the day before a holiday, the sample should be stored in a refrigerator until shipped 
on the next business day.  Ship by FedEx Priority Overnight using the COG FedEx 
account. 
 
Ship specimens to the following address: 
 
 
 
Biopathology Center 
 
 
Nationwide Children’s Hospital 
 
 
Protocol APEC1621C- Peds MATCH* 
 
 
700 Children’s Drive, WA1340 
 
 
Columbus, OH 43205 
 
 
Phone: (614) 722-2865 
 
 
Fax: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
*Labeling is extremely important for this project. Packages must be labeled 
“Peds MATCH” in order to expedite processing at the BPC. Be sure to include 
the room number. Packages received without the room number may be returned 
to the sender. 
 
 


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33 
 
9.0 
AGENT INFORMATION 
 
9.1 
Tazemetostat  
(EPZ-6438, E7438) NSC# 791066  
  
 
Structure and molecular weight  
The chemical structure of tazemetostat drug substance is shown below: 
 
Molecular Formula: 
C34H45BrN4O4 (Hydrobromide salt) 
C34H44N4O4 (Free base) 
 
Molecular Weight:  
653.65 (Hydrobromide salt)  
572.74 (Free base) 
 
 
Supplied by: Epizyme supplies and PMB, CTEP, DCTD, NCI distributes 
tazemetostat. 
 
 
Formulation 
Tazemetostat will be supplied as powder for oral suspension. 
Powder for oral suspension is supplied in 2-gram and 7-gram high-density 
polyethylene bottles containing only drug substance (no excipients). Reconstitute 
tazemetostat powder with Ora-sweet®, which will be provided by the site, to 
produce tazemetostat 30 mg/mL oral suspension (based on free base content). 
Once reconstituted with Ora- sweet®, the suspension contains purified water, 
sucrose, glycerin, sorbitol, citric acid, sodium phosphate, methylparaben, 
potassium sorbate, and citrus-berry flavoring. Once reconstituted, the suspension 
is pink in color.  
- 
A site-supplied a press-in bottle adapter is required for use with an 
oral syringe for dosing purposes.  
Oral Suspension Preparation Instructions [Refer to Appendix IV for the 
Tazemetostat Oral Suspension Preparation Worksheet and Guidance Table]:   
1) The oral suspension should be prepared in a biologic safety cabinet, personal 
protective equipment (PPE) should be worn during preparation as per 
institutional guidelines. 


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34 
2) Determine the total number of tazemetostat powder for oral suspension bottles 
required to prepare 14 days of dosing (including overfill per institutional 
guidelines), while using a combination of bottle sizes to minimize waste.  
3) Determine the amount of Ora-Sweet® required: 32.5 mL is needed per gram of 
tazemetostat. Each 2 gram bottle requires 65 mL Ora-Sweet® and each 7 gram 
bottle requires 227.5 mL Ora-Sweet®. 
4) Select the appropriate size and number of empty medication bottles required.  
Choose bottles that are large enough so that each bottle can be filled to 40-80% 
of capacity to ensure adequate mixing. The medication bottles should be light 
protective, HDPE, PETE, or glass bottle with a child-resistant, liquid-tight 
closure. Note: Use of a funnel is helpful to transfer tazemetostat powder to the 
bottle containing Ora-Sweet 
5) Add the required amount of Ora-Sweet® to each empty medication bottle. 
6) Transfer the appropriate amount of tazemetostat powder for oral suspension to 
the corresponding medication bottle containing Ora-Sweet®. 
7) Tightly seal with cap and shake the bottle vigorously for 1 minute. 
8) Allow the bottle to rest for approximately 5 minutes then re-shake the bottle 
vigorously for an additional 1 minute. 
9) Remove the bottle cap and inspect visually for any unwetted powder.  If 
present, repeat steps 7-8 above. 
10) Apply appropriate label(s) as required by law/institution. 
11) The final concentration is 30 mg/mL. 
12) Assign a 21-day expiration from preparation date and store the bottles at 
refrigerated temperature between 2-8 °C (36-46 °F) and protect from light. 
13) Instruct the patient or caregiver to shake the bottle for 1 minute prior to dosing.  
Avoid vigorous shaking due to foaming and allow sufficient time for any bubbles 
to dissipate prior to measuring the dose. If multiple bottles are dispensed, daily 
shaking of all bottles is required to ensure the suspension stays properly 
suspended. 
 
 
Storage 
Powder for oral suspension: Do not store above 25°C (77°F). Protect from light.  
Once oral suspension is prepared, store refrigerated between 2-8 °C (36-46 °F) and 
protect from light. Brief excursion (less than 4 hours) up to 30°C is allowable for 
transfer from the clinic to home, but bottles must be immediately refrigerated upon 
arrival. A cold pack may be provided to the patient as required. 
 
If a storage temperature excursion is identified, promptly return tazemetostat 
unreconstituted powder for oral suspension to below 25°C (77°F) and prepared 
oral suspension to 2-8°C (36-46 °F) 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. 
 
 
Stability 
Stability studies are ongoing. Powder for oral suspension is stable for 21 days 
following reconstitution under refrigerated storage conditions. 
 


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35 
 
Administration 
See Treatment (Section 5.0) and Dose Modification (Section 6.0) sections of the      
protocol. 
 
Tazemetostat will be given orally twice daily without regard to meals. The powder 
for suspension must be reconstituted prior to administration.  Doses must be taken 
twice per day with no less than 8 hours between each dose.  If vomiting occurs after 
taking oral suspension formulation, the dose should NOT be repeated and the next 
dose should be administered at the regularly scheduled time. 
 
The oral suspension should be given by mouth immediately after the dose is prepared 
in the oral syringe.  Patients should drink additional water after administration (about 
4 ounces).  For feeding tube dosing, administer directly into the feeding tube with the 
syringe. Rinsing with 10 mL of water for NG tubes and 40 mL of water for G-tubes 
is recommended. 
 
 
Potential Drug Interactions 
In vitro, tazemetostat is metabolized primarily by CYP3A and to a lesser extent by 
CYP2C8 and CYP2D6.  It is a P-gp substrate but not a substrate of BCRP, 
OAT1B1, OAT1B3, OAT1, OAT3, OCT2, and MATE1.  Therefore, treatment 
with strong inhibitors or strong inducers of CYP3A are prohibited from 14 days 
prior to the first dose of tazemetostat to the end of the study. Strong inhibitors and 
inducers of CYP2C8, 2D6, and P-gp should be used with caution. 
 
In vitro, tazemetostat inhibits CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, P-
gp, OATP1B1, OATP1B3, OAT3, MATE1, and MATE2K. . Tazemetostat also 
induces CYP3A4 and is a weak inducer of CYP1A, CYP2B6, and CYP2C9. 
Medications that are sensitive or narrow therapeutic range substrates of CYP3A, 
CYP2C8, CYP2C9, CYP2C19, or CYP2D6 should be avoided if possible. Other 
substrates of CYP2C8, 2C9, 2C19, 2D6, 3A, P-gp, OATP1B1, OATP1B3, OAT3, 
MATE1, and MATE2K should be used with caution. 
 
No grapefruit juice, Seville oranges, or grapefruit can be consumed while on 
tazemetostat. 
 
 
Patient care implications: 
Prolonged exposure to sunlight should be avoided during treatment with 
tazemetostat.  Patients should wear protective clothing, sunscreen, and avoid 
tanning beds. Female subjects of childbearing potential should agree to remain 
abstinent or use adequate contraceptive methods for 30 days after the last dose of 
tazemetostat. Female subjects that use hormonal contraceptives should also use an 
additional barrier method. Male subjects should agree to remain abstinent or use 
adequate contraceptive methods, and agree to refrain from donating sperm for 90 
days after the last dose of tazemetostat.    
 
 
Tazemetostat Toxicities 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Tazemetostat (NSC 791066) 
 
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 


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36 
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/aeguidelines.pd
f for further clarification. Frequency is provided based on 815 patients. Below is the 
CAEPR for Tazemetostat. 
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 2.4, March 30, 20211 
 
Adverse Events with Possible 
Relationship to Tazemetostat 
(CTCAE 5.0 Term) 
[n= 815] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
   
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Constipation 
 
  
 
Diarrhea 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 2) 
INVESTIGATIONS 
  
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)   
 
 
Leukemia 
secondary 
to 
oncology chemotherapy 
  
 
 
Myelodysplastic syndrome 
  
 
 
Treatment related secondary 
malignancy2 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Cough 
  
 
 
Dyspnea 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Dry skin 
 
  
 
 
Photosensitivity 
  
 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal     


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37 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2 Treatment related secondary malignancies includes Peripheral T-cell lymphoma (PTCL), T-cell lymphoblastic 
lymphoma (T-LBL), and B-cell acute lymphoblastic leukemia (B-ALL). It may be worth noting that the adult patient 
observed with B-ALL may be due to an underlying Diffuse large B-cell lymphoma (DLBCL). 
 
 Adverse events reported on tazemetostat trials, but for which there is insufficient evidence to suggest that there 
was a reasonable possibility that tazemetostat caused the adverse event:  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Febrile neutropenia 
CARDIAC DISORDERS - Chest pain - cardiac; Left ventricular systolic dysfunction 
EAR AND LABYRINTH DISORDERS - Vertigo 
ENDOCRINE DISORDERS - Hypothyroidism 
EYE DISORDERS - Dry eye; Periorbital edema; Vision decreased; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal pain; Dry mouth; Dyspepsia; 
Dysphagia; Flatulence; Gastric perforation; Gastrointestinal disorders - Other (defecation urgency); Hemorrhoids; 
Mucositis oral; Rectal hemorrhage; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Fever; Flu 
like symptoms; General disorders and administration site conditions - Other (early satiety); General disorders and 
administration site conditions - Other (general physical health deterioration); Localized edema; Malaise; Non-cardiac 
chest pain 
HEPATOBILIARY DISORDERS - Gallbladder obstruction; Hepatobiliary disorders - Other (hepatocellular injury) 
INFECTIONS AND INFESTATIONS - Conjunctivitis; Device related infection; Esophageal infection; Infections 
and infestations - Other (lower respiratory tract infection); Lung infection; Pharyngitis; Sepsis; Sinusitis; Skin 
infection; Soft tissue infection; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Wound dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood bilirubin 
increased; CPK increased; Electrocardiogram QT corrected interval prolonged; Investigations - Other (c-reactive 
protein increased); Lymphocyte count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hyperglycemia; 
Hyperkalemia; 
Hyperlipidemia; Hypertriglyceridemia; Hypokalemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition 
disorders - Other (diabetic metabolic decompensation); Metabolism and nutrition disorders - Other (polydipsia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Muscle cramp; 
Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor 
hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Dysgeusia; Dysphasia; Headache; Hydrocephalus; 
Lethargy; Memory impairment; Nervous system disorders - Other (vocal cord paralysis); Paresthesia; Peripheral 
motor neuropathy; Peripheral sensory neuropathy; Radiculitis; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Depression; Hallucinations; Insomnia; Psychiatric disorders - Other 
(mood swings) 
RENAL AND URINARY DISORDERS - Proteinuria; Renal and urinary disorders - Other (polyuria); Urinary 
frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - Other 
(vulvovaginal rash) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Epistaxis; Hypoxia; Nasal congestion; Oropharyngeal pain; Pleural effusion; Pulmonary edema; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (tachypnea) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Hair color changes; Hair texture 
abnormal; Hirsutism; Hyperhidrosis; Hypertrichosis; Nail ridging; Pruritus; Purpura; Rash acneiform; Rash maculo-
papular; Skin and subcutaneous tissue disorders - Other (psoriasis); Skin hyperpigmentation; Urticaria 
VASCULAR DISORDERS - Hot flashes; Hypertension; Superior vena cava syndrome; Thromboembolic event; 
Vascular disorders - Other (peripheral venous disease) 
 


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Note: Tazemetostat 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. 
 
Note: AESI:  Based on preclinical findings in toxicology studies, FDA has requested the following Adverse Events 
of Special Interest (AESI) to be reported in an expedited manner: 1) T-cell lymphoma; and 2) abnormal bone growth. 
It should be noted that abnormal bone growth has not been observed in clinical trials of tazemetostat. 
 
9.2 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol number 
must be used for ordering all CTEP-supplied investigational agents.  The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there are 
several participating investigators at one institution, CTEP-supplied investigational agents 
for the study should be ordered under the name of one lead participating investigator at that 
institution. 
 
Note: No starter supplies will be provided. Study agent must be ordered after 
enrollment and treatment assignment to APEC1621C 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 field when submitting an order request. 
 
 
9.3 
Clinical Drug Request and Investigator Brochure Availability 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. The current versions of the IBs for the agents will also be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a “current” 
password, and active person registration status. For questions about drug orders, transfers, 
returns, or accountability call or email PMB anytime. Refer to the PMB’s website for 
specific policies and guidelines related to agent management. Questions about IB access 
may be directed to the PMB IB coordinator via email. 
  
9.4 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page.  Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
 
Useful Links and Contacts  
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 


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39 
 
 
http://ctep.cancer.gov/branches/pmb/agent_management.htm    
• PMB Online Agent Order Processing (OAOP) application:  
 
 
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account:  
   
 https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help: 
 
ctepreghelp@ctep.nci.nih.gov  
• PMB email: PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575  
Monday through Friday between 8:30 am and 4:30 pm (ET) 
• PMB IB Coordinator: IBcoordinator@mail.nih.gov 
• Registration and Credential Repository (RCR): 
https://ctepcore.nci.nih.gov/rcr/  
 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12). 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6). 
c) 
Refusal of protocol therapy by patient/parent/guardian 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Completion of 26 cycles of therapy;  
f) 
Physician determines it is not in the patient’s best interest. 
g) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of protocol therapy (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
j) 
Patient did not receive protocol treatment after study enrollment. 
 
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent from the APEC1621SC screening protocol. Patients who are removed from 
protocol therapy in subsequent cycles should have the necessary observations to 
ensure adequate clinical care.  
 
10.2 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
Patients who are off subprotocol therapy will continue to be followed on the APEC1621SC 
screening protocol. Follow-up data submission will occur until one of the APEC1621SC 
Off Study Criteria is met (See Section 10 of APEC1621SC for details). Ongoing adverse 
events, or adverse events that emerge after the patient is removed from protocol therapy, 
but within 30 days of the last dose of investigational agent, must be followed and reported 
via RAVE and CTEP-AERS (if applicable).  Follow-up data will be required until off study 
criteria are met unless consent is withdrawn or the patient dies or is lost to follow-up. 


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11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size  
APEC1621C will require a minimum of 20 evaluable patients and a maximum of 49 
patients, allowing for 15% inevaluability. Assuming an enrollment rate of 4-9 biomarker 
positive patients per year, the primary cohort of this subprotocol is expected to be 
completed within 2.7-6 years. 
 
11.2 
Dosing Considerations  
Please see Section 5.1 for a specific discussion of the dosing of tazemetostat to be used in 
this study, based on site of disease.   
 
11.3 
Study Design 
The primary cohort will employ a single stage A’Hern designs of N=20. Tazemetostat will 
be deemed worthy of further study in the relevant subset of patients (i.e. biomarker positive 
in any histology, biomarker positive in a particular histology, etc) if the decision rule is 
met. Operating characteristics are shown below. 
 
Cohort 
N 
Decision Rule 
Alpha Power 
Primary biomarker positive 20 ≥ 3 responses 
10% 
90% 
 
Per amendment 3B, Tazemetostat will be administered at a dose of 520 mg/m2/dose BID 
for patients without any CNS involvement; or 1200 mg/m2/dose BID for patients with CNS 
involvement. The response will be examined in the combined primary cohort consisting of 
patients with or without CNS involvement. Patients who enrolled pre-amendment #3B 
treated with at 1200 mg/m2/dose BID and meet evaluation criteria will also be counted in 
the evaluation. 
 
Histology-specific biomarker positive expansion cohorts will, by definition, be deemed 
worthy of further study, since they will have at least 3 responses. The table below shows 
90% confidence intervals (Wilson method) for a range of observable response rates. 
 
Cohort Size Observed Response Rate 90% Confidence Interval 
10 
30% 
13% - 56% 
10 
40% 
19% - 65% 
10 
50% 
27% - 73% 
 
 Primary Cohort:  
APEC1621C will evaluate a primary cohort of 20 mutation-matched (“biomarker 
positive”) evaluable patients of any histology for the primary study aim of 
determining the objective response rate (CR/PR according to the response criteria 
in Section 12.3) to tazemetostat. Using an A’Hern design8 with alpha=10%, a 
sample of N=20 will provide 90% power to detect an improvement in response 
rate from 5%, if the treatment is ineffective, to 25% if the targeted therapy is 
sufficiently effective to warrant further study. If there are at least 3 responses out 
of 20 in the primary cohort, the biomarker/therapy match will be deemed a success.  
 
If at any time, there is one occurrence of secondary T-cell lymphomas in patients 
exposed to tazemetostat, we will suspend the accrual and consider dose, schedule 


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41 
or duration of treatment modification. The COG DSMC will be notified and CTEP 
consulted regarding the next steps to take with respect to the protocol. 
 
 Histology-Specific Biomarker Positive Expansion Cohorts:  
If ≥ 3 patients in the primary cohort with the same histology show signs of 
objective response (CR/PR according to the response criteria in Section 12.3), a 
histology-specific biomarker positive expansion cohort will open after the primary 
cohort is completed to up to 7 evaluable patients for a total sample size of 10 
evaluable biomarker positive patients with that histology. This will allow us to 
estimate more precisely the activity in biomarker positive patients of that 
histology. See Appendix VI for a list of target tumor histologies/types.  
 
We will open up to 3 such expansion cohorts for biomarker positive patients (i.e., 
if 3 histologies have ≥ 3 responses, we will open a total of 3 expansion cohorts as 
described above). Note that this can only happen if the response rate in the primary 
cohort is at least 45% (9/20) and there cannot be more than 21 additional evaluable 
patients in total for these expansion cohorts. 
 
 
11.4 
Methods of Analysis 
Response criteria are described in Section 12. A responder is defined as a patient who 
achieves a best response of PR or CR on the study. Response rates will be calculated as the 
percent of evaluable patients who are responders, and confidence intervals will be 
constructed using the Wilson score interval method.9 Decision making for A’Hern design 
cohorts will follow rules described above. 
 
Toxicity tables will be constructed to summarize the observed incidence by type of toxicity 
and grade. A patient will be counted only once for a given toxicity for the worst grade of 
that toxicity reported for that patient. Toxicity information recorded will include the type, 
severity, time of onset, time of resolution, and the probable association with the study 
regimen.   
 
11.5 
Evaluability for Response 
Any eligible patient who is enrolled and receives at least one dose of protocol therapy will 
be considered evaluable for response. Any patient who receives non-protocol anti-cancer 
therapy during the response evaluation period will be considered a non-responder for the 
purposes of the statistical rule, unless they show an objective response prior to receiving 
the non-protocol anti-cancer therapy (in which case they will be considered a responder). 
Patients who demonstrate a complete or partial response confirmed by central review will 
be considered to have experienced a response. When opening expansion cohorts, the 
evaluation period for determination of best response will be 6 treatment cycles. All other 
patients will be considered non-responders. Patients who are not evaluable for response 
evaluation may be replaced for the purposes of the statistical rule. All patients considered 
to have a response (CR or PR) must have imaging studies reviewed centrally at the COG. 
Centers will be notified by the COG about requests for scans of patients with stable disease. 
Preliminary assessment of activity using institutionally provided tumor measurements will 
be entered into CDUS quarterly. The central review by COG will be provided as the final 
reviewed assessment of response when such becomes available. 
11.6 
Evaluability for Toxicity 
All eligible patients who receive at least one dose of protocol therapy will be considered in 
the evaluation of toxicity. 


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11.7 
Progression free survival (PFS) 
Progression free survival will be defined as time from the initiation of protocol treatment 
to the occurrence of any of the following events: disease progression or disease recurrence 
or death from any cause. All patients surviving at the time of analyses without events will 
be censored at their last follow-up date. 
 
PFS along with the confidence intervals will be estimated using the Kaplan-Meier method. 
Patients with local calls of disease progression (i.e. calls made by the treating institution), 
will be counted as having had an event, even if the central review does not declare 
progression. We will also report PFS based on central radiology review as a secondary 
analysis, if adequate number of disagreements in progressions exist between the treating 
institutions and the central radiology review to make such an analysis meaningful.     
 
11.8 
Correlative Studies 
A descriptive analysis of the exploratory aims described in Section 1.3 will be performed 
and will be summarized with simple summary statistics. All of these analyses will be 
descriptive in nature. 
 
11.9 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
Racial category 
Ethnicity 
Total 
Not Hispanic 
or Latino 
Hispanic or 
Latino 
Female Male Female Male 
American Indian/Alaska Native 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
2 
Native 
Hawaiian 
or 
Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
3 
5 
0 
0 
8 
White 
12 
20 
4 
2 
38 
More than one race 
1 
0 
0 
0 
1 
Total 
17 
26 
4 
2 
49 
 
This distribution was derived from the demographic data for patients enrolled on recent COG 
Phase 2 trials. 
 
12.0 
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE)  
The descriptions and grading scales found in the current version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the current 
CTCAE V 5.0.  A copy of the CTCAE V 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov). 
 
12.2 
Progression-Free Survival 


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Progression-free survival (PFS) is defined as the duration of time from start of subprotocol 
treatment to time of progression or death, whichever occurs first. 
 
Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions – e.g., when multiple lesions 
show opposite responses, the progressive disease takes precedence. 
 
12.3 
Response Criteria for Patients with Solid Tumors  
See the table in Section 8.0 for the schedule of tumor evaluations. Eligible patients must 
have measurable disease present at baseline and have had their disease re-evaluated after 
one dose of protocol therapy.  In addition to the scheduled scans, a confirmatory scan 
should be obtained on the next consecutive cycle following initial documentation of 
objective response. 
 
As outlined, patients will be assigned to one of the following categories for assessment of 
response:  a) solid tumor (non-CNS) and measurable disease (Section 12.4); b) 
neuroblastoma with MIBG positive lesions (Section 12.5); c) CNS tumor (Section 12.7); 
and d) non-Hodgkin lymphoma/hystiocytosis (Section 12.8). Note: Neuroblastoma patients 
who do not have MIBG positive lesions should be assessed for response as solid tumor 
patients with measurable disease. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009].  Key points are that 5 target lesions are identified and that changes in the largest 
diameter (unidimensional measurement) of the tumor lesions but the shortest diameter of 
malignant lymph nodes are used in the RECIST v 1.1 criteria. 
 
 Definitions 
 
12.3.1.1 Evaluable for objective response: Eligible patients who receive at least 
one dose of protocol therapy will be considered evaluable for response. 
Evaluable patients who demonstrate a complete or partial response 
confirmed by central review before receiving non-protocol anti-cancer 
therapy will be considered a responder. All other evaluable patients will 
be considered non-responders. 
 
12.3.1.2 Evaluable Non-Target Disease Response: Eligible patients who have 
lesions present at baseline that are evaluable but do not meet the 
definitions of measurable disease and have received at least one dose of 
protocol therapy will be considered evaluable for non-target disease. 
The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
 
 Disease Parameters 
 
12.3.2.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 
mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 


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


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


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46 
 FDG-PET: While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly 
possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
             For patients with a positive PET scan at diagnosis, PET can be 
used to follow response in addition to a CT scan using the 
International Pediatric non-Hodgkin Lymphoma Response 
Criteria.10 
 
12.4 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions 


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47 
is also considered progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
 
 Overall Response Assessment 
 
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥ 28 days Confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
≥ 28 days Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
No 
SD 
documented at least once ≥ 


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CR/Non-
PD/not 
evaluated 
28 days from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Table 3: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.9  from a sequence of overall response assessments. 
 
12.5 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
 MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 


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49 
 
 
 
 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease: Development of new MIBG positive lesions 
 
 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess efficacy 
for study endpoint. See Section 8.2 for details on transferring images to the 
Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 
 
 
The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 


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classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
 Overall Response Assessment 
 
Table 4: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease 
Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly 
identified lesion by CT/MRI that occurs during therapy would be considered 
progressive disease. 
 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.9. 
 
12.6 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
 Bone Marrow Involvement  
Note: patients with bone marrow as the ONLY site of disease are not eligible for 
this study. Response criteria in this section are intended to be used when 
assessing marrow involvement as a component of overall response.  
 
Histologic analysis at the local institution of marrow tumor cell involvement is 
required for patients with a history of marrow involvement. Marrow aspirate and 
biopsy should be evaluated at baseline and every 2 cycles thereafter. Note: If 
progressive disease is documented by RECIST criteria using tumor measurements 
or by MIBG scan, then a repeat BM is not needed to confirm PD.  
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 


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performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there 
is a doubling in the amount of tumor in the marrow AND 
a minimum of 25% tumor in bone marrow by 
morphology. (For example, a patient entering with 5% 
tumor in marrow by morphology must increase to ≥ 25% 
tumor to have progressive disease; a patient entering with 
30% tumor must increase to > 60%). 
 
In patients who enroll without evidence of neuroblastoma 
in bone marrow will be defined as progressive disease if 
tumor is detected in 2 consecutive bone marrow biopsies 
or aspirations done at least 21 days apart. 
 
 
Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.9. 
12.7 
Response Criteria for Patients with CNS Tumors 
 
 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
 Evaluable Disease  
Evaluable disease is defined as at least one lesion, with no lesion that can be 
accurately measured in at least one dimension. Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures. 
 
 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice). 
 


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


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53 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns.   
 
 
Target Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 
Response 
CR 
CR 
Normal 
No 
CR 
CR 
IR/SD 
Normal 
No 
PR 
CR  
CR, IR/SD 
Abnormal 
No 
PR 
PR 
CR, IR/SD 
Any 
No 
PR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.9 from a sequence of overall response assessments. 
 
 
12.8 
Response Criteria for Patients with non-Hodgkin Lymphoma/Histiocytosis 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Pediatric non-Hodgkin 
Lymphoma Criteria10, with modification from the Lugano classification.11 
 
 Disease Parameters 
 
 Measurable disease: A measurable node must have an LDi (longest 
diameter) greater than 1.5 cm. A measurable extranodal lesion should 
have an LDi greater than 1.0 cm. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
 Non-measured disease: All other lesions (including nodal, extranodal, and 
assessable disease) should be followed as nonmeasured disease (e.g., 
cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial 
effusions, ascites).   
 
 Target lesions: For patients staged with CT, up to six of the largest target 
nodes, nodal masses, or other lymphomatous lesions that are measurable 
in two diameters (longest diameter [LDi] and shortest diameter) should 
be identified from different body regions representative of the patient’s 
overall disease burden and include mediastinal and retroperitoneal 
disease, if involved. 
 
 Evaluation of Measurable Disease 
 
Complete Response (CR) 


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Disappearance of all disease. CT or MRI should be free of residual mass or 
evidence of new disease. FDG-PET should be negative. 
 
Complete Response Unconfirmed (CRu) 
Residual mass is negative by FDG-PET; no new lesions by imaging examination; 
no new and/or progressive disease elsewhere 
 
Partial Response (PR) 
50% decrease in SPD (the sum of the products of the largest diameter and the 
perpendicular diameter for a tumor mass) on CT or MRI; FDG-PET may be 
positive (Deauville score or 4 or 5 with reduced lesional uptake compared with 
baseline); no new and/or PD; morphologic evidence of disease may be present in 
BM if present at diagnosis; however, there should be 50% reduction in percentage 
of lymphoma cells. 
 
No Response (Stable Disease) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
Progressive disease 
For those with > 25% increase in SPD on CT or MRI, Deauville score 4 or 5 on 
FDG-PET with increase in lesional uptake from baseline, or development of new 
morphologic evidence of disease in BM  
 
 Evaluation of Non-measured Lesions (CT-based response, PET/CT based 
response not applicable)11 
 
Complete Response (CR): 
Absent non-measured lesions.  
 
Partial response (PR): 
Absent/normal, regressed, lesions, but no increase. 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): New 
or 
clear 
progression 
of 
preexisting 
non-measured lesions. 
 
 Evaluation of organ enlargement11  
 
Complete Response (CR): 
Regress to normal  
 
Partial response (PR): 
Spleen must have regressed by >50% in length 
beyond normal 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): In the setting of splenomegaly, the splenic length 
must increase by 50% of the extent of its prior 
increase beyond baseline. If no prior splenomegaly, 
must increase by at least 2 cm from baseline.  
 
New or recurrent splenomegaly 


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12.9 
Best Response 
Two objective status determinations of disease status, obtained on two consecutive 
determinations, separated by at least a 3 week time period, are required to determine the 
patient’s overall best response. Two objective status determinations of CR before 
progression are required for best response of CR. Two determinations of PR or better 
before progression, but not qualifying for a CR, are required for a best response of PR. 
Two determinations of stable/no response or better before progression, but not qualifying 
as CR or PR, are required for a best response of stable/no response; if the first objective 
status is unknown, only one such determination is required. Patients with an objective 
status of progression on or before the second evaluations (the first evaluation is the first 
radiographic evaluation after treatment has been administered) will have a best response of 
progressive disease. Best response is unknown if the patient does not qualify for a best 
response of progressive disease and if all objective statuses after the first determination and 
before progression are unknown. 
 
 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
Table 5.  Sequences of overall response assessments with corresponding best 
response. 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
 
 Duration of Response 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
 


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


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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.   
 
 CTEP-AERS Expedited Reporting Methods  
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page https://ctepcore
.nci.nih.gov/ctepaers/pages/task 
 
Send supporting documentation to the NCI by fax (fax# 301-897-7404) and by 
email to both COGCAdEERS@childrensoncologygroup.org and to the APEC16-
21C COG Study Assigned Research Coordinator.  ALWAYS include the ticket 
number on all faxed and emailed documents. 
 
13.2 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the current version of the NCI CTCAE v5.  
The descriptions and grading scales found in the current version of the CTCAE 
v5.0 will be used for AE reporting. All appropriate treatment areas should have 
access to a copy of the CTCAE v5.0.  A copy of the CTCAE v5.0 can be 
downloaded from the CTEP website (http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAE v5. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
• 
Any medical event equivalent to CTCAE v5 grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported regardless 
of attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions. 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
• 
As referenced in the CTEP Adverse Events Reporting Requirements, an AE that 
resolves and then recurs during a subsequent cycle does not require CTEP-AERS 
reporting unless (1) the Grade increases; or (2) hospitalization is associated with the 
recurring AE. 
• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via 
the web at http://ctep.cancer.gov (telephone CTEP at: 301-897-7497 within 24 hours of 
becoming aware of the event if the CTEP-AERS 24-Hour Notification web-based 
application is unavailable). Once internet connectivity is restored, a 24-hour notification 
phoned in must be entered electronically into CTEP-AERS by the original submitter at 
the site. 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 


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calendar days of learning of the event (refer to Table A). 
 
Table A: Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported via CTEP-AERS within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
13.3 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements: 
 


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• Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), 
does not require expedited reporting, unless it is associated with hospitalization. 
Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD/LYMPHATICS DISORDERS 
Anemia 
 
• Grade 1 and 2 adverse events listed in the table below do not require expedited reporting 
via CTEP-AERS, unless it is associated with hospitalization. 
Category 
Adverse Events 
GASTROINTESTINAL DISORDERS   
Abdominal Pain 
GASTROINTESTINAL DISORDERS   
Constipation 
GASTROINTESTINAL DISORDERS   
Diarrhea 
GASTROINTESTINAL DISORDERS   
Vomiting 
METABOLISM AND NUTRITION DISORDERS 
Anorexia  
MUSCULOSKELETAL AND CONNECTIVE 
TISSUE DISORDERS 
Muscle Cramp 
NERVOUS SYSTEM DISORDERS 
Dysgeusia 
NERVOUS SYSTEM DISORDERS 
Headache 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
Photosensitivity 
• See also the Specific Protocol Exceptions to Expedited Reporting (SPEER) in Section 9.1.9 
of the protocol.   
 
13.4 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG case report 
forms and do not alter the guidelines for CTEP-AERS reporting. 
 
 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
 If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported. 
 
 The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects.  
 
 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than or equal to Grade 1, whichever level is higher (note that the 
resolution date may therefore be different from the date at which the grade of the 
AE decreased from its highest grade).  If the AE does not return to baseline the 
resolution date should be recorded as "ongoing."   
 
 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  


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13.5 
Other Recipients of Adverse Event Reports 
 
 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the CRF 
packet (See Section 14.1). 
 Adverse events determined to be reportable must also be reported according to 
the local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
13.6 
Specific Examples for Expedited Reporting 
 
 Reportable Categories of Death 
• Death attributable to a CTCAE v5.0 term.  
• Death Neonatal: A disorder characterized by “Newborn deaths occurring during 
the first 28 days after birth.” 
• Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be attributed 
to a CTCAE v5.0 term associated with Grade 5.  
• Death NOS: A cessation of life that cannot be attributed to a CTCAE v5.0 term 
associated with Grade 5.  
• Death due to progressive disease should be reported as Grade 5 “Disease 
Progression” under the system organ class (SOC) of “General Disorders and 
Administration Site Conditions.” Evidence that the death was a manifestation 
of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
• Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 
hours.  
 
• Any death that occurs more than 30 days after the last dose of treatment with 
an investigational agent which can be attributed (possibly, probably, or 
definitely) to the agent and is not clearly due to progressive disease must be 
reported via CTEP-AERS per the timelines outlined in the table above. 
 
 Reporting Secondary Malignancy 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., 
treatment 
with 
investigational 
agent/intervention, 
radiation 
or 
chemotherapy). A secondary malignancy is not considered a metastasis of the 
initial neoplasm. The occurrence of T-cell lymphoma should be reported via 
CTEP-AERS. 
 


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CTEP requires all secondary malignancies that occur following treatment with an 
agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute 
myelocytic leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy).  Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 
 
 Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Neonatal loss”, the Pregnancy Information Form, available at: https://ctep.cance
r.gov/protocoldevelopment/electronic_applications/docs/PregnancyReportFormU
pdated.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 should be documented in the “Description of Event” section 
of the CTEP-AERS report. 
 
Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the fetus to 
agents that may be teratogenic. For this reason, pregnancy needs to be reported in 
an expedited manner via CTEP-AERS as Grade 3 “Pregnancy, puerperium and 
perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and 
perinatal conditions SOC. 
 
Pregnancy needs to be followed until the outcome of the pregnancy is known at 
intervals deemed appropriate by her physicians. The “Pregnancy Information 
Form” should be used for all necessary follow-ups. This form is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregn
ancyReportForm.pdf. If the baby is born with a birth defect or anomaly, then a 
second CTEP-AERS report is required. 
 
Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE v5.0 as “Death in utero.” 
 
Any pregnancy loss needs to be reported expeditiously, as Grade 4 “Pregnancy 
loss” under the “puerperium and perinatal conditions” SOC. Do NOT report a 
pregnancy loss as a Grade 5 event since CTEP-AERS recognizes any Grade 5 
event as a patient death. 
 
Death Neonatal 
Neonatal death, defined in CTCAE v5.0 as Newborn deaths occurring during the 


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first 28 days after birth” that is felt by the investigator to be at least possibly due 
to the investigational agent/intervention, should be reported expeditiously, as 
Grade 4 “Death Neonatal” under the system organ class (SOC) of “General 
disorders and administration site conditions.” When the death is the result of a 
patient pregnancy or pregnancy in partners of men on study. Do NOT report 
a neonatal death resulting from a patient pregnancy or pregnancy in partners of 
men on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event 
as a patient death.  
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
entered in RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the case report form (CRF) 
packet. 
 
See separate CRF Packet, which includes submission schedule. 
 
14.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted 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. 
Note:  This study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS 
reporting guidelines must be reported via the monitoring method identified above.   
 
14.3 
CRADA/CTA/CSA 
Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by 
a Clinical Trials Agreement (CTA) or a Cooperative Research and Development 
Agreement. 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the provisions in the “Intellectual Property Option to Collaborator” (http://ctep.cancer.go
v/industryCollaborations2/intellectual_property.htm) contained within the terms of award, 
apply to the use of the Agent(s) in this study: 


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63 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order as described in the IP Option to Collaborator (http://ctep.cancer.gov/industr
yCollaborations2/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. 


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6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP for immediate delivery to Collaborator(s) for advisory review and comment 
prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and 
other media presentations must also be forwarded to CTEP prior to release. Copies 
of any manuscript, abstract and/or press release/ media presentation should be sent 
to: 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
14.4 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the developmental therapy 
scientific committee; and a member from the NCI. The DSMC meets at least every 
6 months to review current study results, as well as data available to the DSMC 
from other related studies. Approximately 6 weeks before each meeting of the 
Phase 1 and 2 DSMC, study chairs will be responsible for working with the study 
statistician to prepare study reports for review by the DSMC. The DSMC will 
provide recommendations to the COG Developmental Therapeutics Chair and the 
Group Chair for each study reviewed to change the study or to continue the study 
unchanged. Data and Safety Committee reports for institutional review boards can 
be prepared using the public data monitoring report as posted on the COG Web 
site. 
 
 Monitoring by the Study Chair and MATCH Leadership  
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the 
MATCH Chair, Vice Chair and Statistician on a weekly conference call. 


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65 
REFERENCES 
1. 
Knutson SK, Wigle TJ, Warholic NM, et al: A selective inhibitor of EZH2 blocks H3K27 
methylation and kills mutant lymphoma cells. Nat Chem Biol 8:890-6, 2012 
2. 
Sneeringer CJ, Scott MP, Kuntz KW, et al: Coordinated activities of wild-type plus mutant EZH2 
drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell 
lymphomas. Proc Natl Acad Sci U S A 107:20980-5, 2010 
3. 
Morin RD, Johnson NA, Severson TM, et al: Somatic mutations altering EZH2 (Tyr641) in 
follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 42:181-5, 2010 
4. 
Wilson BG, Wang X, Shen X, et al: Epigenetic antagonism between polycomb and SWI/SNF 
complexes during oncogenic transformation. Cancer Cell 18:316-28, 2010 
5. 
Knutson SK, Warholic NM, Wigle TJ, et al: Durable tumor regression in genetically altered 
malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A 
110:7922-7, 2013 
6. 
Knutson SK, Warholic NM, Johnston LD, et al: Synergistic Anti-Tumor Activity of EZH2 
Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin 
Lymphomas. PLoS One 9:e111840, 2014 
7. 
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.,  
8. 
A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 20:859-66, 2001 
9. 
Agresti A, Coull BA: Approximate Is Better than "Exact" for Interval Estimation of Binomial 
Proportions. The American Statistician 52:119-126, 1998 
10. 
Sandlund JT, Guillerman RP, Perkins SL, et al: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. J Clin Oncol 33:2106-11, 2015 
11. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 32:3059-68, 2014 
 
 


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66 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
Karnofsky 
Lansky 
Score 
Description 
Score Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time spent 
in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet 
play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to very 
passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 
 
 
 


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67 
APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
 
This is NOT an all-inclusive list. Because the lists of these agents are constantly changing, it is 
important to regularly consult frequently updated medical references. 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong 
Inducers 
Moderate 
Inducers 
abemaciclib 
acalabrutinib5 
alfentanil4,5  
alprazolam5 
amiodarone4 
amlodipine 
aprepitant/fosaprepitant 
atorvastatin 
avanafil5 
axitinib 
bortezomib 
bosutinib5 
brexpiprazole 
brigatinib 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
colchicine5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
ebastine5 
eletriptan5 
eliglustat5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
felodipine5 
fentanyl4 
atazanavir 
boceprevir 
clarithromycin 
ceritinib 
cobicistat 
danoprevir/ritonavir 
darunavir 
delavirdine 
elvitegravir/ritonavir 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir/ritonavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
paritaprevir/ritonavir/ 
ombitasvir +/- dasabuvir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
tipranavir/ritonavir 
tucatinib 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
duvelisib 
erythromycin 
fedratinib 
fluconazole 
fosamprenavir 
fosnetupitant 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
lefamulin 
letermovir 
mifepristone 
netupitant 
nilotinib 
ribociclib 
verapamil 
apalutamide 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
lumacaftor/ 
ivacaftor 
mitotane 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
cenobamate 
dabrafenib 
efavirenz 
eslicarbazepine 
etravirine 
lorlatinib 
modafinil 
nafcillin 
rifabutin 
rifapentin 
 
 
 


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68 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
lomitapide5 
lorlatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
naloxegol5 
nefazodone 
nilotinib 
nisoldipine5 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
pimozide5 
quetiapine5 
quinidine4  
regorafenib 
rilpivirine5 
rivaroxaban5 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
tadalafil5 
telaprevir 
temsirolimus 


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69 
teniposide 
tetracycline 
ticagrelor5 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 7.5 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥ 5-fold with strong inhibitors) 


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70 
APPENDIX III-A:  MEDICATION DIARY FOR TAZEMETOSTAT (ORAL SUSPENSION 
FORMULATION) 
 
COG Patient ID:___________   Acc#____________ Institution :__________________________  
Please do not write patient names on this form. 
 
 
Instructions: Complete each day with the time and dose given for tazemetostat. Make note of other drugs and 
supplements taken in the Comments section below. Tazemetostat suspension should be given twice a day without 
regard to meals, with no less than 8 hours between each dose. Shake the bottle for one minute before you take 
tazemetostat, do not shake too much if there are bubbles wait for them to dissipate before measuring the dose.  
 Note: If multiple bottles are dispensed, daily shaking of all bottles is required to ensure the suspension stays properly 
suspended. Store your oral suspension in the refrigerator. If you vomit after taking tazemetostat suspension, the dose 
should NOT be repeated and the next dose should be taken at a regular scheduled time. This should be noted in the 
Comments section. Add the dates to the calendar below and return the completed diary to the study clinic at each visit 
(weekly during Cycle 1, and then after each treatment cycle).  
 
 
EXAMPLE 
 
 
AM Dose: Take 12 mL 
PM Dose:  Take 12 mL  
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
WEEK 1 
Date 
Time 
Amount of oral suspension 
taken (mL) 
Day 1 
2/15/19 
8:30 
AM 
12 
He felt nauseated an hour after 
taking the drug but did not vomit. 
8:30 
PM 
12 
 
  
 
          Cycle #: _____         Start Date: |__/__|__/__|__/__|   End Date: |__/__|__/__|__/__|  
 
           Dose Level:            mg/m2/dose                               
 
WEEK 1 
Date 
Time 
AM Dose: Take _____mL  
PM Dose:  Take _____mL 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
Amount of oral solution 
taken (mL) 
Day 1 
 
 
AM 
 
 
 
PM 
 
 
Day 2 
 
 
AM 
 
 
 
PM 
 
 
Day 3 
 
 
AM 
 
 
 
PM 
 
 
Day 4 
 
 
AM 
 
 
 
PM 
 
 
Day 5 
 
 
AM 
 
 
 
PM 
 
 
Day 6 
 
 
AM 
 
 
 
PM 
 
 
Day 7 
 
 
AM 
 
 
 
PM 
 
 
 
 
 


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COG Patient ID: ___________   ACC # : _____     Institution :__________________  
Please do not write patient names on this form. 
 
           Cycle #: _____          Start Date: |__/__|__/__|__/__|   End Date: |__/__|__/__|__/__|  
 
           Dose Level:            mg/m2/dose    
                             
WEEK 2 
Date 
Time 
AM Dose: Take _____mL  
PM Dose:  Take _____mL 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
Amount of oral suspension 
taken (mL) 
Day 8 
 
 
AM 
 
 
 
PM 
 
 
Day 9 
 
 
AM 
 
 
 
PM 
 
 
Day 10 
 
 
AM 
 
 
 
PM 
 
 
Day 11 
 
 
AM 
 
 
 
PM 
 
 
Day 12 
 
 
AM 
 
 
 
PM 
 
 
Day 13 
 
 
AM 
 
 
 
PM 
 
 
Day 14 
 
 
AM 
 
 
 
PM 
 
 
 
WEEK 3 
Date 
Time 
AM Dose: Take _____mL 
PM Dose:  Take _____mL 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
Amount of oral suspension 
taken (mL) 
Day 15 
 
 
AM 
 
 
 
PM 
 
 
Day 16 
 
 
AM 
 
 
 
PM 
 
 
Day 17 
 
 
AM 
 
 
 
PM 
 
 
Day 18 
 
 
AM 
 
 
 
PM 
 
 
Day 19 
 
 
AM 
 
 
 
PM 
 
 
Day 20 
 
 
AM 
 
 
 
PM 
 
 
Day 21 
 
 
AM 
 
 
 
PM 
 
 
 
 


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72 
 
WEEK 4 
Date 
Time 
AM Dose: Take _____mL 
PM Dose:  Take _____mL 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
Amount of oral suspension 
taken (mL) 
Day 22 
 
 
AM 
 
 
 
PM 
 
 
Day 23 
 
 
AM 
 
 
 
PM 
 
 
Day 24 
 
 
AM 
 
 
 
PM 
 
 
Day 25 
 
 
AM 
 
 
 
PM 
 
 
Day 26 
 
 
AM 
 
 
 
PM 
 
 
Day 27 
 
 
AM 
 
 
 
PM 
 
 
Day 28 
 
 
AM 
 
 
 
PM 
 
 
 
 
 
If this form will be used as a source document, the site personnel who administered the study drug must 
sign and date this form below: 
 
Signature: ________________________________________          Date: __________________________ 
 
     (Site personnel who administered the study drug) 
 


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73 
 
APPENDIX III-B:  PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the experimental 
study drug, tazemetostat.  This clinical trial is sponsored by the National Cancer Institute.  This 
form is addressed to the patient but includes important information for others who care for this 
patient.  
 
These are the things that you as a healthcare provider need to know: 
  
Tazemetostat interacts with certain specific enzyme(s) in your liver and certain transport proteins 
that help move drugs in and out of cells.  
 
• The enzymes in question are CYP3A, 2C8, 2D6, 2C9, and 2C19.   
• Tazemetostat is broken down by CYP3A, 2C8, and 2D6, and may be affected by other 
drugs that inhibit or induce these enzymes. Treatment with strong inhibitors or inducers 
of CYP3A are prohibited from 14 days prior to the first dose of tazemetostat to the end 
of the study. 
• Tazemetostat inhibits CYP3A4, 2C8, 2C9, 2C19, and 2D6 and may affect other drugs 
that are broken down by these enzymes.   
• Tazemetostat induces CYP3A4 and may affect other drugs that are broken down by this 
enzyme. 
• The proteins in question are P-gp, OATP1B1, OATP1B3, OAT3, MATE1, and 
MATE2K.  
• Tazemetostat is moved in and out of cells/organs by P-gp and may be affected by other 
drugs that inhibit or induce this protein. 
• Tazemetostat inhibits P-gp, OATP1B1, OATP1B3, OAT3, MATE1, and MATE2K and 
may affect other drugs that require them to move in and out of cells. 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Tazemetostat may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular medicines, 
or if you start taking a new medicine while you take part in this study.  When you talk about your 
current medications with your doctors, include medicine you buy without a prescription (over-the-
counter remedy), or any herbal supplements such as St. John’s Wort.  It is helpful to bring your 
medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical 
trial.  


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74 
 
These are the things that you and they need to know:  
 
Tazemetostat must be used very carefully with other medicines that use certain liver enzymes or 
transport proteins to be effective or to be cleared from your system.  Before you enroll onto the 
clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong inducers/inhibitors of CYP3A, 2C8, 
2D6, or P-gp; or substrates of CYP3A, 2C8, 2D6, 2C9, 2C19, P-gp, OATP1B1, OATP1B3, OAT3, 
MATE1, or MATE2K.” 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
• No grapefruit juice, Seville oranges, or grapefruit can be consumed while on tazemetostat. 
• Avoid prolonged exposure to the sun and wear protective clothing and sunscreen when out 
in the sun. 
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is  
_____________________________________ and he or she can be contacted at  
 
_____________________________________. 
 
October 2018 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
tazemetostat.  This clinical trial is sponsored by the NCI.  Tazemetostat 
may interact with drugs that are processed by your liver or use certain 
transport proteins in your body.  Because of this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
➢ No grapefruit juice, Seville oranges, or grapefruit can be consumed 
while on tazemetostat. 
➢ Avoid prolonged exposure to the sun and wear protective clothing 
and sunscreen when out in the sun. 
 
 
 
Tazemetostat interacts with specific liver enzymes called CYP3A, 
2C8, 2D6, 2C9, 2C19 and transport proteins P-gp, OATP1B1, 
OATP1B3, OAT3, MATE1, and MATE2K, and must be used very 
carefully with other medicines that interact with these enzymes or 
transporter.  
➢ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong 
inducers/inhibitors of CYP3A, 2C8, 2D6 or P-gp or substrates of 
CYP3A, 2C8, 2D6, 2C9, 2C19 or transporters P-gp, OATP1B1, 
OATP1B3, OAT3, MATE1, and MATE2K.”  
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  
➢  


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75 
APPENDIX IV: TAZEMETOSTAT DOSING PREPARATION (ORAL SUSPENSION 
FORMULATION) 
 
Drug doses should be adjusted based on the BSA calculated from height and weight measured within 7 
days prior to the beginning of each cycle.  Shake the bottle for one minute before you take tazemetostat; 
do not shake too much if there are bubbles wait for them to dissipate before measuring the dose. Note: If 
multiple bottles are dispensed, daily shaking of all bottles is required to ensure the suspension stays 
properly suspended. Store your oral suspension in the refrigerator. 
 
Patients who experience dose-limiting toxicity should have their dose reduced by 25% so that patients 
receive 75% of the original administered dose. A site-supplied press-in bottle adapter is required for 
use with an oral syringe for dosing purposes.  
 
Tazemetostat Oral Suspension Preparation Worksheet and Guidance Table 
 
Protocol:  
Date of preparation: 
Subject ID and Initials: 
Cycle #: 
BSA (m2): 
• Assigned dose level: 1200mg/m2/dose BID (Pre-AMD#3) 
• Assigned dose level: 520 mg/m2/dose BID      
 (For patients enrolled post-AMD#3 Patients without CNS involvement see Section 5.1) 
• Assigned dose level: 1200 mg/m2/dose BID                                                                         
(For patients enrolled post-AMD#3 — Patients with CNS involvement see Section 5.1) 
 
Steps: 
 
 
1) Calculate the mg of tazemetostat required 
per dose: 
BSA x dose level 
 
__________________ mg per dose BID 
2) Calculate the total mg of tazemetostat 
required per dosing period, including any 
overfill per institution guidelines* 
mg per dose x # of doses per day x # 
of days x overfill (if needed) 
*An overfill will most likely be needed in 
order to dispense sufficient quantity to last 14 
days 
 
__________________ mg per dosing period 
3) Calculate total # of grams of tazemetostat 
required per dosing period. 
mg from step 2 divided by 1000 
 
_________ grams per dosing period (round up to nearest whole 
number) 
4) Enter # of 2 gram and 7 gram bottles 
required for dosing period. 
(refer to the suspension preparation 
guidance table) 
 
2 gram bottles: ______ 
 
7 gram bottles: ______ 
Total # of grams: 
 
________ 
5) Calculate the total volume of Ora-Sweet® 
required. 
Total grams of tazemetostat from 
step 4 x 32.5 mL/gram 
 
___________ mL (refer to the suspension preparation guidance table) 


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76 
6) Determine # of empty medication bottles 
required so that each bottle is filled 
between 40-80% capacity for adequate 
mixing. 
7) Follow the oral suspension preparation 
instructions in the protocol. 
Bottle 
# 
Grams 
of 
tazemetostat 
mL 
of 
Ora-
Sweet® to add 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8) Calculate the volume required per dose 
mg per step 1 divided by 30 mg/ml 
 
___________ mL per dose BID 
 
 
Suspension preparation guidance table: 
Total 
tazemetostat 
required 
2 
gm 
bottles 
7 
gm 
bottles 
Ora-Sweet® 
volume* (mL) 
Allowable 
medication 
bottle size** (mL) 
< 2 grams 
1 
0 
65 
100-150 
2 to <4 grams 
2 
0 
130 
200-300 
4 to <6 grams 
3 
0 
195 
250-500 
6 to <7 grams 
0 
1 
228 
250-500 
7 to <9 grams 
1 
1 
293 
400-700 
9 to <11 grams 
2 
1 
358 
400-800 
11 to <12 grams 
3 
1 
423 
600-1000 
12 to <14 grams 
0 
2 
455 
600-1100 
14 to <16 grams 
1 
2 
520 
600-1200 
16 to <18 grams 
2 
2 
585 
700-1400 
18 to <20 grams 
3 
2 
650 
750-1500 
20 to <21 grams 
0 
3 
683 
850-1600 
21 to <23 grams 
1 
3 
748 
1000-1800 
23 to <25 grams 
2 
3 
813 
1000-2000 
25 to <27 grams 
3 
3 
878 
1100-2100 
27 to <28 grams 
0 
4 
910 
1200-2400 
28 to <30 grams 
1 
4 
975 
1300-2500 
30 to <32 grams 
2 
4 
1040 
1400-2600 
32 to <34 grams 
3 
4 
1105 
1500-2800 
This table is for guidance purposes only, larger volumes should be calculated using the 
Tazemetostat Oral Suspension Preparation Worksheet. 
 
*The volume of Ora-Sweet® to obtain a concentration of 30 mg tazemetostat/mL of suspension 
accounts for the volume of tazemetostat in the solution. 
** Total volume listed may require more than one medication bottle to accommodate.  Each 
medication bottle must be prepared separately but multiple whole bottles of tazemetostat powder for 
oral suspension can be combined into one medication bottle.   
 
 
 
 
 


  
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77 
Cycle 1  
APPENDIX V: APEC1621C THERAPY DELIVERY MAP
Therapy Delivery Map – Cycle 1 
This Therapy Delivery Map (TDM) relates to Cycle 1. Each cycle lasts 28 days.  
____________________________ 
Patient COG ID number 
_______________________ 
Accession number 
 
Criteria to start each cycle are listed in Section 5.2. Extensive treatment details are in Section 5.1.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tazemetostat 
 
PO 
Please circle one: 
 
-1200 mg/m2/dose BID  
(Pre-Amendment #3B) 
 
 
-Patient without CNS 
involvement: 520 
mg/m2/dose BID 
 
 
-Patient with CNS 
involvement:1200 
mg/m2/dose BID  
 
Refer to the dosing 
preparation Appendix IV. 
1-28 
Tazemetostat will be administered as a liquid 
suspension orally given twice a day without 
regard to meals with no less than 8 hours 
between each dose.  If vomiting occurs after 
taking oral suspension formulation, the dose 
should NOT be repeated and the next dose 
should be administered at the regularly 
scheduled time. See Section 9.1.6 and 
Appendix IV for additional oral suspension 
administration and preparation instructions. 
 
Ht ______cm Wt ______kg BSA _______m2 Patient with CNS involvement: Yes/No (please circle 1) 
 
Date Due 
Date 
Given 
Day 
Tazemetostat 
________mg AM        ______mg PM 
Studies 
 
 
 
Enter calculated dose above and actual 
dose administered below 
 
 
 
1 
________mg AM        ______mg PM 
 
 
 
2 
________mg AM        ______mg PM 
 
 
 
3 
________mg AM        ______mg PM 
 
 
 
4 
________mg AM        ______mg PM 
 
 
 
5 
________mg AM        ______mg PM 
 
 
 
6 
________mg AM        ______mg PM 
 
 
 
7 
________mg AM        ______mg PM 
 
 
 
8 
________mg AM        ______mg PM 
a, c, d, e, h 
 
 
9 
________mg AM        ______mg PM 
 
 
 
10 
________mg AM        ______mg PM 
 
 
 
11 
________mg AM        ______mg PM 
 
 
 
12 
________mg AM        ______mg PM 
 
 
 
13 
________mg AM        ______mg PM 
 
 
 
14 
________mg AM        ______mg PM 
 
 
 
15 
________mg AM        ______mg PM 
a, c, d, e, h 
 
 
16 
________mg AM        ______mg PM 
 
 
 
17 
________mg AM        ______mg PM 
 
 
 
18 
________mg AM        ______mg PM 
 
 
 
19 
________mg AM        ______mg PM 
 
 
 
20 
________mg AM        ______mg PM 
 
 
 
21 
________mg AM        ______mg PM 
 


  
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78 
Cycle 1  
 
 
22 
________mg AM        ______mg PM 
a, c, d, e, h 
 
 
23 
________mg AM        ______mg PM 
 
 
 
24 
________mg AM        ______mg PM 
 
 
 
25 
________mg AM        ______mg PM 
 
 
 
26 
________mg AM        ______mg PM 
 
 
 
27 
________mg AM        ______mg PM 
 
 
 
28/1 
________mg AM        ______mg PM 
a, b , c, d, e, f, h, i, j*,k  
See Section 6.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care 
Guidelines. 
 
 
 
Required Observations in Cycle 1  
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below. For information related to prestudy observations please refer to Section 8.1. Studies on Day 
28/1 may be obtained within 72 hours prior to the start of the subsequent cycle. 
 
a. 
History/Physical Exam (including VS) 
b. 
Ht/Wt/BSA 
c. 
 
CBC/differential/platelets- If patients have Grade 4 neutropenia then CBCs should be checked at least 
every other day until recovery to Grade 3 or until meeting the criteria for dose limiting toxicity. 
Automated differentials acceptable unless concern for blasts; then please obtain manual differential. 
d. 
Electrolytes including Ca++, PO4, Mg++ 
e. 
Creatinine, ALT, bilirubin 
f. 
Albumin 
g. 
Bone Marrow Aspirate and/or biopsy- Only required in patients suspected of having bone marrow 
metastasis on the basis of history, symptoms, laboratory evaluation or other clinical data. Should only 
be performed on patients with known bone marrow involvement at baseline. Bone marrow aspirate 
and/or biopsy should be performed only when complete response or partial response is identified in 
target disease or when progression in bone marrow is suspected 
h 
Medication Diary- (see Appendix III-A and Appendix II-B) should be reviewed after completion of 
each treatment cycle and uploaded into RAVE. The medication diary should be collected weekly.  
i. 
Bromide Level 
j. 
 
   Plain radiograph tibial growth plate (Bone X-Ray Tests).  Plain radiographs of at least one tibial 
growth plate should be obtained in all patients prior to first dose of protocol therapy. In patients with 
open growth plates, follow-up plain radiographs of the same growth plate(s) should be obtained 
according to Section 8.2. 
k. 
Neurological Exam. 
 
 
 
 
 
 
 
 
 
 


  
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79 
Cycle 1  
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
Treatment Details: Cycle 1 
 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 
5.2 are met (whichever occurs later). 


  
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Subsequent Cycles 
All Subsequent Cycles
 
Therapy Delivery Map – All Subsequent Cycles 
This Therapy Delivery Map (TDM) relates to all subsequent cycles. Each cycle lasts 28 
days. Treatment may continue in the absence of disease progression or unacceptable 
toxicity. Use a copy of this page once for each cycle (please note cycle number below).  
____________________________ 
Patient COG ID number 
_______________________ 
Accession number  
 
Criteria to start each cycle are listed in Section 5.2. Extensive treatment details are in Section 5.1. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tazemetostat 
 
PO 
Please circle one: 
 
-1200 mg/m2/dose BID 
  (for patients enrolled pre-
amendment #3B) 
 
 
-Patient without CNS 
involvement: 520 
mg/m2/dose BID 
(only for patients enrolled 
post-amendment #3B) 
 
 
 
-Patient with CNS 
involvement: 1200 
mg/m2/dose BID 
(only for patients enrolled 
post-amendment #3B) 
 
 
Refer to the dosing 
preparation Appendix IV. 
1-28 
Tazemetostat will be administered as a liquid 
suspension orally given twice a day without 
regard to meals with no less than 8 hours 
between each dose.  If vomiting occurs after 
taking oral suspension formulation, the dose 
should NOT be repeated and the next dose 
should be administered at the regularly 
scheduled time. See Section 9.1.6 and 
Appendix IV for additional oral suspension 
administration and preparation instructions. 
 
Ht ______cm 
Wt ______kg BSA _______m2 Patient with CNS involvement: y/n (please circle 1) 
 
Date Due 
Date 
Given 
Day 
Tazemetostat 
________mg AM        ______mg PM 
Studies 
 
 
 
Enter calculated dose above and actual 
dose administered below 
 
 
 
1 
________mg AM        ______mg PM 
a-g, m, n, k  
 
 
2 
________mg AM        ______mg PM 
 
 
 
3 
________mg AM        ______mg PM 
 
 
 
4 
________mg AM        ______mg PM 
 
 
 
5 
________mg AM        ______mg PM 
 
 
 
6 
________mg AM        ______mg PM 
 
 
 
7 
________mg AM        ______mg PM 
 
 
 
8 
________mg AM        ______mg PM 
 
 
 
9 
________mg AM        ______mg PM 
 
 
 
10 
________mg AM        ______mg PM 
 
 
 
11 
________mg AM        ______mg PM 
 
 
 
12 
________mg AM        ______mg PM 
 
 
 
13 
________mg AM        ______mg PM 
 


  
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81 
Subsequent Cycles 
 
 
14 
________mg AM        ______mg PM 
 
 
 
15 
________mg AM        ______mg PM 
 
 
 
16 
________mg AM        ______mg PM 
 
 
 
17 
________mg AM        ______mg PM 
 
 
 
18 
________mg AM        ______mg PM 
 
 
 
19 
________mg AM        ______mg PM 
 
 
 
20 
________mg AM        ______mg PM 
 
 
 
21 
________mg AM        ______mg PM 
 
 
 
22 
________mg AM        ______mg PM 
 
 
 
23 
________mg AM        ______mg PM 
 
 
 
24 
________mg AM        ______mg PM 
 
 
 
25 
________mg AM        ______mg PM 
 
 
 
26 
________mg AM        ______mg PM 
 
 
 
27 
________mg AM        ______mg PM 
 
 
 
28/1 
________mg AM        ______mg PM 
a-g, h*, j*, k*, l*  m, n  
See Section 6.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines 
* Please refer to Section 8.1 for the specific timing of these observations. Studies on Day 28/1 may be obtained 
within 72 hours prior to the start of the subsequent cycle. 
 
Required Observations in All Subsequent Cycles 
 
a. 
History/Physical Exam (including VS) 
b. 
Neurological Exam 
 
c.    Ht/Wt/BSA 
d. 
CBC/differential/platelets If patients develop Grade 4 neutropenia then CBCs should be 
checked every 3 to 4 days until recovery to Grade 3. Automated differentials acceptable unless 
concern for blasts; then please obtain manual differential. 
e. 
Electrolytes including Ca++, PO4, Mg++ 
f. 
Creatinine, ALT, bilirubin 
g. 
Albumin 
h. 
Tumor Disease Evaluation – Every other cycle x 3 then q 3 cycles. Tumor Disease Evaluation 
should be obtained on the next consecutive cycle after initial documentation of either a PR or 
CR.  Subsequent scans may restart 2 cycles after the confirmatory scan. If the institutional 
investigator determines that the patient has progressed based on clinical or laboratory evidence, 
he/she may opt not to confirm this finding radiographically.  
i.    Bone Marrow Aspirate and/or biopsy- Only required in patients suspected of having bone 
marrow metastasis on the basis of history, symptoms, laboratory evaluation or other clinical 
data. Should only be performed on patients with known bone marrow involvement at baseline.  
 
  
j. 
Circulating Tumor DNA (ctDNA-optional) - With consent, two samples will be collected on 
this protocol (Cycle 5 Day 1; and for patients receiving ≥ 5 cycles, at progression or end of 
protocol therapy) see Section 8.4 for details of the ctDNA studies.  
k. 
 Plain radiograph tibial growth plate (Bone X-Ray Tests).  Plain radiographs of at least one 
tibial growth plate should be obtained in all patients prior to first dose of protocol therapy. In 
patients with open growth plates, follow-up plain radiographs of the same growth plate(s) 
should be obtained according to Section 8.2. 
l. 
EKG.  
m. 
Medication Diary- (see Appendix III-A and Appendix-B) should be reviewed after completion 
of each treatment cycle and uploaded into RAVE. 
n. 
 Bromide Level 
 


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


  
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83 
APPENDIX VI: TARGET HISTOLOGIES FOR APEC1621C EXPANSION COHORTS 
Target tumor types considered for biomarker-positive expansion cohorts in the event of agent activity 
in a specific tumor type. 
 
 
 
 
 
 
Tumor type 
1. Ependymoma 
2. Ewing Sarcoma/Peripheral PNET 
3. Hepatoblastoma 
4. Glioma, high grade 
5. Glioma, low grade 
6. Langerhans Cell Histiocytosis 
7. Malignant Germ Cell Tumor 
8. Medulloblastoma  
9. Neuroblastoma 
10. Non-Hodgkin Lymphoma 
11. Non-RMS Soft Tissue Sarcoma 
12. Osteosarcoma 
13. Rhabdoid Malignancy 
14. Rhabdomyosarcoma 
15. Wilms Tumor 
16. Other Histology (based on COG/NCI-CTEP approval) 


  
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84 
APPENDIX VII: APEC1621C ACTIONABLE MUTATIONS OF INTEREST 
 
Actionable Mutations for Sub-Protocol APEC1621C 
 
NON-HOTSPOT RULES 
(To be used only if IHC testing of gene is equivocal or cannot be performed.) 
Gene Name 
Description 
Variant Type 
LOE 
SMARCB1 
Include 
Two Deleterious mutations 
2 
SMARCA4 
Include 
Two Deleterious mutations  
2 
INCLUSION 
VARIANTS 
  
  
  
Gene Name 
Variant ID 
Variant Type 
aMOI 
LOE 
EZH2 
COSM37032 
SNV 
p.Y646C 
3 
EZH2 
COSM37028 
SNV 
p.Y646F 
3 
EZH2 
COSM37030 
SNV 
p.Y646H 
3 
EZH2 
COSM37031 
SNV 
p.Y646N 
3 
EZH2 
COSM37029 
SNV 
p.Y646S 
3 
EZH2 
COSM220386 
SNV 
p.A682G 
3 
EZH2 
COSM1315851 
SNV 
p.A682V 
3 
EZH2 
COSM220529 
SNV 
p.A692V 
3 
IHC  
RESULTS 
GENE: 
STATUS: 
SMARCB1 
NEGATIVE  
SMARCA4 
NEGATIVE  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
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85 
APPENDIX VIII CORRELATIVE STUDIES GUIDE  
 
 
Correlative 
Study 
 
Section 
Blood Volume 
Tube Type 
Volume per Sample 
Total 
Cycle 5 
Day 1 
Circulating tumor 
DNA (optional) 
8.4 
• 
For patients ≥ 10 kg collect 
20 mLs (10 mL per tube x 2 
tubes)  
• 
For patients ≥ 5 kg but < 10 
kg collect 10 mL (one tube)  
• 
For patients < 5 kg research 
samples will not be collected  
 
10-20 
mL 
Streck Cell-Free DNA BCT 
tubes 
Total Blood Volume in 
Cycle 5 Day 1 
 
10-20 
mL 
 
 
 
Correlative 
Study 
 
Section 
Blood Volume 
Tube Type 
Volume per Sample 
Total  ‘Time of 
progression’ or ‘End 
of protocol therapy’ 
Circulating 
tumor DNA 
(optional) 
8.4 
• 
For patients ≥ 10 kg collect 20 
mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥ 5 kg but < 10 kg 
collect 10 mL (one tube)  
• 
For patients < 5 kg research 
samples will not be collected  
 
10-20 mL* 
Streck Cell-Free 
DNA BCT tubes 
Total Blood Volume in 
‘Time of progression or 
End of protocol therapy’ 
 
10-20 mL 
 
* Only collected from patients from whom the sample at Cycle 5 Day 1 is collected. 
 


  
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86 
APPENDIX IX YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621C 
(For Children from 7 through 12 Years of Age) 
A study of Molecular Analysis for Therapy Choice (MATCH) in children 
with a cancer that has come back after treatment or is difficult to treat 
 
1. We have been talking with you about your cancer. You have had treatment for the cancer already 
but it did not go away or it came back after treatment.  
 
2. We are asking you to take part in a research study because other treatments did not get rid of the 
cancer. A research study is when doctors work together to try out new ways to help people who are 
sick. In this study, we are trying to learn more about how to treat the kind of cancer that you have.  
 
3. You agreed to be part of a study to see if your cancer has any specific changes that could help us 
decide what medicine might “match” best to your cancer. 
 
4. We have found a medicine called tazemetostat that could “match” your tumor. The doctors want to 
see if tazemetostat will help children with your type of cancer get better. We don’t know if 
tazemetostat will work well to get rid of your cancer. That is why we are doing the study. 
 
5. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is that tazemetostat 
may cause your cancer to stop growing or to shrink for a period of time but we don’t know for sure 
if there is any benefit of being part of this study. 
 
6. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that you may have problems, or side effects 
from tazemetostat. There may be risks that we don’t know about. 
 
7. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your cancer that your 
doctor can tell you about.  
8. If you decide to be treated with tazemetostat you might have some tests and check-ups done more 
often that you might if you weren’t part of the study. 
 
9. As part of the study we are also trying to learn more about children’s cancers and how 
tazemetostat works in them. We will draw some extra blood samples for this if your family 
agrees. 
 
 


  
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87 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621C 
(For Teens from 13 through 17 Years of Age) 
A study of Molecular Analysis for Therapy Choice (MATCH) in children 
with a cancer that has come back after treatment or is difficult to treat 
 
1. We have been talking with you about your cancer. You have had treatment for the cancer already but 
the cancer did not go away or it came back after treatment.  
 
2. We are asking you to take part in a research study because other treatments did not get rid of the cancer. 
A research study is when doctors work together to try out new ways to help people who are sick. In this 
study, we are trying to learn more about how to treat the kind of cancer that you have. 
 
3. The main purpose of this study is to learn how well cancers that have specific changes (mutations) 
respond to medicines that are aimed at those changes. This combination of a tumor with a mutation and 
a medicine that aims at that mutation is called a “match”. 
 
4.  Your tumor has a mutation that matches tazemetostat, and so you have been assigned to tazemetostat. 
The doctors want to see if tazemetostat will make children with your type of cancer get better. We don’t 
know if tazemetostat will work well to get rid of your cancer. That is why we are doing the study. 
 
5.  You will get tazemetostat by mouth twice daily for a 28-day period. This entire 28-day period is called 
a cycle. You may continue to receive tazemetostat for up to about 24 months (approximately 26 cycles) 
as long as you do not have bad effects from it and your cancer does not get any worse. If you decide to 
be treated with tazemetostat, you will also have exams and tests done that are part of normal cancer 
care. Some of these may be done more often while you are being treated with tazemetostat. The doctors 
want to see if tazemetostat will help children or adolescents with your type of cancer get better. We 
don’t know if tazemetostat is better than other medicines. That is why we are doing this study.  
 
6. Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that tazemetostat may 
cause your cancer to stop growing or to shrink for a period of time but we don’t know for sure if there 
is any benefit of being part of this study. 
 
7. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The primary risk to you from this study is that you may have side effects, from 
tazemetostat. Your doctor will talk to you about the risks we know about from tazemetostat. There may 
be other risks from tazemetostat that we don’t know about yet.  
 
8. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. There may be other treatments for your illness that your doctor can 
tell you about. Make sure to ask your doctors any questions that you have.  
 
9. As part of the study we are also trying to learn more about the mutations that occur in cancers that happen 
in children and teens, as well as how tazemetostat works. If your family agrees we will draw some extra 
blood samples to do these tests. 
 


  
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88 
APPENDIX X CTEP AND CTSU REGISTRATION PROCEDURES 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require 
all investigators participating in any NCI-sponsored clinical trial to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program 
(CTEP) Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In 
addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), 
or Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, or TRIAD or 
acting as a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation 
requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs 
must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in 
RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
Additional information can be found on the CTEP website at https://ctep.cancer.gov
/investigatorResources/default.htm. For questions, please contact the RCR Help Desk by email at 
RCRHelpDesk@nih.gov. 
 
 
 
 
 


  
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89 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements for APEC1621C Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
IROC Credentialing Status Inquiry (CSI) Form  
NOTE: For studies with a radiation and/or imaging (RTI) component, the enrolling site must 
be aligned to a RTI provider.  To manage provider associations access the Provider Association 
tab on the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or 
remove associated providers.  Sites must be linked to at least one IROC credentialed provider 
to participate on trials with an RT component.   
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory 
Office immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
 
 


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


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