NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of AG-120 (Ivosidenib) in Patients With Tumors Harboring IDH1 Mutations
Phase: PHASE2
Conditions: Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Hepatoblastoma, 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 Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Recurrent WHO Grade 2 Glioma, Refractory Ependymoma, Refractory Ewing Sarcoma, Refractory Hepatoblastoma, 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 Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Refractory WHO Grade 2 Glioma, Wilms Tumor
Sponsor: National Cancer Institute (NCI)

  
 
 
 
i 
 
G 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 
Lee Ann DeRita, MBA, CMA,  
CFE 
lderita@childrensoncology 
group.org 
 
Group Operations Center  
and 
Statistics & Data Center  
(SDC) Headquarters 
1333 S. Mayflower Avenue 
Suite 260 
Monrovia, CA 91016 
P 626 241 1500 
F 626 445 4334 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A National Cancer Institute- 
funded group member of the  
National Clinical Trials Network 
 
October 28, 2022 
 
 
Martha Kruhm, M.S., RAC 
Protocol and Information Office (PIO) Head 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
RE: Request for Amendments with FDA requested language for Pediatric 
MATCH consents 
 
Dear Ms. Kruhm, 
 
The study committee thanks CTEP for forwarding the Amendment Request 
dated October 17, 2022. In response to the request, please see attached 
Amendment #3 to APEC1621K. The complete list of changes can be found 
below.  
 
Please contact us if you have any further questions. 
 
Sincerely, 
 
Emma Archuleta, B.S., Protocol Coordinator (for) 
Elizabeth Alva, M.D., MSPH, APEC1621K Study Chair, and 
Douglas S. Hawkins, M.D., Group Chair, Children’s Oncology Group 
 

 
APEC1621K 
 
Version Date: 10/28/2022 
 
 
Page 1 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
APEC1621K 
 
NCI-COG PEDIATRIC MATCH 
(MOLECULAR ANALYSIS FOR THERAPY CHOICE)- 
PHASE 2 SUBPROTOCOL OF AG-120 (IVOSIDENIB) IN PATIENTS WITH TUMORS 
HARBORING IDH1 MUTATIONS 
 
Open to COG Member Institutions in Australia, Canada, and 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 
Elizabeth Alva MD MSPH 
 Children's Hospital of Alabama  
 1600 7th Ave. South 
 Birmingham, AL, 35233  
 Phone: (205) 638- 9285 
 Fax: (205) 975-1941 
 Email: ealva@peds.uab.edu  
 
 
 
 
 
 
 
 
 
 
 
Activated: 06/08/2020 
 
Version Date:  
10/28/2022 
Closed: 
 
Amendment #:  
3 

 
APEC1621K 
 
Version Date: 10/28/2022 
 
 
Page 2 
 
 
Contact Information 
For Regulatory Requirements 
For patient enrollments: 
For Data Submission 
Regulatory documentation must be 
submitted to the Cancer Trials 
Support Unit (CTSU) via the 
Regulatory Submission Portal. 
 (Sign in at www.ctsu.org, and 
select the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately by phone or 
email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment section 
of the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN). OPEN is accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or 
https://open.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or email:  
1-888-823-5923, or  ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. Please 
see the Data Submission 
Schedule in the CRF packet for 
further instructions. 
The most current version of the study protocol must be downloaded from the protocol-specific page located on the 
CTSU members’ website (https://www.ctsu.org). Access to the CTSU members’ website is managed through the 
Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and 
requires log in with a CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the CTSU Regulatory 
Support System (RSS). 
For clinical questions (ie, patient eligibility or treatment-related)  
Contact the Study PI of the Lead Protocol Organization. 
For non-clinical questions (ie, unrelated to patient eligibility, treatment, or clinical data submission)  
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence will be 
triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 
 
 

 
APEC1621K 
 
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Page 3 
 
TABLE OF CONTENTS 
SECTION 
PAGE 
 
CHILDREN’S ONCOLOGY GROUP 
1 
STUDY COMMITTEE 
6 
STUDY COMMITTEE, CONT. 
7 
ABSTRACT 
8 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
 
Primary Aims 
9 
 
Secondary Aims 
9 
 
Exploratory Aims 
9 
2.0 
BACKGROUND 
9 
 
Introduction/Rationale for Development 
9 
 
Preclinical Studies 
10 
 
Adult Studies 
12 
 
Pediatric Studies 
14 
 
Overview of Proposed Pediatric Study 
15 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
15 
 
Study Enrollment 
15 
 
Informed Consent/Assent 
18 
 
Screening Procedures 
18 
 
Eligibility Checklist 
18 
 
Study Enrollment 
18 
 
Institutional Pathology Report 
19 
 
Dose Assignment 
19 
4.0 
PATIENT ELIGIBILITY 
19 
 
Inclusion Criteria 
19 
 
Exclusion Criteria 
23 
5.0 
TREATMENT PROGRAM 
24 
 
Overview of Treatment Plan 
24 
 
Criteria for Starting Subsequent Cycles 
25 
 
Grading of Adverse Events 
25 
 
Definition of Dose-Limiting Toxicity (DLT) 
25 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
26 
 
Dose Modifications for Hematological Toxicity 
26 
 
Dose Modifications for Non-Hematological Toxicity 
26 
 
Dose Modification for QTc Prolongation 
27 
 
Dose Modifications for mIDH1 differentiation Syndrome (only applicable to NHL or His
tocytosis) 
27 
 
Dose Modifications for Noninfectious leukocytosis (only applicable to NHL or 
Histiocytosis) 
28 
 
Dose Modification for Guillain-Barré Syndrome 
28 
 
If a new case of Progressive Multifocal Leukoencephalopathy (PML) occurs, the patient 

 
APEC1621K 
 
Version Date: 10/28/2022 
 
 
Page 4 
will be discontinued from treatment permanently. 
28 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
28 
 
Concurrent Anticancer Therapy 
28 
 
Investigational Agents 
28 
 
Supportive Care 
28 
 
Growth Factors 
29 
 
Concomitant Medications 
29 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
30 
 
Required Clinical, Laboratory and Disease Evaluation 
30 
 
Radiology Studies 
31 
 
Pharmacology and Pharmacodynamics Correlatives (optional) 
33 
 
Circulating Tumor DNA Study (optional) 
35 
9.0 
AGENT INFORMATION 
36 
 
AG-120         (09/22/2020) 
36 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
43 
 
Criteria for Removal from Protocol Therapy 
43 
 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
43 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
44 
 
Sample Size and Study Duration 
44 
 
Dosing Considerations: 
44 
 
Study Design 
44 
 
Methods of Analysis 
45 
 
Evaluability for Response 
46 
 
Evaluability for Toxicity 
46 
 
Progression free survival (PFS) 
46 
 
Correlative Studies 
46 
 
Gender and Minority Accrual Estimates 
47 
12.0 
EVALUATION CRITERIA 
47 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
47 
 
Progression-Free Survival 
47 
 
Response Criteria for Patients with Solid Tumors 
47 
 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
51 
 
Response Criteria for Neuroblastoma Patients 
53 
 
Response Criteria for Patients with CNS Tumors 
60 
 
Response Criteria for Patients with non- Hodgkin Lymphoma/Histiocytosis 
61 
 
Best Response 
63 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
64 
 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
64 
 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
66 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements:
 
67 
 
Definition of Onset and Resolution of Adverse Events 
68 
 
Other Recipients of Adverse Event Reports 
68 
 
Specific Examples for Expedited Reporting 
69 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
71 
 
Categories of Research Records 
71 

 
APEC1621K 
 
Version Date: 10/28/2022 
 
 
Page 5 
 
CDUS 
71 
 
CRADA/CTA/CSA 
71 
 
Data and Safety Monitoring Plan 
73 
REFERENCES 
75 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
77 
APPENDIX II:  CYP3A4 SUBSTRATES INDUCERS AND INHIBITORS 
78 
APPENDIX III:  MEDICATION DIARY FOR AG-120 (IVOSIDENIB) 
81 
APPENDIX IV: CORRELATIVE STUDIES 
91 
APPENDIX V:  AG-120 (IVOSIDENIB) DOSING NOMOGRAM 
92 
APPENDIX VI: APEC1621K THERAPY DELIVERY MAP 
93 
APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621K EXPANSION COHORTS 
98 
APPENDIX VIII: EXAMPLES OF ACTIONABLE MUTATIONS OF INTEREST FOR APECH1621K
 
99 
APPENDIX IX: CTEP AND CTSU REGISTRATION PROCEDURES 
100 
APPENDIX X: MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
104 
APPENDIX XI: YOUTH INFORMATION SHEETS 
106 
APPENDIX XII: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
108 
APPENDIX XII: TOXICITY-SPECIFIC GRADING 
109 
 

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Version Date: 10/28/2022 
 
 
Page 6 
STUDY COMMITTEE 
 Study Chair 
Study Vice Chair 
 Elizabeth Alva MD MSPH 
Alyssa Reddy, MD 
 Children's Hospital of Alabama 
Pediatric Hematology/Oncology and Neurology 
 1600 7th Ave. South 
UCSF Medical Center-Mission Bay 
 Birmingham, AL, 35233  
550 16th Street, UC Box 0137 
 Phone: (205) 638- 9285 
San Francisco, CA 94158 
 Fax: (205) 975-1941 
Phone: (415) 353-2657 
 Email: ealva@peds.uab.edu 
Fax: (415) 353-2400 
 
E-mail: alyssa.reddy@ucsf.edu 
Will Parsons, MD, PhD 
 
Baylor College of Medicine 
 
1102 Bates, Suite 1030.15 
Nita Seibel, MD 
Houston, TX 77030 
National Cancer Institute 
Phone: (832) 824-4643 
9609 Medical Center Drive, MSC 9739 
Email: dwparson@txch.org 
Rockville, MD 20892 
 
Phone:  (240) 276-6560 
 
Fax:  (240) 276-7892 
Todd Alonzo, PhD 
E-mail: seibelnl@mail.nih.gov  
Study Statistician  
 
COG Statistics and Data Center- Monrovia 
 
222 East Huntington Dr., Suite 100 
Stacey Berg, MD 
Monrovia, CA 91016 
Study Design and Logistics 
Phone: (626) 241-1522 
Baylor College of Medicine 
Fax: (626) 445-4334 
Pediatric Oncology  
Email: talonzo@childrensoncologygroup.org 
6621 Fannin Street 
 
MC3-3320 
Joel Reid, PhD. 
Houston, TX 77030 
Study Pharmacologist 
Phone: (832) 824-4588 
Mayo Clinic 
Fax:  (832) 825-4039 
Guggenheim 17-37 
Email: sberg@txch.org 
200 First St SW 
 
Rochester, MN 55905 
Elizabeth Fox, MD 
Phone: (507) 284-0822 
Study Design and Logistics 
Fax: (507) 284-3906 
Saint Jude Children’s Research Hospital 
E-mail: reid.joel@mayo.edu  
262 Danny Thomas Place 
 
Memphis, TN 38105 
Jin Piao, PhD 
Phone: (901) 595-3300 
Study Statistician 
Fax:  (901) 595-7031 
COG Statistics and Data Center- Monrovia 
Email: elizabeth.fox@stjude.org 
222 East Huntington Dr., Suite 100 
 
Monrovia, CA 91016 
 
Phone: (626) 241-1572 
 
Fax: (626) 445-4334 
 
Email: jpiao@childrensoncologygroup.org 
 
 
 
 
 
 
 
 
 
 
 
 

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Version Date: 10/28/2022 
 
 
Page 7 
STUDY COMMITTEE, CONT. 
Bridget Tate, RN MSN 
Study CRA 
Emily S. Waite, PharmD  
Study Pharmacist 
Children's Hospital of Alabama 
Children's Hospital of Alabama 
1600 7th Avenue South 
1604 6th Ave South, Dock A 
Birmingham, AL 35233 
Birmingham, AL 35233 
Phone: (205) 638-2984 
Fax: (205) 996-7570 
Phone: (205) 638-9717 
Fax: (205) 638-5217 
E-mail: btate@peds.uab.edu 
E-mail: Emily.Waite@childrensal.org 
 
 
  COG Operations Staff 
Vanessa Fierro, BS  
Lauren Saguilig, MS 
Research Coordintor 
Master Statistician  
Children’s Oncology Group – Operations Center 
Children’s Oncology Group – Operations Center 
Phone: (626) 241-1615 
Phone: (626) 241-1547 
Email: vafierro@childrensoncologygroup.org  
Email: lsaguilig@childrensoncologygroup.org 
 
 
 
 
 
 
Emma Archuleta, BS 
 
Scientific Writer/Protocol Coordinator 
 
Children’s Oncology Group – Operations Center 
 
Phone: (626) 241-1645 
 
E-mail: earchuleta@childrensoncologygroup.org 
 
 
 
 
For Group Operations (GOC) and 
 
Statistics & Data Center (SDC) contacts see: 
 
https://members.childrensoncologygroup.org 
 
 
 
AGENT NSC# AND IND#’s 
 
NCI-Supplied Agents: 
 
 
AG-120 (ivosidenib) (NSC# 804600 , IND#
 ) 
 
IND Sponsor: DCTD, NCI 
 
 
SEE Section 8.3.6 AND Section 8.4.4 FOR 
SPECIMEN SHIPPING ADDRESSES 
 
 
 

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APEC1621K 
Version Date: 10/28/2022 
 
 
Page 8 
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 Pediatric MATCH trial APEC1621. The APEC1621SC screening 
protocol details the process used to identify actionable mutations in patient tumor samples will determine 
eligibility for this subprotocol. This is a phase 2 trial of AG-120 (ivosidenib) in children with relapsed or 
refractory solid tumors (including lymphomas, histiocytoses and CNS tumors) harboring specified 
activating mutations of the IDH pathway. AG-120 (ivosidenib) will be given at a dose of 290 mg/m2 by 
mouth once daily for 28-day cycles. The primary endpoint will be objective response rate as determined by 
RECIST. Progression free survival (PFS) will be assessed as a secondary endpoint. 
 
EXPERIMENTAL DESIGN SCHEMA 
 
Treatment Schedule Table 
Days 1-28 
AG-120 (ivosidenib) 
Day 28 
Evaluation 
 
 
Patients will receive AG-120 (ivosidenib) 290 mg/m2 by mouth once daily for 28 days, which is 
equivalent to the adult RP2D of 500 mg by mouth; a cycle will be 28 days. Disease evaluations will occur 
every other cycle x 3, then every 3 cycles.  
 
Therapy will be discontinued if there is evidence of progressive disease or drug related dose-limiting 
toxicity that requires removal from therapy. Therapy may otherwise continue for up to 2 years provided the 
patient meets the criteria for starting subsequent cycles (Section 5.2) and does not meet any of the criteria 
for removal from protocol therapy criteria (Section 10.0).  
 
 
 
 
 
 
 
 

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Page 9 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
 
Primary Aims 
 
 
To determine the objective response rate (ORR; complete response + partial response) 
in pediatric patients treated with AG-120 (ivosidenib) with advanced solid tumors 
(including CNS tumors), lymphomas or histiocytic disorders that harbor activating 
genetic alterations in the IDH1 pathway. 
 
 
Secondary Aims 
 
 
To estimate the progression free survival in pediatric patients treated with AG-120 
(ivosidenib) with advanced solid tumors (including CNS tumors), lymphomas or 
histiocytic disorders that harbor activating genetic alterations in the IDH1 pathway. 
 
 
To obtain information about the tolerability of AG-120 (ivosidenib) in children and 
adolescents with relapsed or refractory cancer. 
 
 
To provide preliminary estimates of the pharmacokinetics and pharmacodynamics of 
AG-120 (ivosidenib) in children and adolescents with relapsed or refractory cancer. 
 
 
Exploratory Aims 
 
 
To evaluate other biomarkers as predictors of response to AG-120 (ivosidenib) and 
specifically, whether tumors that harbor different missense mutations or fusions will 
demonstrate differential response to AG-120 (ivosidenib) treatment. 
 
 
To explore approaches to the profiling changes in tumor genomics over time through 
evaluation of circulating tumor DNA.  
 
 
2.0 
BACKGROUND 
 
 
Introduction/Rationale for Development 
 
The isocitrate dehydrogenase (IDH) family is comprised of three isozymes (IDH1, IDH2 and 
IDH3) that play a critical role in the citric acid cycle by converting isocitrate to αKG via 
oxidative decarboxylation.  Mutations in IDH1 can alter this pathway to increase production 
of the oncometabolite 2-hydroxyglutarate (2-HG).  Increased 2-HG induces histone and 
DNA hypermethylation and blocks cellular differentiation resulting in tumorigenesis.1,2,3,4  
Mouse models expressing IDH1 mutations in hematopoietic tissue have shown that 
expression of IDH1 mutations lead to block in myeloid differentiation, extramedullary 
hematopoiesis and an mRNA signature similar to AML, helping establish the link between 
IDH1 mutations and leukaemogenesis.5  The majority of cancer associated IDH mutations 
can been mapped to an arginine within the catalytic pocket of the enzyme, which is critical 
for isocitrate binding.  IDH1 mutations typically occur at arginine 132 and are missense 
substitutions.6  
 
IDH1 mutations have been identified as a therapeutic target in multiple adult cancer types, 
including acute myeloid leukemia (AML), central nervous system (CNS) malignancies, 
including both high and low grade gliomas, chondrosarcomas, and cholangiocarcinoma.  In 

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Page 10 
adult AML, approximately 10-15% of patients harbor IDH mutations.7,8, 9   The incidence of 
IDH1 mutations in patients with WHO grade II and WHO grade III gliomas as well as 
secondary glioblastoma is 70-80%.10,11  However, the incidence of IDH1 mutations in adult 
primary glioblastoma is less than 10%.10,11  IDH mutations have also been found in ~50% of 
chondrosarcomas and ~15-20% of cholangiocarcinoma.12, 13 
 
IDH1 mutations have also been identified in several pediatric malignancies.  In pediatric 
AML, the frequency of IDH1 mutations is approximately 1-2%.14, 15,16,17  For pediatric 
patients with high grade gliomas, the incidence of IDH1 mutations appears to be age 
dependent, with 35% of patients greater than or equal to 14 years of age being found to have 
IDH1 mutations compared to 0% of patients under the age of 14.18  Additionally, IDH1 
mutations have been shown to be present in 8% of pediatric patients with gliomatosis 
cerebri.19   
 
 
Preclinical Studies 
 
 
Antitumor Activity 
The information provided in this protocol is from the AG-120 (ivosidenib)   
investigator’s brochure and is summarized here.20 The inhibitory activity of                 
AG-120 (ivosidenib) against IDH1 and IDH2 mutant enzymes and selectivity of          
AG-120 (ivosidenib) against IDH1-WT and IDH2-WT were characterized in a 
diaphorase/resazurin coupled system.   AG-120 (ivosidenib) is highly selective for 
IDH1 mutant isoforms with IC50 values (µM) ranging from 0.002-0.017.  Against 
IDH1 (R132H), AG-120 (ivosidenib) showed noncompetitive inhibition with respect 
to α-KG substrate and NADPH cofactor, and no time-dependence in IC50 values 
between 1 and 16 hours of incubation.  These observations are consistent with AG-
120 (ivosidenib) being a rapid equilibrium inhibitor of IDH1 homodimer in the 
presence or absence of substrate and cofactor. Against IDH1-WT homodimer, AG-
120 (ivosidenib) showed noncompetitive inhibition with respect to NADP cofactor.  
IC50 for IDH1 WT alone at     1 hour was 1.326 µM compared to 0.071 µM and 0.024 
µM when incubated with NADP and 1 hour and 16 hours respectively. The increase 
in potency observed when incubation was carried out in the presence of cofactor is 
consistent with the mechanism of action.   AG-120 (ivosidenib) was shown to be a 
low-binding inhibitor of IDH1-WT homodimer.  
 
The potency and specificity of AG-120 (ivosidenib) against cellular IDH1 mutations 
were evaluated in multiple cell based systems. AG-120 (ivosidenib) is a potent 
inhibitor of 2-HG production in cells expressing IDH1 R132 mutations but not for cell 
lines expressing IDH2. The potency and specificity against cellular IDH1 and IDH2 
mutations of AG-120 (ivosidenib) is shown in the table below. 
 
Cell Line 
2-HG IC50 (nM) 
N 
GI50 
(3 µM top dose) 
COR-L105 (R132C) 
10 ± 4 
3 
> 3 µM 
HCCC-9810 (R132S) 
10 ± 2 
4 
> 3 µM 
RBE (R132S) 
3 
1 
> 3 µM 
HT1080 (R132C) 
8 ± 4 
15 
> 3 µM 
U876MG pLVS IDH1 
(R132C) 
4 ± 1.6 
4 
> 3 µM 
U876MG pLVS IDH1 
(R132H) 
20 ±11 
14 
> 3 µM 

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Page 11 
Neurosphere 603 (R132H) 
2.4 ± 0.2 
8 
> 3 µM 
TF1 pLVX IDH1 (R132H) 
clone 27 
20 
1 
> 3 µM 
U87MG pLVX IDH2 
(R140Q) 
No Fit 
1 
> 3 µM 
Abbreviations: 2-HG = 2-hydroxyglutarate; GI50 = concentration of drug which effects half-
maximal growth inhibition; IC50 = concentration of drug which achieves half maximal 
inhibition; pLVX = control cell line 
Source: AG-120 (ivosidenib) investigator’s brochure20 
 
 
Animal Toxicology 
 
The information provided in this protocol is from the investigator’s brochure and 
summarized here.20  In vivo GLP toxicology studies included repeat-dose GLP 28-day and 
3-month Sprague-Dawley rat and cynomolgus monkey studies, and definitive embryo/fetal 
development studies in Sprague-Dawley rats and New Zealand White rabbits, and a GLP 
micronucleus study in Sprague-Dawley rats.  AG-120 (ivosidenib) was well tolerated at 
AUC0-12hr exposure levels that are 0.5- to 1.1-fold (3 month rat) and 2.4-fold (3-month 
monkey) the human 500 mg/day AUC0-10hr exposure level. 
 
Dose limiting toxicity in the rat occurred at a dosage of 2000 mg/kg/day in the 28-day 
study.  At this dose level, the AUC0-12hr values were 3.5- to 3.7-fold the human AUC0-10hr 
value on Day 0 and declined to 1.2- to 1.8-fold on Day 27.  The cause of early DLT 
(between days 2 and 6) was centrilobular hepatocellular degeneration and necrosis with 
additional contributing factors including tubular necrosis in the kidney as well as 
hypocellularity, hemorrhage, and necrosis of the femoral and/or sternal bone marrow. 
When DLT occurred later in the dosing period (day 19-20), it was due to mucosal atrophy 
of the intestines, erosions and ulcerations of the glandular stomach and/or rectum, and 
lymphoid depletion. The next lower dose level tested in rats (500 mg/kg/day) was tolerated 
over 28 days of dosing and was utilized as the top dose in the GLP 3-month toxicology 
study.   
 
In the rat, the dosage level of 500 mg/kg/day (highest dosage tested) was tolerated over a 
3-month dosing period and did not result in any test article-related moribundity or 
mortality.  The Day 90 plasma AUC0-12hr values at this dosage level were 0.5- to 1.1-fold 
the C2D1 human AUC0-10hr valuate at 500 mg/day.  Target tissues and findings at this dose 
level in the 3-month rat study included liver and thyroid findings consistent with 
hepatocellular enzyme induction and red cell parameter alterations and splenic 
extramedullary hematopoiesis.  All significant findings at this dose level in both 28-day 
and 3-month studies were partially or fully reversible following a 14- and 28-day non-
dosing period respectively.   
 
In the GLP, 28-day monkey study, DLT occurred in male monkeys at the highest dose level 
tested, 270 mg/kg/day) at a Day 27 AUC0-12hrs value which is 4.2-fold the human AUC0-10hr 
value.  The cause of DLT was general malaise and poor body condition, gastrointestinal 
clinical signs with emesis and secondary aspiration.  The next lower dose level in monkeys 
(90 mg/kg/day) was very well tolerated.  A dose of 180mg/kg/day was subsequently chose 
as the top dose in the GLP 3-month toxicology study. 
 
In the 3-month dosing period, the dose level of 180 mg/kg/day was well tolerated and did 
not result in any test article-related morbundity or mortality.  The day 90 plasma                 

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AUC0-12hr value at this dose level was approximately 2.4-fold the C2D1 human AUC0-10hr 
value at 500 mg/day.  Findings at this dose level included intermittent diarrhea as well as 
liver findings consistent with hepatocellular enzyme induction. A cardiovascular 
assessment was conducted toward the end of the study (week 12) and possible/probable 
test-article-related prolongations of QTcB intervals were noted in individual animals.  All 
findings were partially or fully reversible following a 28-day non-dosing period.  
 
 
Adult Studies 
 
 
Phase 1 and Phase 2 Studies 
Phase 1 trials with AG-120 (ivosidenib) are ongoing in patients with advanced 
hematologic malignancies harboring IDH1 mutations (AG120-C-001) and patients 
with advanced solid tumors harboring IDH1 mutations, including gliomas 
(AG120-C-002). Durable responses were seen in patients with relapsed/ refractory 
AML with IDH1 mutations treated with AG-120 (ivosidenib). 21 Similarly, patients 
with non-enhancing gliomas treated with AG-120 (ivosidenib) on AG120-C-002 
were found to have 6% overall response rate (ORR) and 83% stable disease (SD).22 
AG-120 (ivosidenib) also showed encouraging responses in patients with 
chondrosarcoma treated on AG120-C-002, with a 58% progression free survival 
(PFS) at 3 months.23 Similarly, patients with cholangiocarcinoma treated on 
AG120-C-002 experienced a 6 month PFS of 38.5% and a 12 month PFS of 
20.7%.24 AG-120 (ivosidenib) was found to be well tolerated and no maximum 
tolerated dose (MTD) was reached in either Phase 1 trial. Recommended phase 2 
dose (RP2D) of AG-120 (ivosidenib) in adults is 500 mg PO daily for 28 day 
cycles. 
 
AG120-C-001 (NCT02074839) was a phase 1, multicenter trial to assess the 
safety, pharmacokinetics, pharmacodynamics and clinical activity of AG–120 
(ivosidenib) in advanced hematologic malignancies harboring an IDH1 mutation. 
This study included a dose escalation phase to determine MTD and RP2D as well 
as a dose expansion phase where four cohorts of patients received AG-120 
(ivosidenib) at the RP2D to assess the tolerability, safety and clinical activity of 
AG-120 (ivosidenib). The study included patients with relapsed/refractory AML, 
untreated patients with AML who were not eligible for standard of care treatment 
and other relapsed/refractory advanced hematologic malignancies. A total of 78 
patients were treated in the dose phase of the study. The dose was escalated up to 
a dose of 1200 mg PO daily and no MTD was reached. Pharmacokinetic and 
pharmacodynamics data supported the selection of 500 mg PO daily for the dose 
expansion portion of the trial.  The most common adverse events (AEs) of any 
grade were fatigue (36%), nausea (33%) and diarrhea (32%). The most common 
grade ≥ 3 AEs were febrile neutropenia (21%) and anemia (18%). Dose limiting 
toxicities (DLTs) were observed in only 2 patients. One DLT consisted of a grade 
3 QT prolongation at a dose of 800 mg daily and one consisted of a grade 3 rash at 
1200 mg daily. An ORR of 38% with a complete response (CR) rate of 18% was 
observed with a duration of study treatment up to 24.2 months.  The median 
duration of overall response in all patients was 10.2 months. IDH1 mutational 
clearance was also assessed during this study with next generation sequencing 
(FoundationOne Heme Panel) and it was found that treatment with AG-120 
(ivosidenib) as a single agent can result in mIDH1 clearance by NGS.  
 

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AG120-C-002 (NCT02073994) was a phase 1, multicenter trial to assess the 
safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 
(ivosidenib) in advanced solid tumors, including glioma, that harbor an IDH1 
mutation.  This study also included a dose escalation and a dose expansion phase, 
a total of 168 patients were treated in study AG120-C-002.  The four dose 
expansion cohorts consisted of gliomas, cholangiocarcinoma, chondrosarcoma, 
and other advanced solid tumors.  The dose was escalated to 1200 mg PO daily on 
the dose escalation phase and no MTD was reached.  The RP2D was determined 
to be 500mg PO daily.  The most common adverse events seen in patients with 
gliomas include headache (26%), nausea (21%) and diarrhea (15%). The most 
common grade ≥ 3 AEs in glioma patients were headaches (5%) and 
hypophosphatemia (3%).   An ORR of 9% was observed with 83% SD.   64% of 
tumors showed decrease in tumor growth rate by volumetric assessment.  In the 
chondrosarcoma cohort, the most common AEs included diarrhea (29%), nausea 
(24%), decreased appetite (19%) and QT prolongation (19%).  Grade ≥ 3 AEs were 
rare with only one patient each experiencing anemia, peripheral edema and 
elevated alkaline phosphatase. In the chondrosarcoma cohort, 55% of patients 
experienced stable disease and a 58% progression free survival was observed at 3 
months. Of the evaluable patients with SD, 41% had decrease in the size of target 
lesions. In the cholangiocarcinoma expansion cohort, the most common AEs 
included fatigue (45%), nausea (37%), decreased appetite (31%) and diarrhea 
(29%). The most common grade ≥ 3 AEs in the cholangiocarcinoma cohort 
included ascites (5%), abdominal distension (3%) and anemia (3%). The 6 month 
progression free survival (PFS) rate in the cholangiocarcinoma cohort was 38.5% 
with a 12 months PFS of 20.7%. No DLTs were observed in any of the cohorts.   
 
AG-120 (ivosidenib) is also currently being investigated in a phase 1 randomized, 
open-label study in patients with recurrent, non-enhancing, IDH1 mutant low 
grade, gliomas (NCT03343197).  In this study, patients with recurrent, non-
enhancing low grade gliomas in which surgical resection is indicated are 
randomized to receive 4 weeks of AG-120 (ivosidenib), 4 weeks of AG-881, or no 
treatment prior to surgical resection.  All patients have the option to receive AG-
120 (ivosidenib) or AG-881 post-operatively. 
 
 
Phase 3 Studies 
Currently, there are three phase three trials using AG-120 (ivosidenib) in combination 
with HMA and standard chemotherapy chemotherapeutic agents in previously 
untreated adult patients with IDH1 mutated AML (NCT02632708, NCT03173248, 
NCT02677922).   
 
AG-120 (ivosidenib) has also expanded in to a phase 3 trial in patients with advanced 
IDH1 mutated cholangiocarcinoma (NCT02989857).  In this study,  patients with 
IDH1 mutated cholangiocarcinoma who are not eligible for curative resection, 
transplantation or ablative therapies and have experienced progression of disease after 
at least 1 but nor more than 2 prior treatments are eligible to be randomized to AG-
120/ disease progression while on placebo. 
 
 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
AG-120 (ivosidenib) demonstrated good oral bioavailability, rapid absorption, and a 
long half-life in subjects with IDH1 mutant AML and solid tumors.20 This supports a 

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once daily dosing regimen. Following multiple does of AG-120 (ivosidenib), steady 
state was reached within 14 days, with approximately 2-fold accumulation in plasma 
exposure. Ivosidenib has a terminal half-life of 93 hours and an apparent clearance 
(CL/F) of 4.3 L/hour. The mean apparent volume of distribution of ivosidenib at 
steady-state is 234 L and median time to Cmax is approximately 3 hours. Protein 
binding of ivosidenib ranges from 92 to 96% in vitro. Ivosidenib is primarily 
metabolized by CYP3A4 with minor contributions by N-dealkylation and hydrolytic 
pathways. 25 
The plasma exposure of AG-120 (ivosidenib) increased less than dose proportionally, 
from 200 to 1200 mg. Results from AG120-C-001 and AG120-C-002 indicated that 
plasma 2-HG levels were substantially reduced in subjects with an IDH1 mutation at 
dose ranging from 200 to 1200mg daily.  2-HG levels were reduced to levels similar 
to those in healthy volunteers.  In addition, multiple doses of AG-120 (ivosidenib) at 
doses of 200 to 1200 mg daily also decreased 2-HG levels in bone marrow in patients 
with AML as well as in tumor biopsies in patients with cholangiocarcinoma and 
chondrosarcoma.  
 
The absorption, excretion, and metabolism of AG-120 (ivosidenib) were investigated 
in healthy male subjects. Fecal excretion appeared to be the predominant route of 
elimination. AG-120 (ivosidenib) was readily absorbed and slowly eliminated from 
plasma with unchanged AG-120 (ivosidenib) representing the majority of circulating 
total radioactivity in plasma. PK studies in health volunteers also showed that there 
was an effect of food on AG-120 (ivosidenib) exposure, with a 2-fold increase in 
Cmax and a 25% increase in AUC with a high fat meal; a drug-drug interaction study 
evaluating the effect of itraconazole on the PK of AG-120 (ivosidenib) was also 
performed. Following AG-120 (ivosidenib) administration with itraconazole, AG-120 
(ivosidenib) exposure (assessed by AUC0-t and AUC0-∞) was increased approximately 
2.6-fold. 
 
AG-120 (ivosidenib) is a weak direct inhibitor of CYP2C8, CYP2C19, CYP2D6, and 
CYP3A4/5 with IC50 values >50 μM and shows little or no evidence of direct 
inhibition of CYP1A2, CYP2B6, or CYP2C9. AG-120 (ivosidenib) shows no time- 
or metabolism-dependent inhibition of any of the CYP enzymes evaluated, suggesting 
that formation of reactive metabolites is unlikely. 
 
 AG-120 (ivosidenib) is a substrate of P-gp, but not BCRP. AG-120 (ivosidenib) is an 
inhibitor of P-gp (48% and 99% inhibition at 5 and 100 μM, respectively) and a weak 
inhibitor of BCRP (17% and 48% at 5 and 100 μM, respectively). AG-120 
(ivosidenib)   is not a substrate of OATP1B1 or OATP1B3 transporters but appears to 
be a weak inhibitor of OATP1B1, and OATP1B3 with IC50 values of 9.56 and 22.8 
μM, respectively. AG-120 (ivosidenib) does not inhibit the OAT1- and OCT2-
mediated uptake of the probe substrate (IC50 > 65 μM) but inhibits OAT3 (IC50 
~0.322 μM). 
 
 
Pediatric Studies 
 
 
Prior Experience in Children  
There have been no trials using mIDH inhibitors in pediatric patients.   
 
 
 

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Overview of Proposed Pediatric Study 
This is a phase 2 trial of AG-120 (ivosidenib) in children with recurrent or refractory solid 
tumors, CNS tumors, non-Hodgkin lymphomas and histiocytic disorders harboring specific 
activating mutations that result in pathologic activation of the IDH pathway.  
 
The adult RP2D of AG-120 (ivosidenib) is 500 mg PO once daily.  Doses up to 1200 mg 
PO once daily were evaluated in the Phase 1 trials and no MTD was reached. Since the 
adult RP2D is 500 mg PO daily,  the MTD was not reached and the starting dose as per 
standard Pediatric MATCH routine (described in additional detail in Section 11.2.1 of the 
screening protocol APEC1621SC) will be the adult RP2D adjusted for BSA, which is 290 
mg/m2/day (500 mg/1.7 m2) up to a maximum daily dose of 500 mg PO once daily. 
 
The primary aim of this trial will be to establish the objective response rate to AG-120 
(ivosidenib).  
 
Key secondary objectives include further evaluation of the tolerability of AG-120 
(ivosidenib) 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. 
 
 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
 
Study Enrollment 
Patient enrollment for this study will be facilitated using the Oncology Patient Enrollment 
Network (OPEN), a web-based registration system available on a 24/7 basis. It is integrated 
with the NCI Cancer Trials Support Unit (CTSU) Enterprise System for regulatory and 
roster data and, upon enrollment, initializes the patient position in the RAVE database. 
 
 
Access requirements for OPEN: 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).The Oncology Patient Enrollment Network (OPEN) is a web-based registration 
system available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data 
and with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:  
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 

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approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
Please see Appendix IX 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. 
 
IRB Approval 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. For CTEP and Division 
of Cancer Prevention (DCP) studies open to the National Clinical Trials Network (NCTN) 
and NCI Community Oncology Research Program (NCORP) Research Bases after March 
1, 2019, all U.S.-based sites must be members of the NCI Central Institutional Review 
Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open 
at the site under the local IRB. International sites should continue to submit Research Ethics 
Board (REB) approval to the CTSU Regulatory Office following country-specific 
regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU 
Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 

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IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration packets, 
please see Appendix X. 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. For general (non-regulatory) questions call the CTSU General Helpdesk at: 
1-888-823-5923. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB approval 
for the study are not required to submit separate IRB approval documentation to the 
CTSU Regulatory Office for initial, continuing or amendment review. 
 
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.   
 
 
 
Genetic Screening Procedures for Eligibility  
 
Patient enrollment onto the APEC1621SC screening protocol is required. In Stage 2 of 
Pediatric MATCH (effective with Amendment #4 of APEC1621SC for patients enrolling 
on screening protocol) tumor genomic testing results from a CAP/CLIA-certified 
laboratory will be reviewed by the APEC1621SC Molecular Review Committee after 
APEC1621SC screening protocol enrollment to confirm the identification of an actionable 
Mutation of Interest (aMOI) for which a MATCH treatment subprotocol is available. 
Questions regarding interpretation of tumor testing results for potential APEC1621K study 
patients (such as whether a specific mutation would be considered actionable for the study) 

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should be directed to the APEC1621SC and APEC1621K study chairs. 
 
The treatment assignment to MATCH to a subprotocol (if a relevant aMOI is detected)  
will be communicated to the enrolling institution via the COG treatment assignment 
mechanism, upon which a reservation to APEC1621K 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 APEC1621K. 
 
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. 
 
 
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. 
 
 
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. 
 
 
Study Enrollment 
Patient may be enrolled on the study once all eligibility requirements for the study have 
been met. 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 in Stage 2 of Pediatric 
MATCH (effective with Amendment #4 of APEC1621SC for patients enrolling on 
screening protocol) is outlined in section 3.1.3. 
 
Patients enrolling onto APEC1621K will have a COG ID obtained through their prior 
enrollment onto the APEC1621SC screening protocol or a prior COG study. Patients 
must be enrolled within 2 weeks (14 days) of treatment assignment. Protocol therapy 
must start no later than 7 calendar days after the date of enrollment. Patients enrolling 
onto APEC1621K will have a COG ID obtained through their prior enrollment onto the 
screening protocol or from a prior COG study. Patients who are started on protocol 
therapy prior to study enrollment will be considered ineligible. 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 
days prior to enrollment unless otherwise indicated in the eligibility section below. 
 

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Reassignment Request through APEC1621SC (if unable to enroll within 8 week 
timeframe) 
The treating team may email PedsMATCHOps@childrensoncologygroup.org and the 
APEC1621SC study co-chairs (dwparson@txch.org seibelnl@mail.nih.gov) with a request 
for a single treatment re-assignment for any patient who was previously matched to a 
therapeutic subprotocol arm, but were unable to enroll during the original specified 
reservations window. The request can be made within a year of the ‘Pediatric MATCH-
Reservation expiration date’ stipulated in the original treatment assignment email when the 
patient was assigned. The treatment re-assignment request is subject to slot availability on 
the therapeutic subprotocol at the time of the request 
 
Note:  No starter supplies will be provided. Drug orders of AG-120 (ivosidenib)   
should be placed with CTEP after enrollment and treatment assignment to 
APEC1621K with consideration for timing of processing and shipping to ensure 
receipt of drug supply prior to start of protocol therapy. 
 
 
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 APEC1621 
master screening protocol.  
 
 
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. 
 
 
Inclusion Criteria 
 
 
APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been 
given a treatment assignment to MATCH to APEC1621K based on the presence of 

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an actionable mutation as defined in APEC1621SC. Examples of actionable mutations 
for APEC1621SC are listed in Appendix VIII. 
 
 
Age:  Patients must be ≥ than 12 months and ≤ 21 years of age at the time of study 
enrollment. 
 
 
BSA:  Patients must have a body surface area ≥ 0.78 m2 at enrollment. 
 
 
Patients must be able to swallow intact tablets  
 
 
Disease Status: Patients must have radiographically measurable disease (See 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 any lesion that is at minimum 
10 mm in one dimension on standard MRI or CT. 
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 relatively stable for at least 7 days prior to study 
enrollment.  Patients who are unable to walk because of paralysis, but who are up in 
a wheelchair, will be considered ambulatory for the purpose of assessing the 
performance score. 
 
 
Prior Therapy 
 
4.1.7.1 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the numerical eligibility criteria are met, e.g. blood count 
criteria, the patient is considered to have recovered adequately. 
 
a. Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive. See https://www.cogmembers.org/site/disc/devthe
rapeutics/default.aspx  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. 
 
• 
 ≥ 21 days after the last dose of cytotoxic or myelosuppressive 

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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/devth
erapeutics/default.aspx  for commercial and Phase 1 investigational 
agent classifications. For agents not listed, the duration of this interval 
must be discussed with the study chair and the study-assigned 
Research Coordinator prior to enrollment.  
 
c. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
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. 

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k. Patients must not have received prior exposure to AG-120 (ivosidenib) 
or other IDH1 inhibitors. 
 
 
Organ Function Requirements 
 
4.1.8.1 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 
- 
Platelet count ≥ 100,000/mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in 4.1.8.1.a 
(may receive transfusions provided they are not known to be 
refractory to red cell or platelet transfusions). These patients will 
not be evaluable for hematologic toxicity.  
 
4.1.8.2 Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR utilizing child length and stature data published by 
the CDC. 
 
4.1.8.3 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT) ≤ 135 U/L.  (For the purpose of this study, the ULN for 
SGPT is 45 U/L).  
- 
Serum albumin ≥ 2 g/dL. 
 
4.1.8.4 Adequate Cardiac Function Defined As: 
-  
QTc interval ≤ 450 milliseconds 
 
Note: Patients should avoid concomitant medication known or 
suspected to prolong QTc interval or cause Torsades De Pointes. 
Patients who are receiving drugs that prolong the QTc are eligible if 

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the drug is necessary and no alternatives are available. See Appendix 
X for drugs that may prolong the QTc. 
 
4.1.8.5 Adequate Neurologic Function Defined as: 
- 
Patients with seizure disorder may be enrolled if on anticonvulsants 
and well controlled. 
- 
Nervous system disorders (CTCAEv5.0) resulting from prior therapy 
must be ≤ Grade 2, with the exception of decreased tendon reflex 
(DTR). Any grade of DTR is eligible. 
 
 
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.  
 
 
Exclusion Criteria 
 
 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study due to risks 
because there is yet 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 non-hormonal contraceptive method for the duration of study 
treatment and for at least 1 month after last dose of AG-120 (ivosidenib). Since 
AG-120 (ivosidenib) may decrease concentrations of hormonal contraceptives, 
hormonal contraceptives are not considered effective contraception when co-
administered with AG-120 (ivosidenib). 
 
 
Concomitant Medications 
 
4.2.2.1 Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. If used to modify immune adverse events 
related to prior therapy, ≥ 14 days must have elapsed since last dose of 
corticosteroid (See Section 4.1.6.1.d). 
 
4.2.2.2 Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
 
4.2.2.3 Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible. 
 
4.2.2.4 Anti-GVHD agents post-transplant:  
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease post bone marrow transplant are not 
eligible for this trial. 
 
 
4.2.2.5 CYP3A4 Agents:  
Patients who are currently receiving drugs that are strong inducers or 
moderate to strong inhibitors of CYP3A4 are not eligible. Strong inducers 
or moderate to strong inhibitors of CYP3A4 should be avoided from 14 

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days prior to enrollment to the end of the study. See Appendix II for a list 
of agents.  Note: CYP3A4 inducing anti-epileptic drugs and 
dexamethasone for CNS tumors or metastases, on a stable dose, are 
allowed. 
 
In addition, patients receiving sensitive or narrow therapeutic range 
substrates of CYP3A4 are not eligible. See Appendix II for a list of agents.   
 
 
Patients with a history of progressive multifocal leukoencephalopathy are not eligible.  
 
 
Infection: Patients who have an uncontrolled infection are not eligible. 
 
 
Patients who have received a 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 
 
 
Overview of Treatment Plan 
 
Treatment Schedule Table 
Days 1-28 
 AG-120 (ivosidenib)              
290 mg/m2/dose orally once daily 
(maximum of 500 mg per day). 
Day 28 
Evaluation 
 
Patients will receive AG-120 (ivosidenib) by mouth once daily, continuously for 28-day 
cycles (please see dosing nomogram in Appendix V). Disease evaluations will occur at the 
end of every other cycle x3, then every 3 cycles. A cycle may be repeated up to a total 
duration of therapy of 2 years (maximum of 26 cycles).  
 
Therapy will be discontinued if there is evidence of progressive disease or drug related 
dose-limiting toxicity that requires removal from therapy (Section 6.0). Therapy may 
otherwise continue for up to 2 years provided the patient meets the criteria for starting 
subsequent cycles (Section 5.2) and does not meet any of the criteria for removal from 
protocol therapy criteria (Section 10.0).  
 
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.  Take AG-120 (ivosidenib)   
tablets by mouth, without regard to meals. High fat meals should be avoided when taking 
AG-120 (ivosidenib). Tablets should not be crushed or chewed. Vomited dose should not 
be re-administered. Missed doses of AG-120 (ivosidenib) should not be administered if 
within 12 hours of the next scheduled dose. Otherwise, the dose will be missed. Please refer 
to Section 7.3 for specific supportive care guidelines. 
 
AG-120 (ivosidenib) is supplied by Agios Pharmaceuticals and distributed by DCTD, NCI. 
Do not use commercial supply. 
 

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Since the MTD was not reached and the adult RP2D is 500 mg PO once daily, the starting 
dose as per standard Pediatric MATCH routine (described in additional detail in Section 
11.2.1 of the screening protocol APEC1621SC) will be the adult RP2D adjusted for BSA, 
which is 290 mg/m2 once daily (500 mg/1.72 m2) up to a maximum daily dose of 500 mg 
PO once daily. 
 
 
Therapy Delivery Map 
See Appendix VI for therapy delivery map for Cycle 1 and subsequent cycles. 
 
Intra-Patient Escalation 
Intrapatient dose escalation is not allowed. 
 
 
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 
   
 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the current version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE).  All appropriate treatment 
areas should have access to a copy of the current version of the CTCAEv5.0.  A copy of 
the CTCAEv5.0 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. 
 
 
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 
5.4.1.1  Grade 2 Electrocardiogram QT corrected interval prolonged (QTC > 
480ms) will be considered a non-hematological toxicity. 
5.4.1.2 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 
- 
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 XII 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 
a) 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. 

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b) Note: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
 
 
Hematological dose limiting toxicity  
5.4.2.1 Hematological dose limiting toxicity is defined as: 
 
In patients evaluable for hematological toxicity (see Section 4.1.8.1),   
 
• 
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). 
 
5.4.2.2 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. 
 
 
Dose Modifications for Hematological Toxicity 
 
 
If a patient experiences hematological toxicity as defined in Section 5.4.2.1, 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 V for tablet 
formulation dosing nomogram). 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. 
 
 
 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 V for tablet formulation dosing 
nomogram). Doses reduced for toxicity will not be re-escalated, even if there is 

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Page 27 
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 a dose-limiting toxicity recurs in a patient who has resumed treatment at the reduced 
dose, the patient must be removed from protocol therapy. 
 
 
 Dose Modification for QTc Prolongation 
 
Adverse Reactions  
Recommended Action  
QTc interval > 480 
• Monitor and supplement electrolyte levels as clinically indicated, evaluation 
by a cardiologist and other necessary interventions may be considered.  
• Review and adjust concomitant medications with known QTc interval-
prolonging effects (See Section 7.5.3 and Appendix X).  
• Interrupt AG-120 (ivosidenib). 
 • Restart AG-120 (ivosidenib) at 50% dose once daily (refer to Appendix V) 
(rounding to the closest 50 mg) after the QTc interval returns to less than or 
equal to 480 msec.  
• Monitor ECGs at least weekly for 2 weeks following resolution of QTc 
prolongation.  
• Consider twice weekly monitoring of EKGs in patients with QTc prolongation 
> 500 msec. 
QTc interval prolongation 
with signs/symptoms of life-
threatening arrhythmia 
Discontinue AG-120 (ivosidenib) permanently. 
Please refer to Section 6.2.3 for instructions on management of a recurrence of dose-limiting toxicity who has 
resumed treatment at the reduced dose.  
 
 
Dose Modifications for mIDH1 differentiation Syndrome (only applicable to NHL or Histocytosis) 
Adverse Reactions  
Recommended Action  
Differentiation syndrome [see 
Section 7.3]. 
If differentiation syndrome is suspected administer Dexamethasone 0.25 
mg/kg (up to 10 mg) IV every 12 hours (or equivalent) and hemodynamic 
monitoring should be initiated and continued until improvement.  
Taper corticosteroids after resolution of symptoms. Corticosteroids should 
be administered for a minimum of 3 days; differentiation syndrome 
symptoms may recur if corticosteroid treatment are discontinued too early.  
If severe signs/symptoms persist for more than 48 hours after initiation of 
corticosteroids, interrupt AG-120 (ivosidenib) treatment until signs and 
symptoms are no longer severe (< grade 2) . 
Concomitant Noninfectious 
leukocytosis (white blood cell 
[WBC] count greater than 25 x 
109/L or an absolute increase in 
total WBC of greater than 15 x 
109/L from baseline)  
 
If concomitant noninfectious leukocytosis is present, hydroxyurea treatment 
or leukapheresis should be initiated as clinically indicated. Taper 
corticosteroids and hydroxyurea after resolution of symptoms. 
Corticosteroids should be administered for a minimum of 3 days; 
differentiation syndrome symptoms may recur if corticosteroid and/or 
hydroxyurea treatment are discontinued too early.  

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If severe signs/symptoms persist for more than 48 hours after initiation of 
corticosteroids, interrupt AG-120 (ivosidenib) treatment until signs and 
symptoms are no longer severe (< grade 2). 
 
 
 
Dose Modifications for Noninfectious leukocytosis (only applicable to NHL or Histiocytosis) 
Adverse Reactions  
Recommended Action  
Noninfectious leukocytosis (white 
blood cell [WBC] count greater 
than 25 x 109/L or an absolute 
increase in total WBC of greater 
than 15 x 109/L from baseline)  
 
• 
Initiate treatment with hydroxyurea, as per standard institutional 
practices, and leukapheresis if clinically indicated.  
• 
Taper hydroxyurea only after leukocytosis improves or resolves.  
• 
Interrupt AG-120 (ivosidenib) if leukocytosis is not improved with 
hydroxyurea, and then resume AG-120 (ivosidenib) at 290 mg/m2 
(up to 500 mg) daily when leukocytosis has resolved. 
• 
Contact the APEC1621K study chair 
*Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening 
 
 
Dose Modification for Guillain-Barré Syndrome 
 
Adverse Reactions  
Recommended Action  
• Guillain-Barré syndrome  
• Discontinue AG-120 (ivosidenib) 
permanently 
 
 
If a new case of Progressive Multifocal Leukoencephalopathy (PML) occurs, the patient 
will be discontinued from treatment permanently. 
 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
 
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. 
 
 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
 
 
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               
AG-120 (ivosidenib). See below for recommendations on management of specific toxicities 
associated with AG-120 (ivosidenib). 
 
AG-120 (ivosidenib) is associated with a mild emetic potential; administer antiemetics, if 
necessary, prior to treatment to prevent nausea and vomiting. Patients may receive 
hydroxyurea for management of ivosidenib-induced non-infectious leukocytosis per 
institutional guidelines (see Section 6.5).  
 

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IDH Differentiation Syndrome:  
Patients with hematologic malignancies that are treated with AG-120 (ivosidenib) have 
experienced symptoms of differentiation syndrome (may be fatal if not treated). Symptoms 
include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, 
rapid weight gain or peripheral edema, hypotension, and/or hepatic, renal, or multi-organ 
dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and 
hemodynamic monitoring until symptom resolution. Differentiation syndrome is 
associated with rapid proliferation and differentiation of myeloid cells; may be life-
threatening. Other symptoms of differentiation syndrome have included noninfectious 
leukocytosis, pulmonary edema, pneumonitis, rash, fluid overload, tumor lysis syndrome, 
and/or increased serum creatinine. Of patients who experienced differentiation syndrome, 
most recovered after corticosteroid treatment or AG-120 (ivosidenib) treatment 
interruption. The onset of differentiation syndrome occurred from 1 day up to 3 months 
after AG-120 (ivosidenib) treatment initiation; may occur with or without concomitant 
leukocytosis.  See Section 6.4 for dose modification instructions.  
Guillain-Barré syndrome:  
Guillain-Barré syndrome occurred in a small (2) number of patients treated with ivosidenib. 
Monitor for onset of new signs or symptoms of motor and/or sensory neuropathy (eg, 
unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing). 
Permanently discontinue ivosidenib if Guillain-Barré syndrome is diagnosed. 
 
 
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. 
 
 
Concomitant Medications 
 
 
CYP3A4/5 inhibitors or inducers: 
Strong inducers or moderate to strong inhibitors of CYP3A4 should be avoided from 
14 days prior to enrollment to the end of the study. See Appendix II for a list of agents. 
Grapefruit and grapefruit products should be avoided. Note: CYP3A4 inducing anti-
epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, 
are allowed. 
 
AG-120 (ivosidenib) is a potential inducer of human CYP3A4 and CYP2C9 isozymes. 
Patients receiving sensitive or narrow therapeutic range substrates of CYP3A4 (see 
Appendix II) are not eligibile. In addition, sensitive or narrow therapeutic range 
substrates of CYP2C9 (eg., celecoxib, phenytoin, warfarin) should be used with 
caution or avoided, if reasonable alternatives exist. International normalized ratio 
(INR) levels should be monitored more frequently in subjects receiving warfarin (a 
CYP2C9 substrate) during initiation or discontinuation of ivosidenib.  
 
 
Transporter interactions:  
 
• 
AG-120 (ivosidenib) should be used with caution with agents that are 
inhibitors of P-glycoprotein (P-gp).  
• 
Use caution when co-administering AG-120 (ivosidenib) with other agents 
that may be substrates of OAT3. 
 
 
Avoid combination with other drugs with potential to lead to prolongation of QTc 
interval, if possible (see Appendix X).  
 

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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
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 each Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam  with vital signs 
X 
Weekly 
X 
Neurologic Exam 
X 
 
 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
 
Pregnancy Test1 
X 
 
X1 
CBC, differential, platelets 
X 
Twice Weekly 
(every 3 to 4 
days)2,3 
Weekly2,3 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Albumin 
X 
 
X 
CPK 
X 
 
 
EKG 
X 
 Twice Weekly x 
2 weeks, then 
weekly 
X 
Tumor Disease Evaluation4-A, 4-B, 4-C 
X 
 
Every other cycle x 3 then q 3 
cycles 4 
Bone Marrow Aspirate and/or biopsy5,6 
X 
 
 
Medication Diary7 
 
Weekly 
X 
Pharmacokinetics  and 
Pharmacodynamics (optional)8,9 
X 
X 
X 
Circulating Tumor DNA (ctDNA-
optional)10 
 
 
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 
active patients must use an acceptable method of birth control.  Abstinence is an acceptable method of 
birth control. Prior to the start of each subsequent cycle a pregnancy test may be administered to women 
of childbearing potential, if clinically indicated.  
2 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery 
to Grade 3 or until meeting the criteria for dose limiting toxicity. 

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3 
If patients develop Grade 3 or higher thrombocytopenia then CBCs should be checked every 3-4 days 
until recovery per Section 6.1 
4 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation 
of either a PR or CR.  Subsequent scans may restart 2 cycles after the confirmatory scan. 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 
either FDG-PET/CT or PET/MR 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 FDG-PET/CT. For patients with neuroblastoma and evaluable disease by MIBG 
scintigraphy, use the same modality (MIBG scintigraphy) 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. 
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.  Medication diary (see Appendix III) should be reviewed weekly during Cycle 1, after completion of each 
treatment cycle, and uploaded into RAVE. 
8. See Section 8.3 for details of PK studies. 
9.    Patients who are removed from therapy during Cycle 1 after receiving the dose of AG-120 (ivosidenib) 
on Day 28 should have their last PK sample collected on Day 28 of Cycle 1. Patients who are removed 
from therapy during Cycle 3 after receiving the dose of AG-120 (ivosidenib) on Day 28 should have 
their last PK sample collected on Day 28 of Cycle 3 
10. 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 and Appendix VI for details of the 
ctDNA studies. Note that a ctDNA sample is scheduled to be obtained on the APEC 162SC screening 
protocol prior to the initiation of treatment on this subprotocol  
 
 
Radiology Studies 
 
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 (prestudy) 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 

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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 
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 

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courier with an adequate amount of dry ice. Do not ship samples on Thursdays, 
Fridays, weekends, or holiday. 
 
PPD 
Attn: Jay Schaefgen, Sr. Group Leader Specimen Management 
3230 Deming Way 
Middleton, WI 53562 
Phone: (608) 662-7706 
Fax:  (608) 662-9025 
Email: Jay.Schaefgen@ppdi.com   
 
The FedEx account number for sample shipment is 454696409 
 
 
Circulating Tumor DNA Study (optional)   
 
 
Sampling Schedule   
An initial sample was previously requested 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: 
 
a) Keep patient’s arm in the downward position during the collection procedure. 

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b) 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. 
c) Release tourniquet once blood starts to flow in the tube, or within 2 minutes of 
application. 
d) Fill tube completely. 
e) Remove tube from adapter and immediately mix by gentle inversion 8 to 10 times. 
Inadequate or delayed mixing may result in inaccurate test results. 
 
 
Sample Processing 
Samples do not need to be processed at the collection site. 
 
 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D (APEC1621K), 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 in the Streck tube on 
Friday, over the weekend or on the day before a holiday, the sample should be 
stored in a refrigerator until shipped on the next business day. Ship by FedEx 
Priority Overnight using the COG FedEx account. Blood samples should be 
shipped the same day as collection, ship blood for Saturday delivery if shipped on 
Friday. 
 
Ship specimens to the following address: 
 
 
Biopathology Center 
Nationwide Children’s Hospital 
Protocol APEC1621K-Peds MATCH* 
700 Children’s Drive, WA1340* 
Columbus, OH  43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email:BPCBank@nationwidechildrens.org  
 
*Be sure to include the room number. Packages received without the room number 
may be returned to the sender. Packages must be labeled “Peds MATCH” in order 
to expedite processing at the BPC. 
 
 
9.0 
 AGENT INFORMATION 
 
 
AG-120  
 
 
 
 
 
 
 
(09/22/2020) 
(Ivosidenib, Tibsovo®, AGI-16678) NSC# 804600 IND# 
 
  

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Source and Pharmacology:  
AG-120 is a potent, selective, orally active small molecule inhibitor of mutated 
isocitrate dehydrogenase 1 (IDH1). Isocitrate dehydrogenase is a critical enzyme 
in the citric acid cycle catalyzing the oxidative decarboxylation of isocitrate to 
produce carbon dioxide (CO2) and alpha-ketoglutarate (α-KG). The mutant IDH 
enzymes are not catalytically inactive, but rather possess a novel enzyme activity, 
catalyzing the reduction of α-KG to the “oncometabolite” 2-hydroxyglutarate (2-
HG), which has been found to be elevated in patients with several tumor types, 
including both solid and liquid tumors. Ivosidenib is FDA approved for treatment 
of adult patients with relapsed or refractory acute myeloid leukemia (AML) with 
a susceptible isocitrate dehydrogenase-1 (IDH1) mutation. 
 
Pharmacokinetics/Pharmacodynamics: 
Ivosidenib was rapidly absorbed with a mean peak plasma concentration of 4 hours 
(Tmax range: 2-24 hours). After reaching a peak, mean concentrations of 
ivosidenib declined in a bi-exponential manner, with a mean half-life of 71.8 to 
138 hours after single dosing. Inter-subject variability was generally moderate and 
similar across doses and study days. CLss/F generally increased with increasing 
dose levels after single and multiple doses and ranged from 2.68 to 6.09 L/hr on 
C2D1 of dose escalation across the 100 mg BID and 300 to 1,200 mg QD dose 
range. Moderate accumulation was observed after multiple dosing. Mean 
ivosidenib plasma concentrations and exposure suggests that steady-state is 
achieved within 14 days of dosing. Ivosidenib exposure increased less than 
proportionally to dose after either single or multiple dosing. There was an effect of 
food on ivosidenib exposure, with an approximately 2-fold increase in Cmax and 
a 25% increase in AUC in the fed state. Maximal inhibition of 2-HG by ivosidenib 
was observed in the majority of subjects at 500 mg QD, with no additional 
inhibition observed at higher doses (800 mg or 1,200 mg QD). In subjects with 
newly diagnosed AML receiving intensive chemotherapy, plasma 2-HG reduction 
reached a plateau within 14 days of dosing and was maintained from Day 15 
onward during induction, consolidation, and maintenance cycles.  
 
9.1.1.1 Potential Drug Interactions: 
AG-120 (ivosidenib) is primarily metabolized by CYP3A4, and to a lesser extent by 
CYP2B6 and CYP2C8. Avoid use of concomitant medications that are moderate or 
strong inhibitors or strong inducers of CYP3A4. Patients should be advised to avoid 
grapefruit or grapefruit juice.  
AG-120 is an inducer of CYP3A4 and may also induce CYP2B6, CYP2C8, and 
CYP2C9. Coadministration of AG-120 with sensitive or narrow therapeutic index 
drugs that are extensively metabolized by CYP3A4 or CYP2C9 may result in 
decreased concentrations of these drugs. Patients receiving sensitive or narrow 
therapeutic range substrates of CYP3A4 (see Appendix II) are not eligible. In 
addition, sensitive or narrow therapeutic range substrates of CYP2C9 (eg., 
celecoxib, phenytoin, warfarin) should be used with caution or avoided, if 
reasonable alternatives exist.  International normalized ratio (INR) levels should be 
monitored more frequently in subjects receiving warfarin (a CYP2C9 substrate) 
during initiation or discontinuation of AG-120. Animal studies have shown the 
potential for autoinduction of AG-120 metabolism.   

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AG-120 (ivosidenib) is a weak direct inhibitor CYP2C8, CYP2C19, CYP2D6, and 
CYP3A4/5 and showed little or no evidence of direct inhibition of CYP1A2, 
CYP2B6, or CYP2C9. The likelihood of direct or time-dependent inhibition of these 
enzymes causing drug-drug interactions is low. 
 
Studies show AG-120 (ivosidenib) is a substrate for P-glycoprotein (P-gp), but not 
breast cancer resistance protein (BCRP), organic anion transporting polypeptides 
OATP1B1 or OATP1B3.  AG-120 (ivosidenib) is an inhibitor of P-gp, OATP1B1 
and OATP1B3, and organic anion transporter OAT3, but did not inhibit BCRP, 
OAT1 or organic cation transporter OCT2. . Although the relevance of these 
interactions is unknown at this time, use caution when co-administering with other 
agents that affect or may be affected by these transport enzymes. 
 
Antacid, proton pump inhibitor or H2-receptor antagonist use does not significantly 
alter the pharmacokinetics of AG-120 (ivosidenib).  
 
Co-administration with hormonal contraceptives may decrease the concentrations of 
hormonal contraceptives. 
 
AG-120 (ivosidenib) has the potential to prolong the QTc interval. Avoid co-
administration of medications that are known to prolong the QT interval and have a 
risk of causing Torsade de Pointes. Avoid concomitant administration with moderate 
to strong CYP3A4 inhibitors that may increase the risk of QTc interval prolongation 
from increased AG-120 (ivosidenib) exposure. Clinicians should refer to a regularly 
updated medical reference for a list of medications that can prolong the QT interval 
and have a risk of causing Torsade de Pointes. 
 
9.1.1.2 Patient Care Implications:  
AG-120 (ivosidenib) must not be administered to pregnant or nursing females. 
Women study participants of reproductive potential and fertile men study 
participants and their partners must either abstain or use effective contraception 
while receiving study treatment and for at least 1 month after the last dose of AG-
120 (ivosidenib). Since AG-120 (ivosidenib) may decrease concentrations of 
hormonal contraceptives, hormonal contraceptives are not considered effective 
contraception when co-administered with     AG-120 (ivosidenib).  
 
 
Toxicities: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
AG-120 (Ivosidenib, NSC 804600) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 692 patients. Below is the CAEPR for AG-120 (Ivosidenib). 

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REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - Other 
(increased erection) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Hypoxia; Nasal congestion; Pulmonary edema; Respiratory failure 
 
Note: AG-120 (Ivosidenib) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously associated 
with either agent. 
 
 
Formulation and Stability: 
AG-120 (ivosidenib) is supplied by Agios Pharmaceuticals and distributed by the 
Pharmaceutical Management Branch, CTEP, DCTD, NCI as 50 mg uncoated and 250 mg 
film-coated tablets in 75 cc HDPE bottles with 38 mm child-resistant closures and heat-
induction seals. Bottles contain 30 tablets each with a 1 gm silica gel desiccant. Tablet 
descriptions are as follows:  
50 mg: white, round, uncoated tablets with no markings.  
250 mg: blue, oval, film-coated tablets with no markings.  
Tablets contain the following inactive ingredients: hypromellose acetate succinate, 
microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon 
dioxide, and magnesium stearate. The 250 mg film-coated tablets also include the inactive 
ingredient Opadry® II Blue. 
 
9.1.3.1 Storage: 
Store below 30°C.  
If a storage temperature excursion is identified, promptly return AG-120 
(ivosidenib) to controlled room temperature and quarantine the supplies. 
Provide a detailed report of the excursion (including documentation of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
9.1.3.2 Stability: 
Intact bottles are undergoing on-going stability testing. Dispense medication 
in the original container. 
 
 
Guidelines for Administration 
 See Treatment (Section 5.0) and Dose Modification (Section 6.0) sections of the 
protocol. 
 
Oral tablets are to be swallowed whole; do not crush or chew. AG-120 (ivosidenib) may 
be administered with or without food but avoid administration with a high-fat meal. 
Vomited doses should not be re-administered. Missed doses should not be administered 
if within 12 hours of the next scheduled dose.  
 
 
Supplier:  
AG-120 (ivosidenib) is supplied by Agios Pharmaceuticals and distributed by a Division 

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of Cancer Treatment and Diagnosis the Pharmaceutical Management Branch (DCTD), 
NCI. Do not use commercial supply. 
 
 
Obtaining the Agent 
 
9.1.6.1 Agent Ordering 
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. Drug orders of AG-120 (ivosidenib)   
should be placed with CTEP after enrollment and treatment assignment to 
APEC1621K with consideration for timing of processing and shipping to ensure 
receipt of drug supply prior to start of protocol therapy. Submit agent requests 
through the PMB Online Agent Order Processing (OAOP) application. Access to 
OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status and a “current” password 
and active person registration status. For questions about drug orders, transfers, 
returns, or accountability call or email PMB. Refer to the PMB’s website for specific 
policies and guidelines related to agent management. If expedited shipment is 
required, sites should provide an express courier account through the Online Agent 
Order Processing (OAOP) application. Provide the patient ID number in the comment 
box when submitting an order request. 
  
 
Agent Accountability 
 
9.1.7.1 Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain 
a careful record of the receipt, dispensing and final disposition of all agents received 
from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability 
Record (DARF) available on the CTEP forms page.  Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation 
and ordering investigator on this protocol. 
 
9.1.7.2  Investigator Brochure Availability 
The current version(s) of the IB(s) for the agent will be accessible to site investigators 
and research staff through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP IAM account and 
the maintenance of an “active” account status, a “current” password, and active person 
registration status. Questions about IB access may be directed to the PMB IB 
coordinator via email 
 
 
Useful Links and Contacts  
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 

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• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
 
 
http://ctep.cancer.gov/branches/pmb/agent_management.htm    
• PMB Online Agent Order Processing (OAOP) application:  
 
 
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account:  
   
  https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help: 
 
ctepreghelp@ctep.nci.nih.gov  
• PMB email: PMBAfterHours@mail.nih.gov  
• PMB phone and hours of service: (240) 276-6575  
Monday through Friday between 8:30 am and 4:30 pm (ET) 
• PMB IB Coordinator: IBcoordinator@mail.nih.gov 
• Registration and Credential Repository (RCR): 
https://ctepcore.nci.nih.gov/rcr/  
 
 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
 
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.  
 
 
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 

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events, or adverse events that emerge after the patient is removed from protocol therapy, 
but within 30 days of the last dose of investigational agent, must be followed and reported 
via RAVE and CTEP-AERS (if applicable).  Follow-up data will be required until off study 
criteria are met unless consent is withdrawn or the patient dies or is lost to follow-up. 
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
 
Sample Size and Study Duration 
APEC1621K will require a minimum of 10 evaluable patients and a maximum of 49 
patients, allowing for 15% inevaluability. Assuming an enrollment rate of 2-6 biomarker 
positive patients per year, the primary cohort of this subprotocol is expected to be 
completed within 4-12 years. 
 
 
Dosing Considerations: 
 Pediatric MATCH Sub-arm Dosing in the Absence of Pediatric Phase 1 Data 
Please see Section 5.1 for a specific discussion of the dosing of AG-120 
(ivosidenib) to be used in this study.  If there is no prior pediatric phase 1 data, 
study investigators will review relevant data with the pharmaceutical partner to 
identify a drug specific dosing plan for testing in children with relapsed or 
refractory cancer, and trial participants will be closely monitored to ensure 
tolerability of the selected dose. Limited pharmacokinetic sampling may be done 
for patients enrolled on these arms.  In general, the dosing for the Pediatric 
MATCH subprotocols will follow the guidelines below: 
 
• 
For agents for which the adult RP2D is below the adult MTD, the adult RP2D 
(normalized to body surface area or body weight) will be used for evaluation 
in the Pediatric MATCH, understanding that further dose optimization may be 
required in a future pediatric study.   
 
 
Study Design 
The primary cohort will employ a two-stage design26 with a sample size of 20. In the first 
stage, 10 evaluable mutation-matched (“biomarker positive”) patients of any histology will 
be accrued. Accrual will be suspended when a cohort of ten patients has enrolled or when 
the study endpoints have been met. The evaluation period for determination of opening the 
second stage will be 6 treatment cycles. If there is no response observed in these 10 patients, 
the study will be terminated. Otherwise, 10 additional patients will be accrued for a total 
of 20 evaluable patients. If there are at least 3 responses out of 20 in the primary cohort, 
the study will be deemed a success.  
  
 

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percent of evaluable patients who are responders, and confidence intervals will be 
constructed using the Wilson score interval method.27 Decision making for the two-stage 
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.   
 
 
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. 
 
 
Evaluability for Toxicity 
All eligible patients who receive at least one dose of protocol therapy will be considered in 
the evaluation of toxicity. 
 
 
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.     
 
 
Correlative Studies 
A descriptive analysis of pharmacokinetic (PK) parameters will be performed to define 
systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK 
parameters will be summarized with simple summary statistics, including means, medians, 
ranges, and standard deviations (if numbers and distribution permit).   

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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) 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).  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 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 response. 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). 
 
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 

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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 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
12.3.3.1 Clinical lesions:  Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including a 

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ruler to estimate the size of the lesion, is recommended.  
 
12.3.3.2 Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
 
12.3.3.3 Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans). Ideally, 
the same type of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans.  
 
12.3.3.4 PET-CT:  At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements.  However, if the site can document that 
the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer 
lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
12.3.3.5 Tumor markers: Tumor markers alone cannot be used to assess response.  
If markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response.  
 
12.3.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare cases 
(e.g., residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.3.3.7 FDG-PET: While FDG-PET response assessments need additional study, 
it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly 
possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
 
a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b) No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 

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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.28 
 
 
 
 
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 tumor markers if elevated at 
study 
enrollment 
(for 
patients 
with 
neuroblastoma).  
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions 
is also considered progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 

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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-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once ≥ 
28 days from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 

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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 Marrow 
Overall 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
PD 
SD 
CR/PR/SD 
Non-PD 
SD 
PR 
CR/PR 
Non-PD 
PR 
CR/PR 
PR 
Non-PD 
PR 
CR 
CR 
Non-PD 
PR 
CR 
CR 
CR 
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. 
 
 
 
Response Criteria for Neuroblastoma Patients  
 
This study will use the revised International Neuroblastoma Response Criteria for disease 
assessment.30 The updated response criteria incorporate current approaches to imaging of 
neuroblastoma, including functional imaging. Furthermore, a standardized approach to assessment 
of bone marrow involvement is included.  The current INRC do not include methods of disease 
assessment that are less sensitive and/or specific for neuroblastoma (99Tc bone scan and 
catecholamine levels).  
 
Key sites and terms 
Primary site: The primary site will be identified as a measurable lesion ≥ 10 mm in diameter as 
assessed by cross sectional imaging (CT or MRI scan). Primary site measurements must be 
recorded in millimeters (or decimal fractions of centimeters). The longest diameter of the primary 
tumor will be recorded at baseline. Serial measurements of the primary tumor will include 

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assessment of tumor size in the same orthogonal plane at the time of each evaluation.31 In patients 
with bilateral adrenal lesions, response will be based on the sum of the longest dimensions of both 
adrenal 
lesions 
unless 
biopsy 
proves 
one 
to 
be 
ganglioneuroma 
rather 
than 
neuroblastoma/ganglioneuroblastoma. In patients with multi-focal non-adrenal disease, the largest 
tumor will be considered the primary tumor. Response in additional lesions will be assessed as 
described below for metastatic lesions. 
  
Tracer avidity (123I-MIBG or FDG-PET) in the primary site will be recorded at baseline. The scan 
appropriate for serial disease assessments should be used at each disease re-evaluation timepoint 
(e.g. 123I-MIBG avid primary lesions should be followed using 123I-MIBG scans during therapy). 
  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a metastatic 
lymph node must be ≥ 15 mm in short axis when assessed by CT or MRI scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short 
axis of a discreet lymph node will be measured and followed as per RECIST criteria. Patients with 
neuroblastoma may have conglomerate masses of non-discrete lymph nodes (i.e. multiple 
contiguous retroperitoneal nodes). When a short axis of a discreet node cannot be identified, a 
lymph node conglomerate can be measured using the longest diameter of the composite lesion. 
Tracer avidity of metastatic nodes will be recorded at baseline and during disease evaluations. 
 
For the purposes of response assessment, target lesions are disease sites that are measurable (non-
nodal soft tissue mass ≥ 10 mm in longest dimension or lymph node ≥ 15 mm in short axis) and 
tracer avid OR are biopsy positive for neuroblastoma or ganglioneuroblastoma. The sum of 
diameters of target lesions is defined as the sum of the short axis of discrete lymph nodes (i.e., 
cervical, axillary nodes) added to the sum of the longest diameters of non-lymph node soft tissue 
metastases.   
 
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 are considered non-measurable. 
 
Bone lesions: Osteomedullary disease will be assessed using 123I-MIBG scans or FDG-PET scans. 
Technitium bone scans are no longer used as part of the revised INRC and are not included as part 
of disease reassessments during this trial. The extent of tracer avid disease will be evaluated using 
the Curie scoring system (see Curie Scoring System). SPECT may be used to confirm the presence 
or absence of lesions in a given segment of the body. The absolute Curie score should be reported 
at baseline. A relative score (Curie score at the time of disease assessment divided by baseline Curie 
score) should be recorded at the time of each disease evaluation. 
 
Bone marrow disease: Bilateral bone marrow aspirates and trephine biopsies are required at disease 
assessment timepoints. The extent of marrow involvement in all four samples should be recorded. 
Use of immunohistochemical staining for evaluation of trephine biopsies is strongly encouraged. 
The percentage of tumor infiltration of bone marrow space assessed by histologic evaluation of 
trephine/biopsies or counting the number of tumor cells in aspirates by cytology or 
immunocytology 
(recommended 
if 
available) 
divided 
by 
the 
number 
of 
hematopoietic/mononuclear cells evaluated to obtain a percentage involvement (methodology 
described by Burchill et al.).32 The bone marrow sample with the highest percentage of tumor 
infiltration is used for response assessment. If > 0% to ≤ 5% tumor infiltration is the highest 
percentage seen among samples obtained, the result should be recorded as minimal marrow disease. 
 

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Response Criteria 
 
PRIMARY (SOFT TISSUE) TUMOR RESPONSE1  
RESPONSE 
ANATOMICAL IMAGING + MIBG 
(FDG-PET2) IMAGING 
Complete 
Response 
(CR) 
• 
< 10 mm residual soft tissue at primary site, 
AND 
• 
complete resolution of MIBG or FDG-PET 
uptake (for MIBG non-avid tumors) at 
primary site 
Partial 
Response 
(PR) 
• 
≥ 30% decrease in longest diameter (LD) of 
primary site 
• 
MIBG or FDG-PET uptake at primary site 
stable, improved or resolved 
Progressive 
Disease (PD) 
• 
> 20% increase in longest diameter taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study), AND  
• 
a minimum absolute increase of 5 mm in 
longest dimension3  
Stable 
Disease (SD) 
Neither sufficient shrinkage for PR nor 
sufficient increase for PD at the primary site 
1Not for use in assessment of metastatic sites 
2 For 123I-MIBG non-avid tumors 
3 A mass that has not met PD measurement criteria but has fluctuating 123I-MIBG avidity will not 
be considered progressive disease. 
 
RESPONSE AT METASTATIC SOFT TISSUE AND BONE SITES 
RESPONSE 
ANATOMICAL IMAGING + MIBG (FDG-PET1) IMAGING 
Complete 
Response (CR) 
• 
Resolution of all sites of disease defined as: 
• 
Non-primary target and non-target lesions measure < 10 mm AND 
• 
Lymph nodes identified as target lesions decrease to a short axis < 15 
mm, AND  
• 
MIBG uptake or FDG-PET uptake (for MIBG non-avid tumors) of non-
primary lesions resolves completely 
Partial 
Response (PR) 
• 
≥ 30% decrease in sum of diameters2 of non-primary target lesions compared to 
baseline, AND all of the following: 

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• 
Non-target lesions may be stable or smaller in size AND 
• 
No new lesions AND 
• 
≥ 50% reduction in MIBG absolute bone score (Relative MIBG bone 
score ≥ 0.1 to ≤ 0.5) or ≥ 50% reduction in number of FDG-PET avid 
bone lesions3,4 
Progressive 
Disease (PD) 
Any of the following5: 
• 
Any new soft tissue lesion detected by CT or MRI that is also MIBG avid or 
FDG-PET avid; 
• 
Any new soft tissue lesion seen on anatomic imaging that is biopsied and 
confirmed to be a neuroblastoma or ganglioneuroblastoma; 
• 
Any new bone site that is MIBG avid;   
• 
A new bone site that is FDG-PET avid (for MIBG non-avid tumors) AND has 
CT or MRI findings consistent with tumor OR has been confirmed 
histologically to be neuroblastoma or ganglioneuroblastoma; 
• 
> 20% increase in longest diameter taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study), AND a 
minimum absolute increase of 5 mm in sum of diameters of target soft tissue 
lesions; 
• 
Relative MIBG score ≥ 1.24 
Stable Disease 
(SD) 
Neither sufficient shrinkage for PR nor sufficient increase for PD of non-primary lesions 
1 Used for MIBG non-avid tumors 
2Sum of diameters is defined as the sum of the short axis of discrete lymph nodes (i.e., cervical, axillary 
nodes) added to the sum of the longest diameters of non-lymph node soft tissue metastases.  Masses of 
conglomerate non-discrete lymph nodes will be measured using longest diameter. 
3 For patients with soft tissue metastatic disease, resolution of MIBG and/or FDG-PET uptake at the soft 
tissue sites is not required; all size reduction criteria must be fulfilled. 
4Relative Curie score is the absolute score for bone lesions at time of response assessment divided by 
the absolute score for bone lesions at entry onto a clinical trial. MIBG-SPECT or MIBG-SPECT/CT 
may be used for scoring purposes but the same imaging methodology should be used for all evaluations. 
5The post-infusion MIBG scan is not considered a diagnostic study for the purposes of response 
assessment. Progressive disease should NOT be designated on the basis of this scan. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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BONE MARROW RESPONSE 
RESPONSE 
BONE MARROW STATUS1 
Complete response 
(CR) 
Bone marrow with no tumor infiltration upon reassessment, independent of 
baseline tumor involvement  
Progressive disease 
(PD) 
Any of the following: 
• 
Bone marrow without tumor infiltration that becomes > 5% tumor 
infiltration upon reassessment; or 
• Bone marrow with tumor infiltration that increases by > 2 fold and has 
> 20% tumor infiltration upon reassessment. 
Minimal disease 
(MD) 
Any of the following: 
• 
Bone marrow with ≤ 5% tumor infiltration and remains > 0-≤ 5% 
tumor infiltration upon reassessment; or 
• Bone marrow with no tumor infiltration that becomes ≤ 5% tumor 
infiltration upon reassessment; or 
• Bone marrow with >20% tumor infiltration that has > 0-≤ 5% tumor 
infiltration upon reassessment. 
Stable disease (SD) 
Bone marrow with tumor infiltration that remains positive with > 5% tumor 
infiltration upon reassessment but does not meet CR, MD or PD criteria 
1Immunohistochemistry strongly encouraged 
 
 
DETERMINATION OF OVERALL RESPONSE 
RESPONSE 
CRITERIA 
Complete Response (CR) 
All components meet criteria for CR 
Partial Response (PR) 
PR in at least one component and all other 
components are either CR, MD (Bone 
marrow), PR (Soft tissue or Bone) or Not 
involved (NI); no component with PD.   
Minor Response (MR) 
PR or CR in at least one component but at least 
one other component with SD; no component 
with PD. 
Stable Disease (SD) 
SD in one component with no better than SD or 
NI in any other component; no component with 
PD. 
Progressive Disease (PD) 
Any component with PD 
NI = Not involved, site not involved at study entry and remains not involved; MD = Minimal Disease, for 
bone marrow assessment only. 
 

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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 12.8 from a sequence of overall response 
assessments. 
 
Primary Tumor 
Soft Tissue and Bone Metastatic Disease 
(MIBG or FDG-PET or PET/MR) 
Bone Marrow Metastatic Disease  
Overall 
CR 
CR 
CR 
CR 
CR for one response component with either CR or NI for other components 
CR 
CR 
CR 
MD 
PR 
CR 
PR 
CR 
PR 
CR 
PR 
MD 
PR 
CR 
PR 
NI 
PR 
CR 
NI 
MD 
PR 
PR 
CR 
CR 
PR 
PR 
CR 
NI 
PR 
PR 
CR 
MD 
PR 
PR 
PR 
CR 
PR 
PR 
PR 
NI 
PR 
PR 
PR 
MD 
PR 
PR 
NI 
CR 
PR 
PR 
NI 
NI 
PR 
PR 
NI 
MD 
PR 
NI 
CR 
MD 
PR 
NI 
PR 
CR 
PR 
NI 
PR 
MD 
PR 
CR 
CR 
SD 
MR 
CR 
PR 
SD 
MR 
CR 
SD 
CR 
MR 
CR 
SD 
MD 
MR 
CR 
SD 
SD 
MR 
CR 
SD 
NI 
MR 
CR 
NI 
SD 
MR 
PR 
CR 
SD 
MR 
PR 
PR 
SD 
MR 
PR 
SD 
CR 
MR 
PR 
SD 
MD 
MR 
PR 
SD 
SD 
MR 
PR 
SD 
NI 
MR 
PR 
NI 
SD 
MR 
SD 
CR 
CR 
MR 
SD 
CR 
MD 
MR 
SD 
CR 
SD 
MR 
SD 
CR 
NI 
MR 
SD 
PR 
CR 
MR 
SD 
PR 
MD 
MR 
SD 
PR 
SD 
MR 
SD 
PR 
NI 
MR 
SD 
SD 
CR 
MR 
SD 
NI 
CR 
MR 
NI 
CR 
SD 
MR 
NI 
PR 
SD 
MR 
NI 
SD 
CR 
MR 
SD 
SD 
MD 
SD 
NI 
SD 
MD 
SD 
SD 
NI 
MD 
SD 
NI 
NI 
MD 
SD 
SD 
SD 
SD 
SD 
SD 
NI 
SD 
SD 
NI 
SD 
SD 
SD 
NI 
SD 
NI 
SD 
NI 
NI 
SD 
SD 
PD in any one component 
PD 
Response of Not Evaluable for any one of the 3 components that had measurable/evaluable tumor at study enrollment and no PD for any component 
Not Evaluable 
No response evaluation performed for any of the 3 components 
Not Done 
CR: Complete Response; MD: Minimal Disease; PR: Partial Response; MR: Minor Response; SD: Stable Disease; PD: Progressive disease; NI: 
not involved; site not involved at study entry and remains not involved 

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Curie Scoring Summary  
 
Table 1a. Scoring skeletal disease 
 
Table 1b. Scoring soft tissue disease 
 
 
Regions 1 – 9 
Region 10 (Primary soft tissue site) 
Scoring 
MIBG uptake 
Scoring  
MIBG uptake 
0 
No MIBG uptake 
0 
No soft tissue uptake 
1 
1 focal site  
1 
1 focal soft tissue site 
2 
> 1 focal site  
2 
> 1 focal soft tissue site 
3 
≥ 50% of a region  
3 
≥ 50% of a region (chest, abdomen) 
 
Region 
Site 
Curie 
score 
1 
Head / Neck 
 
 
2 
Cervico-Thoracic spine 
 
 
3 
Ribs / Sternum / Clavicles/ Chest 
 
 
4 
Lumbar / Sacral spine 
 
 
5 
Abdomen/Pelvis 
 
 
6 
Upper Extremity (Proximal) 
 
 
7 
Upper Extremity (Distal) 
 
 
8 
Lower Extremity (Proximal) 
 
 
9 
Lower Extremity (Distal) 
 
 
10 
Soft Tissue 
 
 
TOTAL 
Total scores from Regions 1 - 10 
 
 
 
Figure 1. 

 
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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). 
 
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 

 
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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 
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. 
 
 
 
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 Criteria28, with modification from the Lugano classification.33 

 
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 Disease Parameters 
 
12.7.1.1 Measurable disease: A measurable node must have an LDi (longest diameter) 
greater than 1.5 cm. A measurable extranodal lesion should have an LDi greater 
than 1.0 cm. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
12.7.1.2 Non-measured disease: All other lesions (including nodal, extranodal, and 
assessable disease) should be followed as nonmeasured disease (e.g., cutaneous, 
GI, bone, spleen, liver, kidneys, pleural or pericardial effusions, ascites).   
 
12.7.1.3 Target lesions: For patients staged with CT, up to six of the largest target nodes, 
nodal masses, or other lymphomatous lesions that are measurable in two 
diameters (longest diameter [LDi] and shortest diameter) should be identified 
from different body regions representative of the patient’s overall disease burden 
and include mediastinal and retroperitoneal disease, if involved. 
 
12.7.1.4 Evaluation of Measurable Disease: 
 
Complete Response (CR) 
Disappearance of all disease. CT or MRI should be free of residual mass or 
evidence of new disease. FDG-PET should be negative. 
 
Complete Response Unconfirmed (CRu) 
Residual mass is negative by FDG-PET; no new lesions by imaging examination; 
no new and/or progressive disease elsewhere 
 
Partial Response (PR) 
50% decrease in SPD (the sum of the products of the largest diameter and the 
perpendicular diameter for a tumor mass) on CT or MRI; FDG-PET may be 
positive (Deauville score or 4 or 5 with reduced lesional uptake compared with 
baseline); no new and/or PD; morphologic evidence of disease may be present in 
BM if present at diagnosis; however, there should be 50% reduction in 
percentage of lymphoma cells. 
 
No Response (Stable Disease) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
 
Progressive disease 
For those with > 25% increase in SPD on CT or MRI, Deauville score 4 or 5 on 
FDG-PET with increase in lesional uptake from baseline, or development of new 
morphologic evidence of disease in BM  
 
 Evaluation of Non-measured Lesions (CT-based response, PET/CT based response not 
applicable)33 
 
Complete Response (CR): 
Absent non-measured lesions.  
 

 
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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 enlargement  
 
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 
 
 
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 

 
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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. 
 
 
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. 
 
 
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: 

 
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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.  
 
Any medical documentation supporting an expedited report (eg, H & P, 
admission and/or notes, consultations, ECG results, etc.) MUST be faxed 
within 48-72 hours to the NCI. NOTE: English is required for supporting 
documentation submitted to the numbers listed below in order for the NCI to 
meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents 
supplied under a CTEP IND to: (301) 897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax# 
(310) 640-9193; email: COGAERS@childrensoncologygroup.org; Attention: 
COG AERS Coordinator).  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
   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# 301-640-9193) and by 
email to COGCAdEERS@childrensoncologygroup.org , the APEC1621K COG 
Study 
Assigned 
Research 
Coordinator, 
and 
COGAERS@childrensoncologygroup.org; Attention: COG AERS Coordinator..  
ALWAYS include the ticket number on all faxed and emailed documents. 

 
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Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the current version of the NCI CTCAE 
v5.0. The descriptions and grading scales found in the current version of 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 v5.0. 
 
Step 3:  Review Table A in this section to determine if: 
1. the adverse event is considered serious; 
2. 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 v5.0 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 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) 

 
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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. 
 
 
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) 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.  
 
CTEP requires all secondary malignancies that occur following treatment with an 
agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute 
myelocytic leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
 

 
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Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy).  Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 
 Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Death Neonatal”, the Pregnancy Information Form, available at: http://ctep.canc
er.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportForm
.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://c
tep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReport
Form.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 “Pregnancy, puerperium and perinatal conditions” SOC. Do NOT report 
a pregnancy loss as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event 
as a patient death. 
 
 Death Neonatal 
Neonatal death, defined in CTCAE v5.0 as “Newborn deaths occurring during 
the first 28 days after birth” that is felt by the investigator to be at least possibly 
due to the investigational agent/intervention, should be reported expeditiously, as 
Grade 4 “Death Neonatal” under the system organ class (SOC) of “General 
disorders and administration site conditions.” When the death is the result of a 
patient pregnancy or pregnancy in partners of men on study. Do NOT report 
a neonatal death resulting from a patient pregnancy or pregnancy in partners of 
men on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event 

 
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as a patient death. 
 
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
• 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
 
• 
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. 
 
• 
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. 
 
 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis.  Reports are due January 31, April 30, July 31 and October 31.  
This is not a responsibility of institutions participating in this trial 
Note:  If your 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.   
 
 
CRADA/CTA/CSA 
Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by 
a Clinical Trials Agreement (CTA) or a Cooperative Research and Development 
Agreement. 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 

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

 
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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. 
 
 
 
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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REFERENCES 
1. 
Lu C, Ward PS, Kapoor GS, et al: IDH mutation impairs histone demethylation and results in a 
block to cell differentiation. Nature 483:474-478, 2012 
2. 
Figueroa ME, Wahab OA, Lu C, et al: Leukemic IDH1 and IDH2 mutations result in a 
hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. 
Cancer cell 18:553-567, 2010 
3. 
Turcan S, Rohle D, Goenka A, et al: IDH1 mutation is sufficient to establish the glioma 
hypermethylator phenotype. Nature 483:479-483, 2012 
4. 
Rohle D, Popovici-Muller J, Palaskas N, et al: An Inhibitor of Mutant IDH1 Delays Growth and 
Promotes Differentiation of Glioma Cells. Science (New York, N.Y.) 340:626-630, 2013 
5. 
Sasaki M, Knobbe CB, Munger JC, et al: IDH1(R132H) mutation increases murine haematopoietic 
progenitors and alters epigenetics. Nature 488:656-659, 2012 
6. 
Clark O, Yen K, Mellinghoff IK: Molecular Pathways: Isocitrate Dehydrogenase Mutations in 
Cancer. Clinical cancer research : an official journal of the American Association for Cancer 
Research 22:1837-1842, 2016 
7. 
Mardis ER, Ding L, Dooling DJ, et al: Recurring Mutations Found by Sequencing an Acute 
Myeloid Leukemia Genome. The New England journal of medicine 361:1058-1066, 2009 
8. 
Gross S, Cairns RA, Minden MD, et al: Cancer-associated metabolite 2-hydroxyglutarate 
accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. The 
Journal of Experimental Medicine 207:339-344, 2010 
9. 
Marcucci G, Maharry K, Wu Y-Z, et al: IDH1 and IDH2 Gene Mutations Identify Novel Molecular 
Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and 
Leukemia Group B Study. Journal of Clinical Oncology 28:2348-2355, 2010 
10. 
Yan H, Parsons DW, Jin G, et al: IDH1 and IDH2 Mutations in Gliomas. New England Journal of 
Medicine 360:765-773, 2009 
11. 
Ohgaki H, Kleihues P: The Definition of Primary and Secondary Glioblastoma. Clinical Cancer 
Research 19:764-772, 2013 
12. 
Amary MF, Bacsi K, Maggiani F, et al: IDH1 and IDH2 mutations are frequent events in central 
chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. 
The Journal of Pathology 224:334-343, 2011 
13. 
Borger DR, Tanabe KK, Fan KC, et al: Frequent Mutation of Isocitrate Dehydrogenase (IDH)1 and 
IDH2 in Cholangiocarcinoma Identified Through Broad-Based Tumor Genotyping. The Oncologist 
17:72-79, 2012 
14. 
Liang D-C, Liu H-C, Yang C-P, et al: Cooperating gene mutations in childhood acute myeloid 
leukemia with special reference on mutations of of ASXL1, TET2, IDH1, IDH2, and DNMT3A. 
Blood 121:2988-2995, 2013 
15. 
Ho PA, Kopecky KJ, Alonzo TA, et al: Prognostic implications of the IDH1 synonymous SNP 
rs11554137 in pediatric and adult AML: a report from the Children's Oncology Group and SWOG. 
Blood 118:4561-4566, 2011 
16. 
Ho PA, Alonzo TA, Kopecky KJ, et al: Molecular alterations of the IDH1 gene in AML: a 
Children’s Oncology Group and Southwest Oncology Group study. Leukemia 24:909-913, 2010 
17. 
Andersson AK, Miller DW, Lynch JA, et al: IDH1 and IDH2 mutations in pediatric acute leukemia. 
Leukemia 25:10.1038/leu.2011.133, 2011 
18. 
Pollack IF, Hamilton RL, Sobol RW, et al: IDH1 mutations are common in malignant gliomas 
arising in adolescents: a report from the Children’s Oncology Group. Child's Nervous System 
27:87-94, 2011 
19. 
Broniscer A, Chamdine O, Hwang S, et al: Gliomatosis cerebri in children shares molecular 
characteristics with other pediatric gliomas. Acta neuropathologica 131:299-307, 2016 
20. 
Agios Pharmaceuticals, Inc: AG-120 Investigator's Brochure Version 6.0, 2017.  
21. 
DiNardo CD, Stein EM, de Botton S, et al: Durable Remissions with Ivosidenib in IDH1-Mutated 

 
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Relapsed or Refractory AML. New England Journal of Medicine 378:2386-2398, 2018 
22. 
Mellinghoff IK, Touat M, Maher E, et al: ACTR-46. AG120, A First-in-class mutant IDH1 
inhibitor in patients with recurrent or progressive IDH1 mutant glioma: results from thephase 1 
glioma expansion cohorts. Neuro-Oncology 18:vi12-vi12, 2016 
23. 
Tap W VV, Cote GM, et al.: A phase 1 study of AG-120, and IDH1 mutant enzyme inhibitor: 
results from the chondrosarcoma dose escalation and expansion cohorts., 2016, pp CTOS 2016 
Annual Meeting Program. pp.265-266 (abstr P1-138). 
24. 
Lowery MA, Abou-Alfa GK, Burris HA, et al: Phase I study of AG-120, an IDH1 mutant enzyme 
inhibitor: Results from the cholangiocarcinoma dose escalation and expansion cohorts. Journal of 
Clinical Oncology 35:4015-4015, 2017 
25. 
Tibsovo (ivosidenib) [pacakge insert]. Agios Pharmaceuticals, Inc. Cambridge, MA. 2018 
26. 
Simon R: Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 10:1-10, 
1989 
27. 
Agresti A, Coull BA: Approximate Is Better than "Exact" for Interval Estimation of Binomial 
Proportions. The American Statistician 52:119-126, 1998 
28. 
Sandlund JT, Guillerman RP, Perkins SL, et al: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. J Clin Oncol 33:2106-11, 2015 
29. 
Park JR, Bagatell R, Cohn SL, et al: Revisions to the International Neuroblastoma Response 
Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning 
Meeting. J Clin Oncol:JCO2016720177, 2017 
30. 
Park JR, Bagatell R, Cohn SL, et al: Revisions to the International Neuroblastoma Response 
Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning 
Meeting. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 35:2580-2587, 2017 
31. 
Bagatell R, McHugh K, Naranjo A, et al: Assessment of Primary Site Response in Children With 
High-Risk Neuroblastoma: An International Multicenter Study. J Clin Oncol 34:740-6, 2016 
32. 
Burchill SA, Beiske K, Shimada H, et al: Recommendations for the standardization of bone marrow 
disease assessment and reporting in children with neuroblastoma; on behalf of the International 
Neuroblastoma Response Criteria Bone Marrow Working Group. Cancer, 2016 
33. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 32:3059-68, 2014 
 
 

 
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APPENDIX 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 
acalabrutinib5 
alfentanil4,5  
amiodarone4 
aprepitant/fosaprepitant 
atorvastatin 
axitinib 
bortezomib 
bosutinib5 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
mifepristone 
nilotinib 
verapamil 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
dabrafenib 
efavirenz 
etravirine 
modafinil 
nafcillin 
rifapentin 
 
 
 

 
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everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
nefazodone 
nilotinib 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
quetiapine5 
quinidine4  
regorafenib 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 

 
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sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
telaprevir 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 7.3 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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Cycle 1  
 
 
 
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. 
 
 
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).  
 
a. History/Physical Exam (including VS)   
b. Ht/Wt/BSA 
Additionally, per Section 5.1: 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. 
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. If patients develop Grade 3 or greater thrombocytopenia then CBCs 
should be checked every 3 to 4 days until recovery per Section 6.1. 
d. Electrolytes including Ca++, PO4, Mg++ 
e. 
Creatinine, ALT, bilirubin 
f. 
Albumin 
g. Medication Diary- (see Appendix III) should be reviewed after completion of each 
treatment cycle and uploaded into RAVE. The medication diary should be collected 
weekly. 
h.  Pharmacokinetics and pharmacodynamics (optional) please refer to Section 8.1 for the 
specific timing instructions. Please Note: Patients who are removed from therapy during 
Cycle 1 after receiving the dose of AG-120 (ivosidenib) on Day 28 should have their last 
PK sample collected on Day 28 of Cycle 1. 
i 
EKG- Twice weekly x 2, then weekly 

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Page 96 
Subsequent Cycles 
Required Observations in All Subsequent Cycles 
 
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. If patients develop Grade 3 or greater thrombocytopenia then CBCs 
should be checked every 3 to 4 days until recovery per Section 6.1. 
d. 
Electrolytes including Ca++, PO4, Mg++ 
e. 
Creatinine, ALT, bilirubin 
f. 
Albumin 
g. 
 
 
 
 
Tumor Disease Evaluation – Every other cycle x 3 then q 3 cycles. Tumor Disease 
Evaluation should be obtained on the next consecutive cycle after initial documentation of 
either a PR or CR.  Subsequent scans may restart 2 cycles after the confirmatory scan. If 
the institutional investigator determines that the patient has progressed based on clinical or 
laboratory evidence, he/she may opt not to confirm this finding radiographically 
h. 
 
 
Medication Diary- (see Appendix III) should be reviewed after completion of each 
treatment cycle and uploaded into RAVE. The medication diary should be collected at the 
end of every cycle.  
i. 
 
 
 
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.  
j. 
EKG 
k. 
Bone Marrow Aspirate and/or biopsy- Bone marrow aspirate and/or biopsy should only 
be performed when complete response or partial response is identified in target disease or 
when progression in bone marrow is suspected. 
l. 
Pharmacokinetics and Pharmacodynamics (optional) Please refer to Section 8.3 for the 
specific timing instructions. Please Note: Patients who are removed from therapy during Cycle 3 
after receiving the dose of AG-120 (ivosidenib) on Day 28 should have their last PK sample 
collected on Day 28 of Cycle 3 
m. Pregnancy Test (optional) Prior to the start of each subsequent cycle a pregnancy test may be 
administered to women of childbearing potential as clinically indicated 
 
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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Page 98 
APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621K EXPANSION COHORTS 
Target tumor types considered for biomarker-positive expansion cohorts in the event of agent activity 
in a specific tumor type. 
 
Tumor type 
• 
Ependymoma 
• 
Ewing Sarcoma/Peripheral PNET 
• 
Hepatoblastoma 
• 
Glioma, high grade 
• 
Glioma, low grade 
• 
Langerhans Cell Histiocytosis 
• 
Malignant Germ Cell Tumor 
• 
Medulloblastoma  
• 
Neuroblastoma 
• 
Non-Hodgkin Lymphoma 
• 
Non-RMS Soft Tissue Sarcoma 
• 
Osteosarcoma 
• 
Rhabdoid Malignancy 
• 
Rhabdomyosarcoma 
• 
Wilms Tumor 
• 
Other Histology (based on COG/NCI-CTEP approval) 
 
 
 
 

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Page 99 
APPENDIX VIII: EXAMPLES OF ACTIONABLE MUTATIONS OF INTEREST FOR 
APECH1621K 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INCLUSION 
VARIANTS 
  
  
  
  
  
  
  
  
NON-
HOTSPOT 
RULES 
  
  
  
Gene Name 
Description 
Variant Type 
LOE 
aMOI 
IDH1 
COSM6942014 
Indel 
2 
p.R132I 
IDH1 
COSM221574 
SNV 
2 
p.R132P 
HOTSPOTS 
  
  
  
  
Gene Name 
Variant ID 
Variant Type 
LOE 
aMOI 
IDH1 
COSM28748 
SNV 
1 
p.R132S 
IDH1 
COSM28749 
SNV 
1 
p.R132G 
IDH1 
COSM28747 
SNV 
1 
p.R132C 
IDH1 
COSM28751 
Indel 
2 
p.R132V 
IDH1 
COSM1169216 
Indel 
1 
p.R132S 
IDH1 
COSM28746 
SNV 
1 
p.R132H 
IDH1 
COSM28750 
SNV 
1 
p.R132L 
IDH1 
COSM86993 
Indel 
1 
p.R132H 

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Page 101 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents is 
restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Protocol Organization (PO) 
on the protocol. One way to search for a protocol is listed below.  
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select COG, and 
protocol number (*insert study number*). 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.) 
 
Protocol-Specific Requirements For Site Registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
Checking Your Site’s Registration Status 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory  at the top of the screen; 
• 
Click on Site Registration; and  
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol. It does not reflect compliance with protocol requirements for 

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Page 102 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
Data Submission / Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
 
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) 
or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password and click 
on the accept link in the upper right-corner of the iMedidata page. Site staff will not be able to 
access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be accessed 
by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning is required 
and has not yet been taken, the link to the eLearning will appear under the study name in iMedidata 
instead of the Rave EDC link; once the successful completion of the eLearning has been recorded, 
access to the study in Rave will be granted, and a Rave EDC link will display under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website in the Data 
Management section under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and review 
metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave Home 

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Page 103 
section displays a table providing summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, and timeliness reports. Review the DQP modules 
on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct link on the 
DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, 
DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on the 
DQP. A protocol must have the Calendar functionality implemented in Rave by the Lead Protocol 
Organization for delinquent form details and reports to be available on the DQP. Site staff should 
contact the LPO Data Manager for their protocol regarding questions about Rave Calendaring 
functionality.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Page 104 
APPENDIX X: MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
The use of the following medications should be avoided during protocol therapy if reasonable 
alternatives exist. This is not an inclusive list. Because the lists of these agents are constantly 
changing, it is important to regularly consult frequently updated medical references. For the most 
current list of medications, please refer to the following reference: Woosley, RL and Romero, KA, 
www.Crediblemeds.org, QTdrugs List, Accession Date December 19th, 2019, AZCERT, Inc. 1822 
Innovation Park Dr., Oro Valley, AZ  85755 
 
 
Medications with known risk of Torsades de Pointes (TdP) 
Amiodarone 
Fluconazole 
Anagrelide 
Haloperidol 
Arsenic trioxide 
Hydroxychloroquine 
Azithromycin 
Ibutilide  
Chloroquine 
Levofloxacin 
Chlorpromazine 
Methadone  
Cilostazol  
Moxifloxacin  
Ciprofloxacin  
Ondansetron 
Citalopram 
Oxaliplatin 
Clarithromycin 
Papaverine HCL (intra-coronary) 
Disopyramide 
Pentamidine 
Dofetilide 
Pimozide 
Domperidone 
Procainamide 
Donepezil 
Propofol 
Droperidol 
Quinidine  
Dronedarone 
Sevoflurane 
Erythromycin 
Sotalol 
Escitalopram 
Thioridazine  
Flecainide  
Vandetanib  
 
 
 
Medications with possible risk of Torsades de Pointes (TdP) 
Alfuzosin 
Lofexidine 
Apalutamide 
Lopinavir/Ritonavir 
Apomorphine 
Maprotilin 
Aripiprazole 
Memantine 
Artemeter/Lumefantrine  
Midostaurin 
Asenapine  
Mifepristone 
Atomoxetine  
Mirabegron 
Bedaquiline  
Mirtazapine 
Bendamustine  
Moexipril/Hydrochlorothiazide 
Betrixaban  
Necitumumab 
Bortezomib 
Nicardipine  
Bosutinib 
Nilotinib  
Buprenorphine 
Nortriptyline 
Cabozantinib 
Nusinersen 
Capecitabine 
Ofloxacin 

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Page 105 
Ceritinib 
Osimertinib 
Clomipramine 
Oxytocin 
Clozapine 
Paliperidone 
Cobimetinib 
Palonosetron 
Crizotinib 
Panobinostat 
Dabrafenib 
Pasireotide 
Dasatinib 
Pazopanib  
Degarelix 
Perflutren lipid microspheres 
Desipramine 
Perphenazine 
Deutetrabenazine 
Pimavanserin 
Dexmedetomidine 
Pitolisant (Tiprolisant) 
Dextromethorphan/Quinidine 
Pretomanid 
Dolasetron 
Primaquine phosphate 
Efavirenz 
Promethazine  
Eliglustat 
Ribociclib 
Encorafenib 
Rilpivirine 
Entrectinib 
Romidepsin 
Epirubicin 
Saquinavir 
Eribulin mesylate 
Siponimod 
Ezogabine (Retigabine) 
Sorafenib 
Felbamate 
Sunitinib  
Fingolimod 
Tacrolimus 
Fluorouracil (5-FU) 
Tamoxifen 
Gemifloxacin  
Telavancin 
Gilteritinib  
Telithromycin 
Glasdegib 
Tetrabenazine 
Granisetron 
Tipiracil/Trifluridine 
Hydrocodone-ER 
Tizanidine 
Iloperidone 
Tolterodine 
Imipramine (Melipramine) 
Toremifene 
Inotuzumab ozogamicin 
Tramadol 
Isradipine 
Trimipramine 
Ivosidenib 
Valbenazine 
Lapatinib 
Vardenafil  
Lefamulin 
Vemurafenib  
Lenvatinib 
Venlafaxine 
Leuprolide (Leuprorelin) 
Vorinostat 
Lithium 
 
 
 
 
 
 
 
 
 

                                THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621K 
 
 
                                                                                                           
Version Date: 10/28/2022 
 
 
Page 106 
APPENDIX XI: YOUTH INFORMATION SHEETS  
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621K 
(for children from 7 through 13 years of age) 
 
We want to tell you all about this study. You and your family can decide if you want to be in it. 
Ask questions if you don’t understand. 
 
1. What is the name of the study? 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 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group and is 
being done at other hospitals. 
 
3. What is the study about? 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 you have.  
 
4. What will happen to me in the study? Children who are part of this study have been “matched” to 
a medicine. We think that this medicine will help you and other kids that have the same kind of 
cancer as you have. If you decide to be treated with this medicine, you will have some tests and 
check-ups done more often than if you weren’t part of this study. We will follow your health after 
you finish the study treatment. 
 
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 for your cancer to 
stop growing, or even shrink, but we don’t know for sure if there is any benefit of being part of this 
study. 
 
Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that you may have more problems, or side 
effects, from a medicine used in this study. There may be risks that we don’t know about yet. 
 
5. Do I have to be in the study? You and your family can choose to be part of this study or not. You 
and 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. If you have any questions 
or don’t like what is happening, please tell your parent, the doctor or nurse. 
 
6. We are asking your permission to collect additional tumor tissue. We want to see if there are ways 
to tell how the cancer will respond to treatment. These samples would be taken on tumor samples 
that we already have, so there would be no extra procedures. This would not change what medicines 
we would use to treat your tumor and would not provide any “benefits” to you. We hope that it 
might help us learn how to better treat other children’s cancers in the future. You do not have to 
participate if you do not want to. 
 
 
 
 
 

                                THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621K 
 
 
                                                                                                           
Version Date: 10/28/2022 
 
 
Page 107 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621K 
(for teens from 14 through 17 years of age) 
1. What is the name of the study? 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 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group and is being 
done at other hospitals. 
 
3. What is the study about? 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.  
 
4.  What will happen to me on the study? Your tumor has a mutation that matches AG-
120 (ivosidenib), and so you have been assigned to    AG-120 (ivosidenib). The doctors want to see 
if AG-120 (ivosidenib) will make children with your type of cancer get better. We don’t know if 
AG-120 (ivosidenib) will work well to get rid of your cancer there have only been a few research 
studies using AG-120 (ivosidenib) in children.. That is why we are doing the study. 
 
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 AG-120 
(ivosidenib) 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. 
 
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 
AG-120 (ivosidenib). Your doctor will talk to you about the risks we know about from AG-120 
(ivosidenib). There may be other risks from AG-120 (ivosidenib) that we don’t know about yet.  
 
 
5.  Will I be paid to be in this study? You will not be paid for being in this study  
 
6.   Do I have to be in the study? You and your family can choose to be part of this study or not. You 
and 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. If you have any questions 
or don’t like what is happening, please tell your parent, the doctor or nurse. 
 
7. We are asking your permission to collect additional tumor tissue. We want to see if there are ways 
to tell how the cancer will respond to treatment. These samples would be taken on tumor samples 
that we already have, so there would be no extra procedures. This would not change what medicines 
we would use to treat your tumor and would not provide any “benefits” to you. We hope that it 
might help us learn how to better treat other children’s cancers in the future. You do not have to 
participate if you do not want to. 
 

                                THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621K 
 
 
                                                                                                           
Version Date: 10/28/2022 
 
 
Page 109 
APPENDIX XII: TOXICITY-SPECIFIC GRADING 
Bilirubin 
 
Grade 1: 
≤ 1.5 x ULN 
Grade 2: 
> 1.5 x - 3 x ULN 
Grade 3: 
> 3 x -10 x ULN 
Grade 4: 
> 10 x ULN 
 
ALT: For the purpose of this study, the ULN for ALT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
≤ 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: 
≤ 150 U/L 
Grade 2: 
151 U/L -250 U/L 
Grade 3: 
251 U/L -1000 U/L 
Grade 4: 
> 1000 U/L 
 
GGT: 
 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5 x ULN- 5 x ULN 
Grade 3: 
> 5 x ULN-20 x ULN 
Grade 4: 
> 20 x ULN