A Phase 2 Study of Veliparib (ABT-888) and Local Irradiation, Followed by Maintenance Veliparib and Temozolomide, in Patients With Newly Diagnosed High-Grade Glioma (HGG) Without H3 K27M or BRAFV600 Mutations
Phase: PHASE2
Conditions: Anaplastic Astrocytoma, Glioblastoma, Malignant Glioma
Sponsor: National Cancer Institute (NCI)



iii 
SGPT (ALT) ≤ 135 U/L. For the purpose of this study, the ULN 
for SGPT is 45 U/L. 
11.  
3.3.5 
25 
Revised the following text to clarify the definition of definitive surgery 
and consistency with the amended ACNS1723: 
 
Patients must be enrolled and protocol therapy must be projected to 
begin no later than 31 days after definitive diagnostic surgery (Day 0). 
If a biopsy only was performed, the biopsy date will be 
considered the date of definitive surgery. For patients who have 
a biopsy or incomplete resection at diagnosis followed by 
additional surgery, the date of the last resection will be 
considered the date of definitive surgery. 
12.  
4.1.1 
4.3.1 
 
28 
31 
Revised the protocol language to provide a recommendation rather 
than a mandatory requirement. While preclinical and PK data suggest 
that veliparib may be most effective when administered 60–120 
minutes prior to the daily dose RT, we recognize that this may not 
always be feasible, e.g. when RT is scheduled in the afternoon or 
evening. 
13.  
4.4.3 
4.5.3 
37 
41 
Revised Veliparib treatment details for Cycle 1 and Cycle 2 to allow 
evening administration of temozolomide, if necessary. 
14.  
6.2 
54-57 
Revised Temozolomide drug monograph to reflect current version.  
15.  
7.3 
58 
Revised table to include tumor and biology sample collection as an 
End of Therapy requirement for patients consenting to optional 
studies, consistent with Section 15.2.2. 
16.  
7.3 
58 
Revised language to maintain internal protocol consistency.  
 
The table above indicates required End of Therapy evaluations and 
recommended required Follow-Up imaging scans. 
17.  
9.1.1 
59 
A subheading was created to provide a section of rationale for 
statistical implications of Stratum 1 closure.  
18.  
9.2 
62 
Updated the plot displaying the historical control cohort of IDH 
mutated patients. The previous version of the plot did not include the 
10 subjects from the Cell Metadata (n=6) and the HERBY cohorts 
(n=4). These patients were included in the design of the study and the 
quoted numbers in the text summarizing outcome but the combined 
data plot in the previous version of the protocol did not include them. 
19.  
15.2.1.3 
83 
 
Updated labeling requirements as requested per BPC. 
 
Updated the URL of Biopathology Center (BPC) Kit Management 
website. 
20.  
15.2.2.1 
83 
Removed references to other protocol sections (TDMs) that were 
considered unnecessary or confusing based on site feedback. 
21.  
15.2.2.3 
84-85 
Updated Jabado Lab contact information for specimen shipping. 
22.  
15.2.2.2.1 
84 
Revised instructions for peripheral blood preparation as follows to 
accommodate sites that may not have a refrigerated centrifuge that 
operates at 15,000 rpm. 
 
5. 
For 
the 
second 
centrifugation 
step, 
centrifuge 
the 
supernatant (plasma) from Step 2 at 21000g (15,000 rpm or the 
maximum speed available) at +4°C for 10 minutes. 
23.  
16.2.1 
85 
To correct typographical error, “skip 0A” was replaced by “skip 0”. 

iv 
24.  
16.5 
17.0 
17.9.4 
87 
88 
105 
Scan submission language has been revised to reflect preferred 
submission through TRIAD. Alternative submission methods are still 
available to sites that do not have TRIAD enabled. 
25.  
17.6.4.2.1 
95-96 
Corrected a typographical error by revising “in an isotropic fashion” to 
“in an anisotropic fashion”. This change was made in several places. 
26.  
Appendix III 
113-115 
 
114 
 
Updated to reflect Dr. Chris Fuller’s transition from CCHMC to 
SUNY Upstate. 
 
Updated to include details of EPR18340, the new validated 
antibody that will be used to test Histone H3 K27M. It replaces 
SAB5600095, for which manufacturing has been discontinued. It 
is not completely uncommon for IHC antibodies to be 
discontinued and replaced by an equivalent antibody. Going 
forward, this antibody (or its subsequent equivalent) will be 
utilized for the H3 K27M IHC assay. 
 
 

  
 
 
 
 
 
ACNS1721 
 
Version Date:07/22/2021 
 
Page 1 
 
Activated: 
10/31/2018 
Version Date: 
07/22/2021 
Closed: 
      
Amendment: 
#3A 
 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
ACNS1721 
 
 
A Phase 2 Study of Veliparib (ABT-888, 
) and Local Irradiation, Followed by 
Maintenance Veliparib and Temozolomide, in Patients with Newly Diagnosed High-Grade Glioma 
(HGG) without H3 K27M or BRAFV600 Mutations 
 
 
 
A COG Groupwide Phase 2 Study 
 
 
NCI Supplied Agent: Veliparib (ABT-888, NSC# 737664, 
) 
IND Sponsor: DCTD, NCI 
 
 
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 
 
, MD, MS 
Memorial Sloan Kettering Cancer Center 
1275 York Ave, Box 234 
New York, NY 10560 
Phone:
Fax: 
E-mail:
 
 
 
  
 
 
 
 
 

 
 
 
 
ACNS1721 
 
 
 
 
Version Date:07/22/2021 
 
Page 2 
 
 
CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on using 
the Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN SY
STEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. Please 
see the Data Submission 
Schedule in the CRF packet 
for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at 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 user log on 
with 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 RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. 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. 
 
 
 
 

 
 
 
 
ACNS1721 
Version Date:07/22/2021 
 
Page 3 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
6 
ABSTRACT 
9 
EXPERIMENTAL DESIGN SCHEMA 
10 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Primary Objectives 
11 
1.2 
Exploratory Objectives 
11 
2.0 
BACKGROUND 
11 
2.1 
Introduction/Rationale for Development 
11 
2.2 
Preclinical Studies 
13 
2.3 
Clinical Studies in Patients with IDH wild-type HGG 
15 
2.4 
Clinical Studies in Patients with IDH-Mutant HGG 
16 
2.5 
Pediatric Studies of Veliparib 
17 
2.6 
Dosing Rationale 
17 
2.7 
Genomic Analysis of Germline DNA 
17 
2.8 
Genomic, Epigenomic, and/or Transcriptomic Analysis 
18 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
18 
3.1 
Pre-Enrollment Eligibility Screening (Step 0) 
18 
3.2 
Study Enrollment 
22 
3.3 
Patient Eligibility Criteria 
24 
4.0 
TREATMENT PROGRAM 
28 
4.1 
Overview of Treatment Plan 
28 
4.2 
Concomitant Therapy Restrictions 
30 
4.3 
Chemoradiotherapy 
32 
4.4 
Maintenance Chemotherapy – Cycle 1 
36 
4.5 
Maintenance Chemotherapy – Cycles 2–10 
40 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
44 
5.1 
Dose Levels Tables 
44 
5.2 
Dose Modifications for Veliparib during Chemoradiotherapy 
44 
5.3 
Dose Modifications for Veliparib and Temozolomide during Maintenance  
Chemotherapy 
46 
5.4 
Management of Prolonged Hematological Toxicities while on Study Treatment 
48 
6.0 
DRUG INFORMATION 
49 
6.1 
Veliparib 
49 
6.2 
TEMOZOLOMIDE 
55 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
58 
7.1 
Research Studies for which Patient Participation is Required 
58 
7.2 
Research Studies for which Patient Participation is Optional 
58 
7.3 
End of Therapy & Follow-up 
58 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY     
CRITERIA 
59 
 
 

 
 
 
 
ACNS1721 
Version Date:07/22/2021 
 
Page 4 
8.1 
Criteria for Removal from Protocol Therapy 
59 
8.2 
Off Study Criteria 
59 
9.0 
STATISTICAL CONSIDERATIONS 
59 
9.1 
Sample Size and Study Duration 
59 
9.2 
Study Design 
60 
9.3 
Methods of Analysis 
63 
9.4 
Evaluability for Toxicity and Efficacy Assessments 
64 
9.5 
Analysis Plan for Exploratory Objectives 
64 
9.6 
Gender and Minority Accrual Estimates 
64 
10.0 
EVALUATION CRITERIA 
65 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
65 
10.2 
Methodology to Determine Tumor Measurement 
65 
10.3 
Selection of Target and Non-Target Lesions 
67 
10.4 
Response Criteria for Target Lesions 
68 
10.5 
Response Criteria for Non-Target Lesions 
69 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
69 
11.1 
Purpose 
69 
11.2 
Determination of Reporting Requirements 
69 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
70 
11.4 
Special Situations for Expedited Reporting 
70 
11.5 
Reporting Requirements for Specialized AEs 
73 
11.6 
Exceptions to Expedited Reporting 
73 
11.7 
Reporting Requirements  Investigator Responsibility 
74 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
74 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
76 
11.10 
Protocol Specific Additional Instructions and Reporting Exceptions 
77 
11.11 
Reporting of Adverse Events for Commercial Agents – CTEP-AERS Abbreviated 
Pathway 
77 
11.12 
Routine Adverse Event Reporting 
77 
12.0 
STUDY REPORTING AND MONITORING 
78 
12.1 
CDUS 
78 
12.2 
Data and Safety Monitoring Committee 
78 
12.3 
CRADA/CTA 
78 
13.0 
SURGICAL GUIDELINES 
80 
13.1 
Neurosurgical Procedures 
80 
13.2 
Definitions of Extent of Resection 
80 
13.3 
Imaging Confirmation of Extent of Resection 
81 
13.4 
Peri-operative Corticosteroids 
81 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
81 
14.1 
Required Rapid Central Pathology Review 
81 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
82 
15.1 
Required Studies 
82 
15.2 
Optional Studies 
82 
16.0 
NEUROIMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
86 
16.1 
Timing of MRIs and Retrospective Central Imaging Review 
86 
  

 
 
 
 
ACNS1721 
Version Date:07/22/2021 
 
Page 5 
16.2 
Whole Brain MRI With and Without Contrast 
86 
16.3 
Tumor Response Assessment 
87 
16.4 
Extracranial Disease Progression 
87 
16.5 
Submitting Scans 
87 
17.0 
RADIATION THERAPY GUIDELINES 
88 
17.1 
Radiation Therapy Timing 
89 
17.2 
Radiation Therapy Credentialing 
89 
17.3 
Radiation Therapy Equipment 
90 
17.4 
Radiotherapy Planning and Treatment Verification Imaging 
90 
17.5 
Treatment Delivery Verification Imaging 
91 
17.6 
Radiotherapy Target Volumes 
92 
17.7 
Radiation Therapy Dose 
96 
17.8 
Organs at Risk 
101 
17.9 
Dose Calculations and Reporting 
103 
17.10 
Definitions of Deviations in Protocol Performance 
106 
17.11 
Patterns of Failure Evaluation 
106 
APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
108 
APPENDIX II:  YOUTH INFORMATION SHEETS 
111 
APPENDIX III:  DETAILS OF RAPID CENTRAL PATHOLOGY AND MOLECULAR  
CENTRAL PATHOLOGY REVIEW 
113 
APPENDIX IV:  ACNS1721 RAPID CENTRAL PATHOLOGY AND MOLECULAR  
SCREENING REVIEW SCHEMA (PRIOR TO STUDY ENROLLMENT) 
117 
APPENDIX V:  INSTRUCTIONS FOR TEMOZOLOMIDE PREPARATION, ADMINISTRATION 
AND SAFE HANDLING 
118 
APPENDIX VI:  PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
119 
APPENDIX VII: SUGGESTED VELIPARIB CAPSULE DOSING TABLES 
121 
APPENDIX VIII: SUGGESTED TEMOZOLOMIDE CAPSULE DOSING TABLES 
124 
APPENDIX IX: POSSIBLE DRUG INTERACTIONS 
125 
REFERENCES 
126 
 
 
  

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ACNS1721 
Version Date:07/22/2021 
 
Page 6 
 
STUDY COMMITTEE 
STUDY CHAIR 
 MD, MS 
Hematology/Oncology 
Memorial Sloan Kettering Cancer Center 
1275 York Ave. 
New York, NY 10065 
Phone: 
Fax: 
E-mail: 
 
STUDY VICE CHAIR 
, MD, MBA 
Hematology/Oncology 
Johns Hopkins University 
The Sidney Kimmel Comprehensive Cancer Center 
Bloomberg 11379 
1800 Orleans St. 
Baltimore, MD 21287 
Phone:
   
Fax:
  
E-mail
 
STUDY STATISTICIAN 
, PhD 
Biostatistics 
Saint Jude Children’s Research Hospital 
252 Danny Thomas Place 
MS 768 
Memphis, TN 38105 
Phone:
Fax: 
E-mail: 
 
STUDY COMMITTEE MEMBERS 
, MD 
Hematology/Oncology 
Nationwide Children’s Hospital 
700 Children’s Drive  
Columbus OH 43205 
Phone: 
Fax:
E-mail:
     
 
 MD MS  
Pediatric Oncology  
Seattle Children’s Hospital 
Pediatric Brain Tumor Program 
4800 Sand Point Way  
Seattle, WA 98105  
Phone:  
Fax:  
E-mail: 
 
STUDY COMMITTEE MEMBERS 
, MD 
Hematology/Oncology 
Baylor College of Medicine  
Dan L. Duncan Comprehensive Cancer Center 
6621 Fannin St. 
CCC 1500.00 
Houston, TX 77030-2399 
Phone:
Fax:
E-mail:
   
 
, MD 
Pathology 
State University of New York Upstate Medical 
University 
750 East Adams Street 
UH 68054 
Syracuse, NY 13210 
Phone: 
E-mail: 
    
 
, MD, PhD 
Hematology/Oncology 
The Montreal Children’s Hospital of the MUHC 
1001 Decarie Blvd. 
Montreal, QC H4A 3J1 
Canada 
Phone: 
   
Fax:
E-mail:
 
 
, MD, MS 
Radiation Oncology 
Saint Jude Children’s Research Hospital 
MS 210, Room I3126 
Memphis, TN 38103 
Phone:
Fax:
E-mail:
    
 
, MD 
Radiation Oncology 
Massachusetts General Hospital Cancer Center 
100 Blossom Street, Cox 3 
Boston, MA 02114 
Phone:
Fax: 
E-mail: 
   
 
 

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ACNS1721 
Version Date:07/22/2021 
 
Page 7 
STUDY COMMITTEE MEMBERS 
 
, CCRP 
Clinical Research Associate 
University of Wisconsin Hospital and Clinics 
AFCH 2235 MC C200 
1675 Highland Ave. 
Madison, WI 53792 
Phone: 
Fax: 
E-mail: 
 
, MD, PhD 
Pathology 
Nationwide Children’s Hospital 
Division of Anatomic Pathology, J0359 
700 Children’s Dr. 
Columbus, OH 43205 
Phone:
Fax: 
E-mail: 
 
, MD, PhD 
Pathology  
Nationwide Children’s Hospital 
Section of Laboratory Medicine 
700 Children’s Dr. 
Columbus, OH 43205 
Phone:
Fax: 
E-mail:
 
, PharmD 
Pharmacy 
Lucile Packard Children’s Hospital Stanford University 
725 Welch Rd. 
Palo Alto, CA 94304 
Phone:
Fax: 
E-mail: 
 
, MD 
Hematology/Oncology 
MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit 087 
Houston, TX 77030 
Phone: 
Fax: 
E-mail: 
    
 
 
, MD 
Hematology/Oncology 
Memorial Sloan Kettering Cancer Center 
222 70th Street, Room 412 
New York, NY 10021 
Phone:
Fax: 
E-mail: 
 
, MD 
Diagnostic Imaging 
Memorial Sloan Kettering Cancer Center Radiology 
1275 York Ave. 
New York, NY 10065 
Phone: 
Fax: 
E-mail: 
 
, MSN 
Nursing  
Children’s Healthcare of Atlanta – Egleston 
Clinical Research Office 
2015 Uppergate Drive, 4th Floor  
Atlanta, GA 30322 
Phone: 
E-mail: 
    
 
, MD 
Surgery 
NYP/Weill Cornell Medical Center 
Dept of Neurological Surgery 
525 E. 68th St. Baker 2203 
New York, NY 10065 
Phone: 
Fax: 
E-mail: 
     
 
PROTOCOL COORDINATOR 
, MPH, CHES 
Children’s Oncology Group – Operations Center 
800 Royal Oaks Drive Suite #105 
Monrovia, CA 91016 
Phone
Fax:
Email:
 
RESEARCH COORDINATOR 
, BS 
Children’s Oncology Group – Operations Center 
800 Royal Oaks Drive Suite #105 
Monrovia, CA 91016 
Phone:
Fax:
E-mail
 
  

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ACNS1721 
Version Date:07/22/2021 
 
Page 8 
 
AGENT 
 
NSC# 
Veliparib (ABT-888) 
737664 
 
Temozolomide 
362856 
 
IND#: 
 
IND Sponsor: DCTD, NCI 
SEE SECTION 15.0 , SECTION 16.0, AND SECTION 17.0 FOR SHIPPING ADDRESSES
  

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ACNS1721 
Version Date:07/22/2021 
 
Page 9 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies.  
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings.  However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances.  For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
 
ABSTRACT 
Recent landmark molecular genetic landscape studies of pediatric high-grade glioma (HGG) have 
established distinct, molecularly defined biological subgroups with striking differences in outcome. 
However, in the past accrual to Children’s Oncology Group (COG) HGG studies was based purely on 
histopathological diagnosis, leading to considerable heterogeneity in regard to molecular features and tumor 
biology. As a result, these cohorts included very high-risk tumors with a dismal outcome, such as K27M 
mutant HGG, as well as favorable risk tumors, such as IDH mutant HGG. 
 
In this study, we will select a subset of pediatric HGG based on molecular features at study entry that may 
be most likely to benefit from the experimental therapy. Outcome of this patient cohort will be compared 
to historical controls with closely matching molecular features.  
 
Eligible patients will be treated with an experimental regimen that includes the Poly (ADP-ribose) 
polymerase (PARP) inhibitor, veliparib, during radiation therapy, followed by veliparib in combination 
with temozolomide. Veliparib has a biological rationale for use in pediatric HGG, and synergistic 
mechanisms of action in combination with either radiation therapy or temozolomide.  
 
This study will test whether the proposed combination therapy will improve event-free survival in patients 
with newly-diagnosed HGG who are wild-type for H3 K27M, IDH, and BRAF (Stratum 1). The study will 
also include patients with IDH mutant glioma on a separate study arm (Stratum 2). Please note Stratum 1 
was closed to accrual on January 24, 2020. Outcome for all patients will be compared to clinically and 
molecularly-matched historical control cohorts. 
 
 
 
  

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ACNS1721 
Version Date:07/22/2021 
 
Page 11 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Objectives 
 
1.1.1 
To determine whether veliparib (ABT-888), when added to radiotherapy (RT) and 
temozolomide, is efficacious for the treatment of patients with newly-diagnosed 
high-grade glioma (HGG) whose tumors’ molecular profile are wild-type for H3 
K27M, BRAF, and IDH1/2. 
 
1.1.2 
To determine whether veliparib (ABT-888), when added to RT and temozolomide, 
is efficacious for the treatment of patients with newly-diagnosed HGG whose 
tumors’ molecular profile are wild-type for H3 K27M and BRAF and harbor an 
IDH1/2 mutation. 
 
1.2 
Exploratory Objectives 
 
1.2.1 
To explore associations of genomic, transcriptomic, and/or epigenetic alterations of 
the tumors with treatment response and outcome. 
 
1.2.2 
To explore the extent to which patients with BRCA1/2 gene alterations and other 
DNA damaged genes display tumor genomic features consistent with homologous 
repair deficiency (HRD), including large scale state transitions (LSTs), mutational 
signature 3, and an enrichment for deletions flanked by sequences of (micro) 
homology. 
 
1.2.3 
To explore the burden of high, moderate, and low penetrant germline alterations in 
HRD genes (such as BRCA1, BRCA2, PALB2, Fanconi complex genes, ATM, 
CHEK2, RAD51B/C/D), mis-match repair genes (such as MLH1, MSH2, MSH6, 
PMS2, EPCAM), and energy metabolism genes (such as SDHA, SDHB, SDHC, 
SDHAF2, SDHD, IDH1, IDH2, and FH). 
 
1.2.4 
To explore constitutional imprinting abnormalities associated with EP300 and IGF2 
in peripheral blood from patients with HGGs. 
 
 
2.0 
BACKGROUND 
2.1 
Introduction/Rationale for Development 
The outcome for pediatric patients with HGG remains poor. Single agent temozolomide 
(TEMO), when administered during and after RT, has been shown to significantly prolong 
progression-free survival (PFS) and overall survival (OS) in adults with glioblastoma 
(GBM); however, similar treatment strategies used in ACNS0126 (RT/TEMO→TEMO)1 
and ACNS0423 (RT/TEMO→TEMO+CCNU)2 did not improve outcome in children with 
HGG when compared to a historical control study (CCG-945), which randomized patients 
to different adjuvant chemotherapy regimens. In the most recent COG HGG trial, 
ACNS0822, two different combined modality experimental arms containing vorinostat or 
bevacizumab were compared to a combined modality arm that included temozolomide. 
  

  
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ACNS1721 
Version Date:07/22/2021 
 
Page 12 
Patients were randomized to receive either vorinostat, bevacizumab, or temozolomide 
during RT, and all patients received bevacizumab and temozolomide during maintenance. 
Based on the recommendation of the DSMC in 2014, ACNS0822 was closed to further 
patient entry and was permanently closed effective April 30, 2014. This recommendation 
was based on review of the available data in 95 patients on the phase 2 study. The data 
indicated that it was unlikely that either of the two experimental radiosensitization arms 
(vorinostat or bevacizumab) would demonstrate a greater one-year EFS when compared 
with the control arm (temozolomide) with the enrollment of the 13 additional randomized 
patients required for reaching the planned interim analysis.3 
 
A number of recent landmark molecular genetic landscape studies of pediatric HGG have 
established distinct, molecularly defined biological subgroups with striking differences in 
outcome.2, 4-8 However, in the past accrual to HGG studies was based purely on 
histopathological diagnosis, leading to considerable heterogeneity in regard to molecular 
features and tumor biology within each study. As a result, upon retrospective analysis it 
was apparent that these cohorts included very high risk tumors with a dismal outcome, such 
as K27M mutant HGG, as well as favorable risk tumors, such as IDH mutant HGG. 
Although EFS and OS were noted to be significantly improved in ACNS0423 compared to 
ACNS0126, with 3-year EFS of 0.22 (95% CI, 0.14-0.30) and 0.11 (95% CI, 0.05-0.18), 
respectively, molecular data from both studies is very limited, with IDH1 mutational status 
available on a subset of patients on ACNS0423 only, but not on ACNS0126. Of note, IDH1 
mutations were observed in 16.3% (7/43) tumors analyzed on ACNS0423,9 which 
represents a relatively high percentage compared to other pediatric HGG series, including 
12.5% (8/64) IDH1 mutant tumors in the subsequent ACNS0822 study. Given the lack of 
molecular data available on ACNS0126 and ANCS0423, it is impossible to discern with 
certainty whether the observed modest difference in outcome between the two sequential, 
nonrandomized studies is related to treatment versus a difference in patient cohorts, i.e., 
proportions of molecular high-risk versus favorable-risk tumors. 
 
In this study, we will establish a new paradigm for “precision medicine” trials for pediatric 
HGG in COG, moving away from testing novel therapies in large, unselected, and 
molecularly heterogeneous pediatric HGG populations. Instead, we will enroll a subset of 
pediatric HGG patients based on molecular features at study entry that may be most likely 
to benefit from the experimental therapy. The outcome of this cohort will be compared to 
a historical control cohort with closely matching molecular features. 
 
Eligibility will be limited to patients with tumors that, based on our current knowledge of 
HGG biology, may be the most likely to benefit from the experimental therapy combining 
a PARP1/2 inhibitor with chemoradiotherapy including temozolomide. We will exclude 
BRAF and H3 K27M mutant tumors from the study since current evidence indicates that 
BRAF mutant gliomas, which are rare in both adults and children, are enriched for 
pleomorphic xanthoastrocytomas (PXAs), secondary HGGs, and glioblastomas (GBMs) 
with a PXA-like molecular signature.4 Molecular targeted agents specific for BRAFV600E 
(and also targeting similar BRAF activating mutations including BRAFV600D/J/M/K/R) are 
FDA-approved, and are currently being explored in ongoing clinical trials in adult as well 
as pediatric gliomas. The PBTC-033 trial, which explored the use of veliparib in 
combination with RT and temozolomide in newly diagnosed DIPG, which are almost 
always K27M, was recently closed following a planned interim analysis due to futility with 
respect to the primary endpoint of improving overall survival. For the proposed study, 
initial central pathology review will include molecular testing to determine H3 K27M, 
IDH, and BRAF mutational status. 
  

  
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All eligible patients will be treated with veliparib during radiotherapy (RT)  
(54–59.4 Gy/30–33 fractions) followed by veliparib in combination with temozolomide 
post-RT. There is a strong biological rationale for the use of veliparib in combination with 
RT and temozolomide in the maintenance phase of pediatric HGG, as preclinical data 
would suggest synergistic mechanisms of actions in combination with RT and 
temozolomide (described in Section 2.2). In contrast to other available PARP inhibitors, 
veliparib crosses the blood-brain-barrier,10 was shown to enhance the efficacy of 
temozolomide and XRT in orthotopic HGG models,11 has available safety date in 
combination with XRT and temozolomide in pediatric patients,12 and has successfully 
moved from phase 2 to phase 3 clinical development in adults with newly-diagnosed 
glioblastoma in the NCI-2015-00616 study. Patients will be enrolled in two strata: Stratum 
1 will test whether the proposed therapy improves EFS in patients with newly-diagnosed 
HGGs that are wild-type for H3 K27M, IDH, and BRAF compared to a clinically and 
molecularly matched historical control cohort. Stratum 2 will be comprised of a cohort of 
patients with IDH mutations, a rare occurrence in pediatric HGGs; their outcome will be 
compared to a separate, clinically and molecularly matched historical control cohort. The 
presence of an IDH mutation is generally mutually exclusive with H3 K27M or BRAF 
mutations, and H3 K27M or BRAF mutant tumors are ineligible regardless of IDH status. 
 
2.1.1 
Closure of Stratum 1 (IDH Wild-Type Cohort) Effective January 24, 2020 
Stratum 1 of ACNS1721, for patients with IDH wild-type HGG, was closed to 
accrual as of January 24, 2020. Closure of this stratum was based on the results of 
a planned interim analysis. The currently available data from the first 22 subjects 
suggested that the hypothesized superior outcome for the ACNS1721 treatment 
compared to the historical controls is unlikely. There were no concerns regarding 
excessive toxicities on this protocol. 
 
2.2 
Preclinical Studies  
Veliparib, a potent oral PARP1/2 inhibitor, enhances the activity of DNA-damaging 
chemotherapeutic agents, including temozolomide. PARP has been identified as a 
therapeutic target in brain tumors, including pediatric HGGs,13, 14 and veliparib in 
combination with temozolomide was studied in a phase 1/2 study of adults with recurrent 
GBM.15 Preclinical data indicates that veliparib crosses the blood-brain-barrier10 and 
enhances the efficacy of temozolomide in a subset of adult HGG, with MGMT promoter 
hypermethylation as a potential biomarker for sensitivity to veliparib.11 In preclinical 
studies conducted by Su et al. at Baylor, veliparib treatment enhanced temozolomide 
cytotoxicity and prolonged animal survival in mouse orthotopic xenograft models of 
pediatric GBM, compared to temozolomide treatment alone. Veliparib preferentially 
accumulated in xenograft tumors versus neighboring normal brain, and the tumor to brain 
veliparib ratio was 8.25 ± 6 fold. At plasma concentrations that have been safely achieved 
in humans, veliparib treatment resulted in more than 90% PARP inhibition in mouse 
orthotopic xenograft tumors. Enhancement of temozolomide efficacy by veliparib was 
observed despite high MGMT activity in the xenograft models (Jack Su, unpublished data). 
Preclinical studies also indicate that veliparib may potentiate the effects of RT in HGG.16 
 
IDH1 mutant gliomas have been noted to have increased radiosensitivity relative to  
IDH1 wild-type gliomas by multiple groups. One group evaluated multiple IDH1 mutant 
cell lines using in vitro (clonogenic survival assays, neutral comet assays, and γ-H2Ax 
assays) and in vivo (mutant, wild-type matched tumor xenograft) experiments and note 
  

  
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substantial differences in the colony surviving fraction, sensitivity to apoptosis, and 
capacity of homologous recombination in IDH1 mutant and wild type tumors. Similar 
phenotypic effects could be perpetuated with the exogenous administration of 
2-hydroxyglutarate (2HG) in IDH wild type cells thus confirming the key role that the 
oncometabolite plays in tumorigenesis and sensitivity to therapy.17  
 
The mechanism of IDH1 mutation driven susceptibility to genotoxic stress has been an 
active area of investigation. While early reports suggested that the impaired catalytic 
activity of IDH1 and resultant alteration in the tolerance to oxidative stress was the primary 
mode of increased radiosensitivity in gliomas, recent findings now indicate that the 
oncometabolite is sufficient to cause altered radiosensitivity via epigenetic 
reprogramming.17 Exogenous administration of 2HG or expression of the IDH1 mutant led 
to the inhibition of specific alpha-ketoglutarate dependent dioxygenases (KDM4A, 
KDM4B) which result in epigenetic reprogramming and decreased homologous 
recombination dependent DNA repair in response to genotoxic stress.18 Furthermore, 
increased radiosensitivity was noted to be dependent on IDH1 activity, as inhibition with 
the inhibitor AGI-5198 led to improved homologous repair and reduced cell kill. Likewise, 
given the suggestion that altered oxidative stress may play a role in radiosensitivity in IDH1 
mutant tumors, the investigators measured NAD+ levels in mutant and wild type cells and 
noted that modulation of nicotinamide phosphoribosyltransferases did not substantially 
alter the homologous recombination repair capacity in IDH1 mutant cells. Other groups 
have gone on to show that the impact of increased radiosensitivity is independent of 
oxygenation status.19 Taken together, these data suggest that the oncometabolite 2HG 
produced by mutant IDH1 leads to increased radiosensitivity via a novel potentially 
exploitable mechanism leaving cancer cells vulnerable to genotoxic stress due to impaired 
homologous recombination capacity. 
 
The decreased activity of homologous recombination repair has been noted to be an 
alternative mechanism by which cells may acquire a BRCA-like phenotype. The acquisition 
of “BRCA-ness” is most commonly due to aberrations in genes participating in and 
regulating homologous recombination (ATM, ATR, BAP1, BRCA1, BRCA2, FANCA, 
CDK12, CHEK2, FANCC, FANCD2, FANCE, FANCF, etc.). PARP inhibition in the 
setting of BRCA-ness has resulted in substantial gains in primarily adult cancers including 
breast,20 ovarian,21, 22 gastric,23 and patients known to be BRCA mutant carriers.21, 24-30 The 
recent observation that the oncometabolite 2HG can facilitate this phenotype has inspired 
investigators to explore alternative therapeutic approaches which capitalize on this 
vulnerability.31 
 
While pediatric tumors infrequently exhibit BRCA mutations, the findings by Sulkowski et 
al. have generated interest in employing synthetic lethality approaches in IDH-mutant 
tumors given that the 2HG oncometabolite can confer BRCA-ness.17 PARP inhibition in 
IDH1 mutant tumors has been shown to result in substantial activity both alone and in 
combination with other means of facilitating genotoxic stress (cisplatin, radiation)32 across 
a range of cancer types. The decrease in double-stranded DNA repair in IDH1 mutant 
gliomas with PARP inhibitor treatment was reversible with inhibitors of the mutant IDH1 
enzyme (AGI-5198) confirming the concerns of Molenaar et al. that the aberrant activity 
of the IDH1 mutant enzyme is crucial to facilitating increased sensitivity to genotoxic 
stress.33 PARP inhibition alone and in combination with other therapy led to increased 
killing in IDH1 mutant cells. These in vitro findings have been extended to both patient 
derived primary glioma cells and a sarcoma flank subcutaneous xenograft model.  
 
  

  
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2.3 
Clinical Studies in Patients with IDH wild-type HGG 
Based on the preclinical data identifying MGMT promoter hypermethylation as a candidate 
biomarker for sensitivity to veliparib,16 an ongoing phase 2/3 clinical trial is evaluating the 
combination of veliparib and temozolomide in adult patients with MGMT promoter 
methylated GBM (NCT02152982). The interim analysis of the phase 2 survival data met 
the criteria to allow the study to re-open to the phase 3 portion of the trial. 
 
While MGMT promoter methylation status has been identified as a strong prognostic factor 
regardless of therapy, as well as a predictive factor for significant survival benefit from 
temozolomide in adult glioblastoma,34 the role of MGMT promoter methylation status as a 
biomarker in pediatric HGG is unclear. No randomized controlled HGG trials comparing 
RT + temozolomide to RT alone have been performed in children; hence, the value of 
MGMT promoter methylation as a predictive biomarker for benefit from temozolomide is 
unproven. While ACNS0126 showed shorter survival in patients with strong MGMT 
expression, no such difference was observed on ACNS0423. Of note, MGMT status on 
both trials was determined using immunohistochemistry, which is unreliable and no longer 
considered an acceptable test to determine MGMT status in glioma.34 Remarkably, data 
from both retrospective4 and prospective (ACNS0822) pediatric HGG studies that 
determined MGMT promoter methylation status using currently acceptable assays,34 reveal 
that after removal of patients with BRAF, K27M, and IDH1 mutant tumors, there is no 
association between MGMT promoter methylation status and progression-free or overall 
survival, as shown in Figures 1 and 2 below. This finding is in striking contrast to adult 
glioblastoma patients, where MGMT promoter methylation status has been validated as a 
highly reproducible prognostic and predictive biomarker across prospective, randomized 
clinical trials using RT and RT + temozolomide.34 Therefore, the utility of MGMT promoter 
methylation status as an independent prognostic biomarker in pediatric HGG is not 
supported by the current data, and its role as a predictive biomarker for benefit from 
temozolomide in this population is unproven as well.  
 
Figure 1. PFS (left panel) and OS (right panel) of 85 patients from the Heidelberg 
cohort4 who were 3 and older, had no disease dissemination and their tumor did 
not harbor K27M, IDH, or BRAF mutation treated with RT + temozolomide 
according to the ACNS0126 protocol. Of these, 27 were MGMT promoter 
hypermethylated and 58 were not, as determined by genome-wide methylation 
profiling. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Figure 2. PFS (left panel) and OS (right panel) of 61 patients from the ACNS0822 
cohort who were 3 and older, had no dissemination, their tumor did not harbor 
K27M, IDH, or BRAF mutation, and whose tumor was tested for MGMT promoter 
methylation by methylation-specific PCR. Of these, 22 were MGMT promoter 
hypermethylated and 39 were not. 
 
The Adult Brain Tumor Consortium (ABTC) conducted a dose finding trial of veliparib 
during daily temozolomide with post-operative RT for glioblastoma. In the study, the 
hematologic toxicity of veliparib when administered with concurrent RT and 
temozolomide was severe enough that accrual was discontinued.35 A subsequent NCI-
sponsored phase 2/3 trial for adult patients with newly diagnosed glioblastoma and MGMT 
promoter hypermethylation (ClinicalTrials.gov Identifier: NCT02152982) has proceeded 
to the phase 3 portion and is currently enrolling patients. The Pediatric Brain Tumor 
Consortium (PBTC) completed two pediatric studies with veliparib: a phase 1 study 
(PBTC-027) for pediatric with recurrent/refractory CNS tumors, and a phase 1/2 study 
(PBTC-033) for newly-diagnosed pediatric patients with diffuse intrinsic pontine gliomas 
(DIPGs). Details regarding these studies are outlined below. 
 
2.4 
Clinical Studies in Patients with IDH-Mutant HGG 
Malignant gliomas with mutations in IDH1 or IDH2 have been associated with better PFS 
and OS compared to wild-type in both pediatric and adult HGG.36, 37 As a result, the WHO 
has gone on to define this group as a distinctive subgroup of glioblastoma and strongly 
recommends evaluating for the most common IDH R132H mutation using 
immunohistochemistry.38 While IDH mutant gliomas can be found in as much as 36% of 
adult gliomas, 23% of HGG in children harbored the IDH1 mutation in a retrospective 
series.39 A secondary analysis of ACNS0423 revealed a total of 16.3% (7/43) of evaluable 
HGG samples to harbor an IDH1 mutation.40 This analysis confirmed that IDH mutations 
are rare (0/23 patients) in children below the age of 14 years, but noted that the incidence 
rises to as much as 36% (7/20 patients) throughout teenage and young adulthood.40 
Compared to IDH wild-type patients, the one year EFS and OS among IDH mutant versus 
wild-type patients on ACNS0423 were significantly more favorable at 86.5% vs. 64.8% 
and 100% vs. 81.6%, respectively.40 Given the relative rarity of IDH mutant in pediatric 
patients, and paucity of data from randomized prospective studies, the optimal treatment 
for these patients remains unclear. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  

  
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2.5 
Pediatric Studies of Veliparib 
The PBTC completed a phase 1 study (PBTC-027) for pediatric patients with 
recurrent/refractory CNS tumors.41 When given concomitantly with veliparib at 25 mg/m2 
BID, the maximum tolerated dose (MTD) of temozolomide was established at 135 mg/m2 
(Days 1–5 per 28-day cycle), with myelosuppression as the dose-limiting toxicity (DLT) 
in this pre-treated patient population. The follow-up study (PBTC-033) explored upfront 
therapy in newly-diagnosed patients with DIPGs in a phase 1/2 design, with veliparib given 
concomitantly with RT, followed by veliparib in combination with temozolomide. The 
MTD of temozolomide when given with veliparib in this study was determined to be the 
same as in PBTC-027, and the study was closed because the primary endpoint of improved 
PFS was not met. 
 
The use of veliparib in combination with radiation therapy, followed by combination 
therapy including temozolomide with veliparib, has not been explored prospectively in 
newly-diagnosed pediatric HGG patients (excluding DIPG).  
 
2.6 
Dosing Rationale 
In the phase 1 PBTC-027 study for pediatric patients with recurrent/refractory CNS 
tumors,41 the MTD of temozolomide was established at 135 mg/m2 (Days 1–5 per 28-day 
cycle) when given concomitantly with veliparib at 25 mg/m2 BID, with myelosuppression 
as the DLT in this pre-treated patient population. The subsequent follow-up study (PBTC-
033) explored upfront therapy in newly-diagnosed patients with DIPGs in a phase 1/2 
design, with veliparib given concomitantly with RT, followed by veliparib in combination 
with temozolomide. The study was closed because the primary endpoint of improved PFS 
was not met in the DIPG patient population. The MTD of temozolomide in combination 
with veliparib in this study was determined to be the same as in PBTC-027, despite an 
attempt to further escalate temozolomide dosing in this newly diagnosed population 
without prior therapy.12 Based on these data, ACNS1721 will use the treatment regimen 
and MTD established in PBTC-033, i.e., oral veliparib 65 mg/m2/dose BID 5 days per week 
(Mon–Fri) concurrent with RT (Chemoradiotherapy), followed by 4 week rest and 
subsequent Maintenance chemotherapy with oral temozolomide 135 mg/m2/dose once 
daily (Days 1–5) and oral veliparib 25 mg/m2/dose BID (Days 1–5, 28 days/cycle). 
Maintenance chemotherapy will continue for up to 10 cycles in the absence of progressive 
disease or unacceptable toxicities. 
 
2.7 
Genomic Analysis of Germline DNA 
Recent studies have shown a significant number of childhood cancer patients harbor 
germline mutations.42-45 Specifically, these studies have reported known pathogenic and 
likely pathogenic mutations. These analyses did not analyze germline mutational burden 
in biologic pathways or correlate somatic mutational signatures. Determining germline 
harbingers of alterations in mis-match repair pathways is important to identify candidates 
for immunotherapy and in DNA damage pathways to identify candidate patients for PARP 
inhibitor therapies.46, 47 
 
Past and current initiatives have deployed various combinations of sequencing modalities 
for the detection of germline and somatic genetic alterations in cancer, including whole 
genome, whole exome, targeted capture, and RNA sequencing assays. In addition to the 
efforts characterizing the repertoire of genetic alterations in cancer, recent studies have 
demonstrated that certain patterns of somatic mutations and structural alterations may be 
  

  
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employed to define the mutational processes that shaped a given cancer genome. In fact, 
large-scale state transitions (LSTs), specific mutational signatures and patterns of structural 
rearrangements, have been shown to be present in cancers harboring BRCA1/2 germline 
mutations. Thus, there is a need to elucidate more precisely the significance of mutations 
in other DNA damage repair genes, when detected in tumors and the germline, moreover, 
whether the impact differs from germ line to somatic, if mono- or bi- allelic alterations of 
these HR-related genes would be sufficient for a phenotype to be caused, and whether their 
biological impact would vary according to tumor type.48 
 
Genomic studies of germline DNA are optional on this trial and will be performed in 
consenting patients only. 
 
2.8 
Genomic, Epigenomic, and/or Transcriptomic Analysis 
Mutational screening for known recurrently mutated oncogenes and tumor suppressors in 
pediatric high-grade glioma, including but not limited to PTEN, TP53, PDGFR, PI3K, 
BRAF, IDH1/2, H3F3A, HIST1H3B, SETD2 and ATRX/DAXX, as well as mutations 
conferring DNA repair defects sensitizing to PARP inhibition including but not limited to 
BRCA1/2, RAD51, ATM, and FANCA1/2, using either targeted sequencing or whole 
exome/genome sequencing or transcriptome analysis will be performed on DNA or RNA 
from tumor tissue. We hypothesize that patients with sensitizing mutations to PARP 
inhibition may have improved outcome compared to those with wild-type tumors. 
 
Depending on tissue availability, we will perform additional genomic (targeted sequencing, 
whole genome sequencing, whole exome sequencing), epigenomic (ChIp-Seq, Whole 
Genome Bisulfide Sequencing, HiC-Technology), and transcriptomic (RNA sequencing) 
investigations to correlate the profile of potential alterations or epigenetic signature with 
therapeutic responses. This may help identify other relevant alterations that could be used 
in the future as molecular signature to evaluate potential responders at study enrollment. 
To this effect, we will use additional genomic, epigenomic, and/or transcriptomic analyses 
to identify methylation class, gene expression, mutations, and gene fusions. Whenever 
possible, germline DNA analysis will be performed in parallel to aid in somatic mutation 
calling and to identify underlying germline tumor predispositions (optional study). We will 
also assess whether mutational profiles/oncogenic drivers can be identified in the plasma. 
To this effect, we will use circulating tumor nucleic acids (ctDNA) extracted from the 
plasma to investigate if the presence of genetic alterations identified in the above described 
analysis can be used as biomarkers. The purpose of these correlative studies will be to 
assess whether plasma from these patients can be used as a surrogate marker of the tumor 
in order to monitor disease progression/regression and/or response to therapy. 
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
3.1 
Pre-Enrollment Eligibility Screening (Step 0) 
Prior to enrollment on a COG treatment study for HGG, patients will be screened to 
determine which of the available treatment studies they may be eligible to enroll on. 
Screening will occur through APEC14B1, The Project:EveryChild Protocol: A 
Registry, Eligibility Screening, Biology, and Outcome Study. An overview of the 
currently available HGG treatment studies is provided in the APEC14B1 Manual of 
Procedures (MOP). Please refer to the APEC14B1 MOP for instructions on accessing 
the HGG Pre-Enrollment Eligibility Screening (Step 0) form. 
  

  
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Patients must be consented and enrolled on APEC14B1, followed by same day 
enrollment on the HGG Pre-Enrollment Eligibility Screening (Step 0) to complete the 
RAPID CENTRAL PATHOLOGY and RAPID CENTRAL MOLECULAR 
REVIEWS. The APEC14B1 consent will cover the Pre-Enrollment Eligibility 
Screening (including pathology and molecular central reviews) for the HGG 
treatment study. See Appendix IV, Section 3.1.1, Section 14.0, and Section 15.0. 
 
Once the HGG Pre-Enrollment Eligibility Screening (Step 0) results are known, all 
eligibility criteria for the appropriate treatment study, including patient consent, must be 
met prior to enrollment on Step 1 of that treatment study. 
 
 
To expedite the central review process, it is strongly recommended that sites 
submit tissue on APEC14B1 and commence the enrollment process as soon as 
diagnosis of HGG is suspected. 
 
 
Pathology slides from the time of diagnosis (see Section 3.1.1.4) must be submitted 
on APEC14B1 to the COG Biopathology Center (BPC) ASAP, preferably within 
13 calendar days of surgery to allow for the HGG Pre-Enrollment Eligibility 
Screening (Step 0) prior to consent and enrollment on Step 1 of the treatment trial. 
Patients must be enrolled on APEC14B1 before slides are shipped to the BPC. 
 
IMPORTANT NOTE: Delay of specimen submission (> 13 calendar days after 
surgery) will significantly delay the central review process and will not guarantee 
central review completion within the 31-day window from surgery to initiation of 
protocol therapy. It is strongly suggested that sites submit required specimens no 
later than 13 days after diagnostic biopsy or surgery to meet the timing 
requirements outlined in Section 3.2.4. 
 
 
Sites will receive notification by e-mail regarding central histopathology 
review results within 7 calendar days of receipt of all required materials at 
the BPC. Results from the central molecular review will be available within 
17 calendar days of receipt of all required materials at the BPC (up to 
30 calendar days total after surgical resection). The final screening eligibility 
determination will be made by one of the Study Pathologists once the 
histopathology and molecular results are available. Notification of patient 
eligibility/ineligibility for Step 1 enrollment on a treatment trial, based on 
histopathologic and molecular phenotyping results, will be sent to the e-mail 
addresses entered by the site during the initial CTSU OPEN HGG pre-enrollment 
screening. The information will also be available in RAVE. (Note: The BPC is not 
responsible for sending the final results to sites). 
 
 
Radiotherapy planning should begin as soon as possible at the local sites in order 
to permit commencement of radiotherapy within 31 calendar days of definitive 
surgery (see Section 17.0). Please see Section 3.3.5 for definition of definitive 
surgery. 
 
3.1.1 
Pre-Enrollment Eligibility Screening Criteria 
The following criteria must be met prior to initiating the HGG Pre-
Enrollment Eligibility Screening (Step 0). 
  

  
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For patients undergoing Rapid Central Molecular Review on APEC14B1, real time 
molecular characterization will occur at the Cincinnati Children’s Hospital and 
Medical Center (CCHMC) in a CAP/CLIA certified laboratory. Specimens will 
have targeted Next-Generation Sequencing (NGS) analysis for determination of 
mutations involving BRAF and IDH1/2.  
 
Results from the molecular screening will be available within 17 calendar days of 
receipt of all required samples at the BPC (up to 30 calendar days total after 
surgical resection). Patients will receive results from the treating physician. 
Results from the molecular review for eligibility/ineligibility will be sent to the 
e-mail addresses that were entered by the site during the initial CTSU OPEN 
HGG Pre-Enrollment Screening. (Note: The BPC is not responsible for sending 
final results to sites.) 
 
3.2 
Study Enrollment 
 
3.2.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In order for an institution to maintain COG membership requirements, every patient 
with a known or suspected neoplasm needs to be offered participation in APEC14B1, 
Project:EveryChild A Registry, Eligibility Screening, Biology and Outcome Study.  
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol.  
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
3.2.2 
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.  
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
 
An active Federal Wide Assurance (FWA) number 
  

  
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 
An active roster affiliation with the Lead Network or a participating 
organization 
 
A valid IRB approval 
 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
 
Active registration status 
 
The IRB number of the site IRB of record listed on their Form FDA 1572 
 
An active status on a participating roster at the registering site. 
 
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 I.  
 
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. For sites using the CIRB, IRB approval information is 
received from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. Other site registration 
requirements 
(i.e., 
laboratory 
certifications, 
protocol-specific 
training 
certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
3.2.3 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the lead 
protocol organization (LPO) or participating organization roster. Registrars must 
hold a minimum of an AP registration type. If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
  

  
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transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval.  If a DTL is required for the study, 
the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
 
All eligibility criteria have been met within the protocol stated timeframes. 
 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
All patients have been consented and enrolled on APEC14B1 followed by 
enrollment on the HGG Pre-Enrollment Eligibility Screening (Step 0) on 
the same day to complete the Rapid Central Review. 
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.2.4 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than five (5) calendar days after the date of study 
enrollment and no later than 31 calendar days after definitive surgery as per Section 
3.3.5. Patients who are started on protocol therapy on a phase 2 study prior 
to study enrollment will be considered ineligible.  
 
3.3 
Patient Eligibility Criteria 
 
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/research 
record which will serve as the source document for verification at the time of audit.  
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than 7 days at the time of enrollment. Laboratory 
tests need not be repeated if therapy starts within 7 days of obtaining labs to assess 
eligibility. If a post-enrollment lab value is outside the limits of eligibility, or 
laboratory values are > 7 days old, then the following laboratory evaluations must be 
re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT), and serum creatinine. If the recheck is outside the limits of 
eligibility, the patient may not receive protocol therapy and will be considered off 
protocol therapy. A pre- and post-operative brain MRI with and without contrast 
with sequences specified in Section 16.2 must be obtained prior to enrollment. The 
requirement for post-operative MRI is waived for patients who undergo biopsy only.  
  

  
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3.3.1 
Age 
Stratum 1 (IDH wild-type): Patients must be ≥ 3 years of age and ≤ 21 years of age 
at the time of enrollment. Please note Stratum 1 was closed to accrual on January 
24, 2020. 
 
Stratum 2 (IDH mutant): Patients must be ≥ 3 years of age and ≤ 25 years of age at 
the time of enrollment. 
 
3.3.2 
Diagnosis  
Patients must have eligibility confirmed by rapid central pathology and central 
molecular screening reviews performed on APEC14B1 (see Section 3.1): 
 
Newly-diagnosed high-grade glioma such as anaplastic astrocytoma or 
glioblastoma. 
 
Negative results for H3 K27M by immunohistochemistry (IHC). 
 
Negative results for BRAFV600 mutation by Next-Generation Sequencing 
(NGS). 
 
3.3.2.1 
Patients must have histological verification of diagnosis. Patients with 
M+ disease (defined as evidence of neuraxis dissemination) are not 
eligible. CSF cytology is not required but may be obtained if clinically 
indicated prior to study enrollment. If cytology is positive, the patient 
would be considered to have metastatic disease and would, therefore, be 
ineligible.  
 
3.3.2.2 
Pre-operative and post-operative brain MRI with and without contrast 
must be obtained. The requirement for a post-operative MRI is waived 
for patients who undergo biopsy only. A spine MRI is not required, but 
may be obtained if clinically indicated. If the spine MRI is positive, the 
patient would be considered to have M+ disease (defined as neuraxis 
dissemination) and would be ineligible. 
  
3.3.3 
Performance Level  
Patients must have a performance status corresponding to ECOG scores of 0, 1, or 
2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years 
of age. See  
https://www.cogmembers.org/site/pages/default.aspx?page=Prot reference mate
rials under Standard Sections for Protocols.  
 
3.3.4 
Organ Function Requirements 
3.3.4.1 
Adequate Bone Marrow Function defined as: 
- 
Peripheral absolute neutrophil count (ANC)  1,000/L 
- 
Platelet count  100,000/L (transfusion independent) 
- 
Hemoglobin ≥ 8.0 gm/dL (can be transfused) 
 
  

  
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3.3.6.4 
Patients with treatment-related AML (t-AML)/MDS or with features 
suggestive of AML/MDS. 
 
3.3.6.5 
Prior allogenic bone marrow transplant or double umbilical cord blood 
transplantation. 
 
3.3.6.6 
Prior Therapy 
Patients must not have received any prior tumor-directed therapy 
including radiation therapy, chemotherapy (tumor-directed therapy), 
molecularly targeted agents, or immunotherapy for the treatment of 
HGG other than surgical intervention and/or corticosteroids. 
 
3.3.6.7 
Lumbar CSF cytology is not required, but may be performed if clinically 
indicated prior to study enrollment. If lumbar CSF cytology is positive, 
the patient is considered to have M+ disease and is ineligible.  
Note: False positive cytology can occur within 10 days of surgery. 
 
3.3.6.8 
Patients with gliomatosis cerebri type 1 or 2.  
 
3.3.6.9 
Patients who are not able to receive protocol specified radiation therapy. 
 
3.3.6.10 Patients must not be currently receiving other anti-cancer agents. 
 
3.3.6.11 Patients with known constitutional mismatch repair deficiency syndrome 
(CMMR-D)/biallelic mismatch repair deficiency (bMMRD). 
 
3.3.6.12 Female patients who are pregnant are ineligible due to risks of fetal and 
teratogenic adverse events as seen in animal/human studies. 
 
3.3.6.13 Lactating females are not eligible unless they have agreed not to 
breastfeed their infants. 
 
3.3.6.14 Female patients of childbearing potential are not eligible unless a 
negative pregnancy test result has been obtained. 
 
3.3.6.15 Sexually active patients of reproductive potential are not eligible unless 
they have agreed to use an effective contraceptive method for the 
duration of their study participation and for 6 months after the last dose 
of protocol-specified chemotherapy. 
 
  

  
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3.3.7 
Regulatory Requirements 
 
3.3.7.1 
All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.3.7.2 
All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
 
4.0 
TREATMENT PROGRAM 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
This study will evaluate the efficacy of the proposed regimen in two molecularly defined 
pediatric newly-diagnosed HGG subgroups. Stratum 1 will enroll patients who are wild-
type with respect to H3 K27M, BRAF, and IDH1/2. Stratum 2 will enroll patients who are 
positive for either IDH1/2 mutation. Please note that patients with H3 K27M or BRAF 
mutations are ineligible for this study. Both strata will receive the same treatment regimen 
as described below. Please note Stratum 1 was closed to accrual on January 24, 2020. 
 
Radiation therapy (RT) will be given in standard fractions (dose 54 to 59.4 Gy) over  
6–7 weeks. During radiation, patients will receive veliparib concurrent with RT 
(Chemoradiotherapy), followed by a 4 week rest period. Four weeks after completion of 
RT, patients will start veliparib and oral temozolomide (Maintenance chemotherapy). 
Maintenance chemotherapy will continue for up to 10 cycles in the absence of progressive 
disease and unacceptable toxicities. 
 
IMPORTANT NOTE: Patients must begin protocol therapy within 31 days of definitive 
surgery. If circumstances require, starting veliparib may be delayed up to 3 days if 
necessary, but veliparib must start no later than Day 34 after surgery and no later than the 
4th day of RT (see Section 3.3.5, Section 4.1.1, and Section 8.2). 
 
 
 
  

  
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4.2.1.2 
Filgrastim (G-CSF) or biosimilar may be used at the treating physician’s 
discretion to enhance neutrophil recovery when clinically indicated (e.g., 
for culture proven bacteremia or invasive fungal infection) or as outlined 
in Section 5.0. Routine use of filgrastim in clinically well patients 
awaiting count recovery is not recommended.  
 
4.2.1.3 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes 
and general supportive care are to be used as necessary. Patients may 
receive daily prophylactic ondansetron or granisetron during the 
Chemoradiotherapy phase (receiving veliparib and radiation) per local 
practice. During Maintenance chemotherapy, patients should receive 
prophylactic ondansetron or granisetron during the 5-day course of 
veliparib and temozolomide, and such treatment may be continued 
beyond the 5-day period, if clinically indicated. Corticosteroids should 
not be used as anti-emetics. The use of additional anti-emetics will be at 
the treating physician’s discretion.  
 
4.2.1.4 
Corticosteroid therapy is permissible consistent with good medical 
management. It is strongly recommended that corticosteroids should 
NOT be used as an antiemetic due to their effect on the blood brain 
barrier. Data on corticosteroid use will be collected at baseline and while 
patients are on therapy. Use of corticosteroids must be documented on 
the appropriate case report forms. 
 
For COG Supportive Care Guidelines see:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines 
  

  
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Chemoradiotherapy 
 
4.3.2 
Required Observations in Chemoradiotherapy  
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below.  
 
a. Physical exam 
b. Height, weight 
c. CBC/diff/platelets 
d. Bilirubin, Creatinine 
e. AST/ALT 
f. Brain MRI (pre- and post-operative. Pre-operative MRI should be performed 
prior to enrollment onto the study.) The requirements for a post-operative 
MRI is waived for patients who undergo biopsy only. 
g. Tumor tissue and blood for correlative biology studies: In consenting 
patients, samples will be collected at baseline for exploratory studies. See 
Section 15.2.2. 
h. Pregnancy test: Female patients of childbearing potential require a negative 
serum or urine pregnancy test within 72 hours prior to starting treatment; 
sexually active patients must use an acceptable method of birth control. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
  

  
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Chemoradiotherapy 
4.3.3 
Chemoradiotherapy Treatment Details 
 
Criteria to start Chemoradiotherapy: 
- 
Absolute neutrophil count (ANC)  1000/µL 
- 
Platelet Count ≥ 100,000/L (transfusion independent) 
 
Veliparib: PO 
Days: Monday–Friday 
Dose: 65 mg/m2/dose BID (Total Daily Dose: 130 mg/m2/day) 
 
Veliparib will be given twice daily, Monday through Friday, throughout the 
duration of RT. Veliparib should be continued until the final day of radiation 
therapy with no breaks, except for Saturday/Sunday, or unless required due to 
toxicity.  
 
Administer veliparib orally without regards to meals.  
 
- 
Veliparib Capsules: Swallow capsules whole; do not chew or break.  
 
- 
Veliparib Oral Solution: Do not mix veliparib oral solution directly in apple 
or grape juice; however, patients can drink apple juice or grape juice after 
the dose. Do NOT drink orange juice, other citrus based juices, or grapefruit 
juice while taking veliparib oral solution. 
 
The first dose of veliparib should be given on the first day of RT, but may be 
delayed by up to 3 days if necessary. Veliparib must start no later than the 4th day 
of RT (Day 34 after surgery). A missed dose should not be made up. Dosing will 
be based on the BSA determined at the beginning of radiation therapy. The 
morning dose of veliparib should ideally be given 60–120 minutes prior to daily 
radiation treatment. For patients who require sedation for radiation treatment and 
are not able to take the oral medication due to local requirements for NPO prior to 
sedation, veliparib may be given nightly, and the daytime dose given shortly after 
the child awakens from sedation, adhering as closely to an every 12-hour schedule 
as possible. However, if local sedation guidelines permit, then the morning 
veliparib dose should be taken 60–120 minutes prior to radiation. Periodic 
adjustments in the timing of twice daily veliparib administration are allowed if 
needed to accommodate patient/family convenience, provided that the daytime 
dose is given as close to 60–120 minutes prior to daily RT whenever possible and 
adherence to an every 12-hour dosing schedule is attempted whenever possible. 
 
For patients taking the oral solution, veliparib doses < 30 mg should be rounded to 
the nearest 1 mg [0.1 mL] (e.g., 11.4 mg to be rounded to 11 mg and 19.5 mg to 
be rounded to 20 mg). For doses between 30 to 100 mg, round oral solution doses 
to the nearest 2 mg [0.2 mL] (e.g., 45.4 mg should be rounded to 46 mg).  
Doses > 100 mg can be rounded to the nearest 10 mg [1 mL].  
 
Doses of the capsule formulation should be rounded to the nearest 10 mg and can 
be divided unevenly if necessary to achieve to a total daily dose (e.g., 60 mg in 
AM and 50 mg in PM). See suggested capsule dosing tables in Appendix VII.  
 
  

  
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Chemoradiotherapy 
Patient veliparib wallet cards are provided in Appendix VI.   
 
Note: Patients are not allowed to take a combination of capsules and the oral 
solution of veliparib for an individual dose. 
 
If emesis occurs within 15 minutes of administration of veliparib, the dose should 
be repeated. A missed dose will not be made up, but the missed dose and reason 
for missing the dose should be recorded in the patient’s record. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following 6-7 weeks of Chemoradiotherapy and a 4-week rest period, patients will 
continue onto Maintenance chemotherapy when criteria to begin Maintenance 
chemotherapy are met, absent disease progression or unacceptable toxicity. 
 
 
  

  
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Maintenance Chemotherapy – Cycle 1 
 
4.4.2 
Required Observations in Maintenance Chemotherapy – Cycle 1 
 
a. Physical exam 
b. Height, weight 
c. Performance status 
d. CBC/diff/platelets: Obtain weekly 
e. Bilirubin, Creatinine. 
f. AST/ALT 
g. Brain MRI 
h. Tumor tissue and blood for correlative biology studies: In consenting 
patients, samples will be collected for exploratory studies. See Section 
15.2.2. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
  

  
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Maintenance Chemotherapy – Cycle 1 
 
4.4.3 
Maintenance Chemotherapy Treatment Details – Cycle 1 
Each cycle of Maintenance chemotherapy lasts 28 days. 
 
Prior to beginning Maintenance chemotherapy, obtain biology samples from 
patients who have provided consent. See Section 15.2 for details of optional 
biology specimen collection. 
 
Criteria to start Cycle 1 of Maintenance chemotherapy: 
- 
ANC  1000/L 
- 
Platelets ≥ 100,000/L (without transfusion within the last 7 days) 
- 
Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2, or serum 
creatinine  1.5 x ULN 
- 
Total bilirubin  1.5 x ULN, ALT < 2.5 x ULN, AST < 2.5 x ULN 
- 
Patient has no evidence of progressive disease (see Section 10.4) as 
assessed clinically and/or by imaging studies 
 
Veliparib: PO 
Days: 1–5 
Dose: 25 mg/m2/dose BID (Total Daily Dose: 50 mg/m2/day) 
 
Veliparib will be given twice daily, and the morning (AM) dose should be given 
60–120 minutes prior to the daily dose of temozolomide. Veliparib and 
temozolomide will be given on Days 1–5. 
 
Alternatively, temozolomide may be given with the PM dose of veliparib, as long 
as: 
1) temozolomide is given around the same time consistently every day 
2) veliparib is administered 60-120 minutes prior to temozolomide to 
optimize the synergistic activity between the two agents. 
 
Administer veliparib orally without regards to meals.  
 
- 
Veliparib Oral Solution: Do not mix veliparib oral solution directly in 
apple/grape juice; however, patients can drink apple juice or grape juice 
after the dose. Do NOT drink orange juice, other citrus based juices, or 
grapefruit juice while taking veliparib oral solution (Days 1–5).  
 
- 
Veliparib Capsules: Swallow capsules whole; do not chew or break.  
 
For patients taking the oral solution, veliparib doses < 30 mg should be rounded to 
the nearest 1 mg [0.1 mL] (e.g., 11.4 mg to be rounded to 11 mg and 19.5 mg to 
be rounded to 20 mg). For doses between 30 to 100 mg, round oral solution doses 
to the nearest 2 mg [0.2 mL] (e.g., 45.4 mg should be rounded to 46 mg).  
 
Doses of capsule formulation should be rounded to the nearest 10 mg and can be 
divided unevenly if necessary to achieve a total daily dose (e.g., 30 mg in AM and 
20 mg in PM). See suggested capsule dosing tables in Appendix VII.  
 
Patient veliparib wallet cards are provided in the Appendix VI. 
  

  
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Maintenance Chemotherapy – Cycle 1 
 
Note: Patients are not allowed to take a combination of capsules and the oral 
solution of veliparib for an individual dose. 
 
If emesis occurs within 15 minutes of administration of veliparib, the dose should 
be repeated once. A missed dose will not be made up, but the missed dose and 
reason for missing the dose should be recorded in the patient’s record. 
 
Temozolomide: PO 
Days: 1–5 
Dose: 135 mg/m2/dose once daily 
 
Temozolomide should be administered 60-120 minutes after the veliparib dose and 
should be given consistently around the same time every day. 
 
Note: Temozolomide doses should be rounded to the nearest 5 mg capsule size 
(see Appendix VIII for suggested capsule formulation dosing tables). For patients 
unable to swallow capsules, the capsules can be opened and mixed with apple sauce 
or apple juice, which should be used immediately after mixing (preferred) or must 
be used in 2 hours after mixing (see Section 6.2 and Appendix V). 
 
If emesis occurs within 15 minutes of taking a dose of temozolomide, then the dose 
may be repeated once. If emesis occurs after 15 minutes, the dose should not be 
repeated. Instructions for administration of oral temozolomide to young children 
are included in Appendix V.  
 
Disease evaluations should occur prior to every odd number of Maintenance cycle 
(see Section 4.5.2) for details).  
 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following completion of Cycle 1 of Maintenance chemotherapy, subsequent 
cycles will start on Day 29 or when criteria to begin the next cycle are met, 
whichever occurs later, absent disease progression or unacceptable toxicity. 
 
 
  

  
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Maintenance Chemotherapy – Cycles 2–10 
 
4.5.2 
Required Observations in Maintenance Chemotherapy – Cycles 2–10 
 
a. Physical exam 
b. Height, weight 
c. Performance status: Prior to each odd-numbered cycle of Maintenance 
chemotherapy (e.g., Cycle 1, Cycle 3, Cycle 5, etc.) 
d. CBC/diff/platelets: Obtain weekly 
e. Bilirubin, Creatinine 
f. AST/ALT 
g. Brain MRI: Prior to each odd-numbered cycle of Maintenance chemotherapy 
(e.g., Cycle 3, Cycle 5, etc.) 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
  

  
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Maintenance Chemotherapy – Cycles 2–10 
4.5.3 
Maintenance Chemotherapy Treatment Details – Cycles 2–10 
Each cycle of Maintenance chemotherapy lasts 28 days.  
 
Criteria to start Cycle 2 and subsequent cycles: 
- 
Absolute neutrophil count (ANC)  750/µL 
- 
Platelet Count ≥ 75,000/L (without transfusion within the last 7 days) 
- 
Serum creatinine  1.5 x ULN 
- 
Total bilirubin  1.5 x ULN, ALT < 2.5 x ULN, AST < 2.5 x ULN 
- 
The patient has no evidence of progressive disease (see Section 10.4) as 
assessed clinically and/or by imaging studies. 
 
Disease evaluations should occur prior to every odd number of Maintenance cycle 
(see Section 4.5.2) for details).  
 
Veliparib: PO 
Days: 1–5 
Dose: 25 mg/m2/dose BID (Total Daily Dose: 50 mg/m2/day) 
 
Veliparib will be given twice daily, and the morning (AM) dose should be given 
60–120 minutes prior to the daily dose of temozolomide. Veliparib and 
temozolomide will be given on Days 1–5. 
 
Alternatively, temozolomide may be given with the PM dose of veliparib, as long 
as: 
1) temozolomide is given around the same time consistently every day 
2) veliparib is administered 60–120 minutes prior to temozolomide to 
optimize the synergistic activity between the two agents. 
 
Administer veliparib orally without regards to meals.  
 
- 
Veliparib Oral Solution: Do not mix veliparib oral solution directly in apple 
or grape juice; however, patients can drink apple juice or grape juice after 
the dose. Do NOT drink orange juice, other citrus based juices, or grapefruit 
juice while taking veliparib oral solution (Days 1-5 of each cycle).  
 
- 
Veliparib Capsules: Swallow capsules whole; do not chew or break.  
 
For patients taking the oral solution, veliparib doses < 30 mg should be rounded to 
the nearest 1 mg [0.1 mL] (e.g., 11.4 mg to be rounded to 11 mg and 19.5 mg to 
be rounded to 20 mg). For doses between 30 to 100 mg, round oral solution doses 
to the nearest 2 mg [0.2 mL] (e.g., 45.4 mg should be rounded to 46 mg).  
 
Doses of capsule formulation should be rounded to the nearest 10 mg and can be 
divided unevenly if necessary to achieve a total daily dose (e.g., 30 mg in AM and 
20 mg in PM). See suggested capsule dosing tables in Appendix VII.  
 
Patient veliparib wallet cards are provided in the Appendix VI. 
 
Note: Patients are not allowed to take a combination of capsules and the oral 
solution of veliparib for an individual dose. 
  

  
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Maintenance Chemotherapy – Cycles 2–10 
 
If emesis occurs within 15 minutes of administration of veliparib, the dose should 
be repeated once. A missed dose will not be made up, but the missed dose and 
reason for missing the dose should be recorded in the patient’s record. 
 
Temozolomide: PO 
Days: 1–5 
Dose: 135 mg/m2/dose once daily 
 
Temozolomide should be administered 60-120 minutes after the veliparib dose and 
should be given consistently around the same time every day. 
 
Note: Temozolomide doses should be rounded to the nearest 5 mg capsule size 
(see Appendix VIII for suggested capsule formation dosing tables). For patients 
unable to swallow capsules, the capsules can be opened and mixed with apple sauce 
or juice, which should be used immediately after mixing (preferred) or must be used 
in 2 hours after mixing (see Section 6.2 and Appendix V). 
 
If emesis occurs within 15 minutes of taking a dose of temozolomide, then the dose 
may be repeated once. If emesis occurs after 15 minutes, the dose should not be 
repeated. Instructions for administration of oral temozolomide to young children 
are included in Appendix V.  
 
See Section 5.0 for Dose Modifications based on Toxicities. 
 
Following completion of this cycle of Maintenance chemotherapy, subsequent 
cycles will start on Day 29 or when criteria to begin the next cycle are met, 
whichever occurs later, absent disease progression or unacceptable toxicity. 
Patients may continue for up to 10 cycles.
  

  
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Page 45 
independent). If platelet count is < 75,000/µL after 
withholding veliparib for > 14 days, veliparib during 
Chemoradiotherapy should be discontinued and 
restarted at the time of Maintenance chemotherapy at 
the starting dose level for Maintenance chemotherapy 
(Table 2). 
 
For patients on Dose Level -2: Veliparib during 
Chemoradiotherapy should be discontinued and 
restarted at the time of Maintenance chemotherapy at 
the starting dose level for Maintenance chemotherapy 
(Table 2). 
 
5.2.1.2.2 
If a patient experiences dose-modifying neutropenia 
(ANC < 500/µL): 
Hold veliparib. Obtain twice weekly CBC until ANC  
> 750/µL. Patients may receive filgrastim (G-CSF) or 
biosimilar support at the discretion of the treating physician. 
If G-CSF is utilized, ANC determination for restart of 
veliparib must be after > 48 hours without G-CSF support.  
 
For patients on Dose Level 1 or Dose Level -1: Veliparib 
should be restarted at one dose level lower (Table 1) once 
ANC recovers to ≥ 750/µL. If ANC < 500/µL after 
withholding veliparib for > 14 days, veliparib during 
Chemoradiotherapy should be discontinued and restarted 
at the time of Maintenance chemotherapy at the starting 
dose level for Maintenance chemotherapy (Table 2). 
 
For patients on Dose Level -2: Veliparib during 
Chemoradiotherapy should be discontinued and restarted 
at the time of Maintenance chemotherapy at the starting 
dose level for Maintenance chemotherapy (Table 2). 
 
5.2.2 
Non-Hematological Toxicities 
5.2.2.1 
Definition of Dose-Modifying Toxicity (DMT) 
 
Any Grade 4 non-hematologic toxicity that is at least possibly 
related to veliparib. 
 
Any Grade 3 non-hematologic toxicity that is at least possibly 
related to veliparib, and is considered medically significant or 
sufficiently intolerable by patients requiring treatment interruption, 
with the exception of: 
- 
Grade 3 nausea and vomiting of < 7 days 
- 
Grade 3 elevation of transaminases that returns to levels 
meeting eligibility criteria within 7 days of study drug 
interruption and does not recur upon restarting drug  
- 
Grade 3 fever or infection of < 5 days in duration 
- 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to supplementation 
 
 
 

  
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5.2.2.2 
Dose Modifications for Non-Hematological Toxicities 
Note: Radiation therapy should not be interrupted unless clinically 
indicated. 
 
If any dose-modifying non-hematological toxicity as defined in Section 
5.2.2.1 occurs that is at least possibly related to veliparib, hold veliparib. 
Restart veliparib at one dose level lower (Table 1) if the toxicity resolves 
to meet eligibility criteria (see Section 3.3.4) within 14 days. If the 
toxicity does resolve to meet eligibility criteria within 14 days, or if the 
patient is already on Dose Level -2, veliparib should be discontinued for 
the remainder of Chemoradiotherapy, but should be restarted at 
maintenance chemotherapy at the starting dose level for Maintenance 
chemotherapy (Table 2). 
 
5.2.3 
Veliparib-Related Toxicities Leading to Interruption of Radiation Therapy 
5.2.3.1 
Definition of Dose-Modifying Toxicity (DMT) 
Any toxicity that is at least possibly related to veliparib that results in 
significant delay/interruption of > 2 weeks in the completion of RT. 
 
5.2.3.2 
Dose Modification for Veliparib-Related Toxicities that Lead to 
Interruption of Radiation Therapy 
Veliparib 
should 
be 
discontinued 
for 
the 
remainder 
of 
Chemoradiotherapy, 
but 
should 
be 
restarted 
at 
Maintenance 
chemotherapy at the starting dose level for Maintenance chemotherapy 
(Table 2). 
 
5.3 
Dose Modifications for Veliparib and Temozolomide during Maintenance 
Chemotherapy 
 
5.3.1 
Hematological Toxicities 
Dose modifying toxicities will be defined as any of the following events that are 
at least possibly attributable to veliparib or temozolomide.  
 
5.3.1.1 
Definition of Dose-Modifying Toxicity 
 
Platelets < 50,000/µL (thrombocytopenia ≥ Grade 3) requiring 
transfusions on ≥ 2 separate days in a 7-day period 
 
Platelets < 25,000/µL (thrombocytopenia Grade 4) 
 
ANC < 500/µL (neutropenia Grade 4) for > 7 days 
 
A delay of > 14 days in starting subsequent cycles of Maintenance 
due to ANC < 750/µL and/or platelet count < 75,000/µL 
 
5.3.1.2 
Dose Modifications for Hematologic Toxicities 
 
5.3.1.2.1 
If 
a 
patient 
experiences 
dose-modifying 
thrombocytopenia (platelets < 50,000/µL requiring 
 
 

  
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transfusions on ≥ 2 separate days in a 7-day period OR 
platelets < 25,000/µL OR delay of > 14 days in starting 
subsequent cycles of Maintenance chemotherapy due to 
platelet counts < 75,000/µL): 
Hold veliparib and temozolomide. Obtain twice weekly 
CBC until platelets ≥ 75,000/µL. Platelet transfusion is 
permissible and strongly encouraged for patients with 
platelets < 50,000/µL to minimize the risk of intra-tumoral 
hemorrhage.  
 
Patients on Dose Level 1 should receive subsequent 
cycles at Dose Level -1 (Table 2).  
 
Patients on Dose Level -1 should be removed from 
protocol therapy. 
 
Refer to Section 5.4 (Management of Prolonged 
Hematological Toxicities while on Study Treatment) 
for additional guidelines. 
 
5.3.1.2.2 
If patient experiences dose-modifying neutropenia 
(ANC < 500/µL for > 7 days or delay of > 14 days in 
starting 
subsequent 
cycles 
of 
Maintenance 
chemotherapy due to ANC < 750/µL): 
Hold veliparib and temozolomide. Obtain CBC twice 
weekly until ANC > 750/µL. 
 
Patients should have therapy restarted at the same dose 
level in the next cycle with myeloid growth factor 
support. If G-CSF is given, it can be started 24 hours 
after the lase dose of chemotherapy and continue until 
the post-nadir ANC is ≥ 2,000/µL. ANC determination 
for restart of veliparib must be after > 48 hours without 
G-CSF support. 
 
Patients on Dose Level 1 who experience recurrent 
dose-modifying neutropenia after myeloid growth 
factor is added should have subsequent cycles of 
treatment dose reduced to Dose Level -1 and receive 
myeloid growth factor. 
 
Patients on Dose Level -1 who experience dose-
modifying neutropenia after addition of myeloid growth 
factor must be removed from protocol therapy. 
 
Refer to Section 5.4 (Management of Prolonged 
Hematological Toxicities while on Study Treatment) 
for additional guidelines. 
 
5.3.1.2.3 Patients who experience a hematological toxicity that does 
not resolve to meet parameters to start subsequent cycles of 
therapy (ANC ≥ 750/µL and platelets ≥ 75,000/µL, 
transfusion independent) within 21 days after the planned 
start of the next treatment cycle (i.e., by Day 49) must be 
removed from protocol therapy. Refer to Section 5.4 
(Management of Prolonged Hematological Toxicities while 
on Study Treatment) for additional guidelines. 
 
 

  
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5.3.2 
Non-Hematological Toxicities 
5.3.2.1 
Definition of Dose-Modifying Toxicity 
 
Any Grade 4 non-hematologic toxicity that is at least possibly 
related to veliparib and/or temozolomide. 
 
Grade 3 non-hematologic toxicity that is at least possibly related to 
veliparib and/or temozolomide, and is considered medically 
significant or sufficiently intolerable by patients requiring 
treatment interruption, with the exception of: 
- 
Grade 3 nausea and vomiting of < 5 days 
- 
Grade 3 elevation of transaminases that returns to levels 
meeting eligibility criteria within 7 days of study drug 
interruption and does not recur upon restarting drug  
- 
Grade 3 fever or infection of < 5 days in duration 
- 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to oral supplementation 
 
Any non-hematological toxicity that causes a delay of ≥ 14 days 
between treatment cycles. 
 
5.3.2.2 
Dose Modifications for Non-Hematological Toxicities 
For dose-modifying non-hematologic toxicities listed above that occur 
during Maintenance chemotherapy, veliparib and temozolomide will be 
withheld until the toxicity resolves to meet on eligibility criteria (see 
Section 3.3.4), and the patient will restart veliparib and temozolomide at 
Dose Level -1 (Table 2). Protocol therapy will be discontinued if a non-
hematologic dose modifying toxicity occurs at Dose Level -1. 
 
Patients who experience a dose-modifying non-hematological toxicity 
that does not resolve to meet eligibility or baseline parameters within 
21 days after the planned start of the next treatment cycle (i.e., by 
Day 49) must be removed from protocol therapy. 
 
5.4 
Management of Prolonged Hematological Toxicities while on Study Treatment 
To date, four cases of Grade 4 myelodysplastic syndrome (MDS) and two cases of 
leukemia secondary to oncology therapy (one Grade 4 and one Grade 5) were observed on 
CTEP-sponsored studies utilizing veliparib. It is possible veliparib contributed to these 
adverse events; it is also possible that prior therapy with platinum or alkylating agents 
contributed to the development of MDS or leukemia. If a patient develops prolonged 
hematological toxicity that requires removal from protocol therapy and/or other signs or 
symptoms suggestive of MDS/leukemia, the patient should be further evaluated including 
a bone marrow aspirate with cytogenetics. Protocol therapy should be held and 
discontinued if AML/MDS is documented, and the patient should be managed 
appropriately. 
 
 
 
 

  
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6.0 
DRUG INFORMATION  
6.1 
Veliparib  
(ABT-888, A-861695.0) NSC# 737664,
)  
 
(07/18/18) 
 
 
Source and Pharmacology:  
Veliparib inhibits the formation of poly (ADP-ribose) (PAR) polymers in vitro and in vivo.  
PAR polymerase (PARP) is a nuclear enzyme that recognizes DNA damage and facilitates 
DNA repair. PARP inhibition should enhance the effects of DNA-damaging agents on 
tumor cells defective in DNA damage repair. In a variety of nonclinical tumor models, 
including melanoma, breast, prostate, colon, and glioma, veliparib significantly enhanced 
the antitumor activity when dosed on a schedule that overlapped the administration of a 
DNA-damaging agent. Veliparib increases antitumor efficacy when added to DNA-
damaging therapies such as temozolomide, cisplatin, carboplatin, cyclophosphamide, 
irinotecan, or radiation therapy. 
 
Higher expression of PARP in cancer cells compared to normal cells has been linked to 
drug resistance and the overall ability of cancer cells to sustain genotoxic stress. Therefore, 
PARP inhibitors are proposed as sensitizing agents for a variety of DNA-damaging agents.  
 
Pharmacokinetics (PK): 
In adults, the exposure of veliparib is approximately dose-proportional over 10 through 
500 mg twice daily (BID) dose range. The absorption of veliparib after oral dosing is 
relatively fast where veliparib plasma concentrations peak at approximately 1 to 2 hours 
after dosing across dose levels. The terminal half-life (t1/2) of veliparib in adults is about 
6 hours, with minimal accumulation following multiple BID dosing. Food does not have a 
significant effect on veliparib bioavailability. The administration of a high-fat meal had no 
significant effect on area under the plasma concentration-time curve (AUC) and only 
caused a slight decrease in veliparib maximum observed plasma concentration (Cmax) 
(17%) and a delay of approximately 1 hour in time to maximum observed plasma 
concentration (Tmax). The mean urinary recovery of unchanged veliparib was 73% and the 
total urinary recovery of veliparib (as parent compound and M8 metabolite) was 90%, 
which indicates that renal excretion is a major pathway in veliparib elimination. Mild to 
moderately severe hepatic dysfunction had no significant effect on veliparib PK. However, 
there was a trend of increase in veliparib AUC in subjects with moderate and severe renal 
dysfunction.  
 
In children with recurrent CNS tumors receiving veliparib in combination with 
temozolomide,41 1st PK analysis showed that drug exposure was suboptimal at veliparib 
15 mg/m2/dose BID compared with adults receiving veliparib at 40 mg BID. The second 
PK analysis included 7 patients who received veliparib at 20 mg/m2/dose BID and 3 
patients who received veliparib at 25 mg/m2/dose BID. While veliparib exposure at 20 
mg/m2/dose BID was still suboptimal, the 3 patients who received 25 mg/m2/dose BID 
showed a mean AUC0−12 h of 2 ± 0.64 µg•h/mL and day 4 Cmax of 372 ± 148 ng/mL, which 
achieves 
similar 
exposure 
observed 
in 
adults 
and 
predicted 
to 
maximize 
chemopotentiation. 
 
Potential Drug Interactions:  
Nonclinical studies suggest veliparib is a substrate of P-glycoprotein (P-gp), OCT2, and 
MATE1/MATE2K transporters. Co-administration of veliparib with strong inhibitors of  
 
 

  
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P-gp, OCT2, and MATE1/MATE2K drugs may result in a decrease of veliparib renal 
clearance and an increase in veliparib plasma concentration. Therefore, use caution when 
administering veliparib with strong inhibitors of P-gp, OCT2, and MATE1/MATE2K 
drugs. At high dose (e.g., 400 mg BID), veliparib may inhibit OCT1 in the liver and 
MATE1/MATE2K in the kidney.  
 
Veliparib is NOT a potent inhibitor of the major human CYPs and does not significantly 
induce activities of major human CYP isoforms, suggesting a negligible potential for CYP-
mediated drug-drug interactions as a perpetrator at the anticipated therapeutic 
concentrations. 
 
In humans, veliparib clears primarily in the urine as intact parent drug along with 
metabolites suggesting that renal function plays an important role in the drug clearance and 
its metabolites. Drug-associated with kidney toxicities or kidney diseases could change 
veliparib pharmacokinetics. Use caution when concomitantly administering veliparib with 
other nephrotoxic agents (e.g., platinum agents, aminoglycosides, etc.) or in patients with 
pre-existing renal impairment.  
 
Potential drug-drug interactions (DDI) with veliparib are being evaluated in combination 
studies. There was no significant PK interaction between veliparib and temozolomide, 
carboplatin/paclitaxel, folinic acid/fluorouracil/irinotecan (FOLFIRI), and capecitabine/5-
fluorouracil. Preliminary results also indicate the absence of a DDI between veliparib and 
carboplatin/gemcitabine or carboplatin/etoposide.  
 
Patient Care Implications:  
Patients may feel fatigue or tiredness. Loss of appetite and losing weight are common.  
Provide appropriate supportive care for diarrhea.   
 
Based on veliparib mechanism of action and preclinical studies, teratogenicity is a potential 
risk for this agent. Patients (male and female) of childbearing potential must agree to use 
adequate birth control during study participation and 4 months after completion of veliparib 
administration. It is not known whether veliparib is excreted in human milk. Veliparib 
should not be administered to lactating patients. 
 
Toxicity: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Veliparib (ABT-888, NSC 737664) 
 
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.pd
 
 

  
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MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; 
Arthritis; Back pain; Bone pain; Generalized muscle weakness; Muscle cramp; Myalgia; 
Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) -Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of 
consciousness; Dysarthria; Extrapyramidal disorder; Intracranial hemorrhage; Lethargy; 
Memory impairment; Movements involuntary; Paresthesia; Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Presyncope; Reversible posterior leukoencephalopathy 
syndrome; Stroke; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; 
Psychiatric disorders - Other (emotional instability); Psychosis; Restlessness 
RENAL AND URINARY DISORDERS - Dysuria; Hematuria; Proteinuria  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; 
Dyspnea; Epistaxis; Hypoxia; Nasal congestion; Pharyngolaryngeal pain; Pleural effusion; 
Pneumonitis; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis; Nail changes; Palmar-plantar erythrodysesthesia syndrome; Pruritus; 
Purpura; Rash acneiform 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; 
Vascular disorders - Other (brainstem infarction)  
 
Note: Veliparib (ABT-888) 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: 
Capsules: Veliparib capsules are available in 10 mg, 20 mg, 40 mg, 50 mg, and 100 mg 
immediate release capsules. The inactive ingredients are microcrystaline cellulose, 
colloidal silicon dioxide, magnesium stearate, gelatin, sodium lauryl sulfate, and titanium 
dioxide. It may contain FD&C blue#1, FD&C yellow #6, or FD&C yellow #5. The 
capsules are packaged in HDPE bottles, and each HDPE bottle contains 16 capsules or 
64  capsules. 
 
Veliparib capsules may be repackaged from the supplied HDPE bottles into amber (or other 
low-actinic) child resistant pharmacy dispensing bottles.  Expiration will be 30 days from 
the repackaging date (or the original retest date, whichever is earlier) when stored at 15°C 
to 25°C (59°F to 77°F).  
 
Oral solution: Veliparib oral solution is supplied as a 10 mg/mL colorless solution in  
100 mL amber glass bottle. The inactive ingredients of the Oral Solution are: Sodium 
citrate tribasic, Citric Acid, Sodium Benzoate, Xylitol, Sodium Hydroxide. Oral solution 
must be dispensed in the original bottle. Veliparib oral solution bottles must be stored 
upright. 
 
Storage:   
Capsules: Store the original bottle at 15° to 25° C (59° to 77° F).  
 
Oral Solution: Store intact bottles at controlled room temperature between 15°– 25°C (59°F 
to 77°F); protect from freezing. 
 
 

  
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Stability:   
Capsules: Shelf-life stability studies for veliparib capsules are on-going.  
 
Oral Solution: Shelf-life stability studies for veliparib Oral Solution (intact bottles) will 
have a firm expiration date. Once the intact bottle is opened, the solution is stable up to  
30 days at 25°C. Stability of the solution administered in Baxa, Union Plastic or Neo-med 
oral syringes is up to 4 hours at 25°C. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. Administer veliparib orally without regard to meals. Do not make up for missed 
doses. Veliparib can be re-dosed if vomited within 15 minutes of administration.  
 
Capsules:  Swallow whole; do not chew or break. 
 
Oral Solution:  Do not mix veliparib solution directly in juice. Patients can drink apple juice 
or grape juice after the dose. Do NOT drink orange juice, other citrus-based juices, or 
grapefruit juice on the days that veliparib oral solution is administered.  
 
Supplier:   
Veliparib is supplied by AbbVie and distributed by the Division of Cancer Treatment and 
Diagnosis (DCTD), NCI.  
 
Obtaining the Agent 
 
Agent Ordering: 
NCI supplied agent may be requested by the eligible participating investigator (or their 
authorized designee) at each participating institution. The CTEP assigned protocol number 
must be used for ordering all CTEP supplied investigational agents. The responsible 
investigator at each participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA form 1572 (Statement of Investigator), NIH Biosketch, 
Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several 
participating investigators at one institution, CTEP supplied investigational agents for the 
study should be ordered under the name of one lead participating investigator at that 
institution. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status, and a “current” password, 
and active person registration status.  For questions about drug orders, transfers, returns, or 
accountability, call or email PMB any time.  Refer to the PMB’s website for specific policies 
and guidelines related to agent management.   
 
Agent Accountability 
 
Agent Inventory Records: 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page. Store and maintain separate NCI 
 
 

  
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Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
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 an active person registration status. 
Questions about IB access may be directed to the PMB IB coordinator via email. 
 
Useful Links and Contacts 
 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm  
 
PMB Online Agent Order Processing (OAOP) application: 
https://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 
 
IB Coordinator: IBCoordinator@mail.nih.gov  
 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 
6.2 
TEMOZOLOMIDE     
(Temodar, Temodal) NSC #362856   
 
 
 
(05/28/20) 
 
 
Source and Pharmacology: 
An orally or intravenously administered alkylating agent, a second generation 
imidazotetrazine. A prodrug of MTIC, temozolomide spontaneously decomposes to MTIC 
at physiologic pH. The cytotoxic effects of MTIC are manifested through alkylation 
(methylation) of DNA at the O6, N7 guanine positions which lead to DNA double strand 
breaks and apoptosis. Temozolomide is noncell cycle specific. 
 
Temozolomide is rapidly and completely absorbed after oral administration with a peak 
plasma concentration (Cmax) achieved in a median Tmax of 1 hour. Food reduces the rate and 
extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased 
by 32% and 9%, respectively, and median Tmax increased by 2-fold (from 1-2.25 hours) 
when temozolomide was administered after a modified high-fat breakfast. A 
pharmacokinetic study comparing oral and intravenous temozolomide in patients with 
primary CNS malignancies showed that at 150 mg/m2 dose temozolomide IV and oral 
capsules are bioequivalent with respect to both Cmax and AUC of temozolomide and MTIC. 
Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). It is 
weakly bound to human plasma proteins; the mean percent bound of drug-related total 
radioactivity is 15%. Temozolomide is spontaneously hydrolyzed at physiologic pH to the 
active species, MTIC and to temozolomide acid metabolite. Cytochrome P450 enzymes 
play only a minor role in the metabolism of temozolomide and MTIC. About 38% of the 
administered temozolomide total radioactive dose is recovered in the urine. Overall 
 
 

  
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Only dispense what is needed for the course, and clearly indicate how many days of dosing 
the patient will have and how many days are without temozolomide dosing. When 
counseling patients, it is important for each patient/parent to understand the number of 
capsules per day and the number of days that they take temozolomide. It is also important 
for the patient/parent to understand the number of days that they will be off the medication.  
 
Each strength of temozolomide must be dispensed in a separate vial or in its original 
container (e.g., bottle or sachet). Based on the dose prescribed, determine the number of 
each strength of temozolomide capsules needed for the full course as prescribed by the 
physician. For example, 275 mg/day for 5 days would be dispensed as five 250 mg 
capsules, five 20 mg capsules, and five 5 mg capsules. Label each container with the 
appropriate number of capsules to be taken each day. Dispense to the patient/parent, 
making sure each container lists the strength (mg) per capsule and that he or she 
understands to take the appropriate number of capsules of temozolomide from each bottle 
or vial to equal the total daily dose prescribed by the physician. Institutions that have the 
capability to dispense temozolomide as daily doses in a blister pack may do so, taking 
specific precautions to ensure that the appropriate dose is provided and that the patient is 
educated to understand the daily dosing regimen. 
 
For children unable to swallow the capsules whole, the oral capsules may be formulated into 
a suspension. To prepare a 10 mg/mL suspension triturate the contents of ten 100 mg capsules 
(1000 mg), 500 mg povidone K-30 and 25 mg anhydrous citric acid dissolved in 1.5 mL 
purified water in a glass mortar to form a uniform paste. To the paste add 50 mL of Ora-
Plus® by adding a small amount, mixing, and then adding the balance. Transfer to a glass 
graduated cylinder. Add Ora-Sweet® or Ora-Sweet® SF to a total volume of 100 mL by 
rinsing the mortar with small amounts of the syrup (Ora-Sweet® or Ora-Sweet® SF). Rinse 
at least four times. Package in an amber plastic prescription bottle. The packaged suspension 
should be stored in the refrigerator at 28°C (3646°F) for no more than 2 weeks after 
preparation. The suspension should be shaken well before each use. Procedures for proper 
handling and disposal of cytotoxic drugs should be used when preparing the suspension.50 
 
Extemporaneous temozolomide 10 mg/mL suspension can also be prepared using 100 mg 
temozolomide capsules mixed in Ora-Mix SF®. Open contents of the required number of 100 
mg temozolomide capsules into a mortar and add Ora-Mix SF® until a paste forms. Add more 
vehicle until a liquid is formed (for each 100 mg capsule add 10 mL of Ora-Mix SF®). 
Transfer desired volume to a glass or polyethylene terephthalate bottle. Label the container, 
assigning a beyond-use-date of 30 days, for storage under refrigeration only.51 
 
Alternatively, the capsules can be opened and mixed with apple sauce or juice, which should 
be used immediately after mixing or must be used in 2 hours after mixing (refer to Appendix 
V in the protocol). 
 
Supplier: 
Commercially available. See package insert for further information. 
 
 
 
 

  
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) Relapse or progressive disease (see Section 10.4). 
b) Refusal of further protocol therapy by patient/parent/guardian. 
c) Completion of planned therapy. 
d) Physician determines it is in patient’s best interest. 
e) Unacceptable toxicity due to protocol therapy (see Section 5.0). 
f) Development of a second malignancy, including bone marrow findings consistent with 
acute myeloid leukemia (AML)/MDS. Note: Patients who develop MDS/AML on 
treatment should discontinue protocol therapy and be managed appropriately. 
g) Patient becomes pregnant. 
h) Patient starts breastfeeding. 
i) Repeat eligibility studies (if required) are outside the parameters required for eligibility 
(see Section 3.3). 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Follow-up data will be required unless patient is taken off study. 
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient did not start radiation treatment within 31 days of definitive surgery (see Section 
3.3.5). 
d) Patient did not start veliparib treatment within 34 days of definitive surgery (see Section 
4.1.1). 
e) Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at 
recurrence). 
f) Withdrawal of consent for any further data submission. 
g) The tenth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Sample Size and Study Duration 
For both strata, we will use an information-based design and the final analysis will be 
conducted when the specified number of events are attained. For Stratum 1, we expect to enroll 
65 eligible and evaluable patients in approximately 3 years and we expect follow each patient 
for at least 1 year before the expected number of events (i.e., 35) is observed. For Stratum 2, 
we plan to enroll 30 eligible patients during the same period. The number of events needed to 
achieve the specified power under the design assumptions for this stratum is 13. We expect 
that we will need to follow the last patient for 3 years before 13 events are observed. Only 
patients who pass the screening process and start protocol defined treatment within 31 days 
(34 days for veliparib) of surgery will be eligible and evaluable for assessing efficacy. Patients 
who pass the screening process but are not able to start treatment within 31 days (34 days for 
 
 

  
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veliparib) of surgery will not be eligible and will be replaced. The maximum projected sample 
size for this study is 115 to account for ineligible/inevaluable patients. We expect we will need 
to molecularly screen up to 220 subjects to achieve the targeted sample size of eligible and 
evaluable patients. 
 
Stratum 1 is the primary stratum that will control accrual for this trial. If accrual to Stratum 1 
is completed and 30 patients have not yet been enrolled on Stratum 2, we will consult the COG 
Leadership and COG DSMC regarding whether accrual to Stratum 2 should continue. 
 
9.1.1 
Closure of Stratum 1 IDH (Wild-Type Cohort) Effective January 24, 2020 
Stratum 1 of ACNS1721, for patients with IDH wild-type HGG, was closed to 
accrual as of January 24, 2020. Closure of this stratum was based on the results of 
a planned interim analysis. The available data from the first 22 subjects at the time 
of interim analysis suggested that the hypothesized superior outcome for the 
ACNS1721 treatment compared to the historical controls was unlikely. There were 
no concerns regarding excessive toxicities on this protocol. 
 
9.2 
Study Design 
This study will evaluate the efficacy of the planned regimen in two molecularly defined 
pediatric newly-diagnosed HGG subgroups. Stratum 1 will enroll patients who are wild-
type with respect to H3 K27M, BRAF, and IDH1/2. Stratum 2 will enroll patients whose 
tumors are positive for IDH1/2 mutation and wild-type for BRAF and H3 K27M. The 
primary efficacy endpoint is EFS in both strata and the efficacy of the regimen used in this 
study will be assessed by comparing the stratum-specific EFS outcome to clinically and 
molecularly matched historical controls. These historical controls have been derived from 
Korshunov et al., and from ACNS0822 for Stratum 1 and from Korshunov et al., 
ACNS0822, ACNS0423, the recent Cell meta-analysis paper, and the HERBY trial for 
Stratum 2.4 These historical data sets that will be used for these comparisons have already 
been extracted and will be stored in the COG file share for this study for ease of access at 
future analysis points. These data will not be updated as these cohorts are quite mature at 
the time of the design of this study. 
 
Stratum 1: 
The following is a description of the historical control cohort used in this stratum. 
 
ACNS0822: ACNS0822 is the most recently completed COG phase 2 frontline HGG trial. 
The phase 2 trial enrolled 90 eligible patients and while patients were randomized among 3 
regimens, the results did not indicate any difference among these arms. Thus, for the purposes 
of this study, the data from these 3 regimens will be combined. Of the 90 eligible patients, 62 
had adequate biology information to be included in our analyses and 34 met the molecular 
eligibility criteria defined as no H3 K27M mutant, IDH1/2 mutant, or BRAFV600 mutant 
tumors.  
 
Korshunov et al. Cohort (aka Heidelberg Cohort): The second cohort which will be used to 
construct our historical control group for Stratum 1 is derived from the cohort analyzed by 
Korshunov et al.4 This cohort included 140 patients who were aged 3 years and older, had 
tumors outside the brainstem and had non-disseminated disease. Of these, 84 (60%) were also 
negative for H3 K27M, IDH, and BRAF mutations. This group of 84 subjects will be included 
in the historical control cohort. 
 
 

  
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To determine if there are systematic differences between these two cohorts that may preclude 
us from combining them for the purpose of constructing a larger historical control cohort for 
the proposed trial, we analyzed both of these cohorts simultaneously. The plot below displays 
the PFS distribution by cohort and suggests no notable differences between these two data 
sets. The logrank p-value associated with the PFS comparisons is 0.296. There were no 
secondary malignancies reported as the first event in these cohorts so EFS and PFS are the 
same.  
 
Combining these data into one dataset (n=118), we obtain the following PFS curve which 
we propose to use as our historical control cohort against which the outcome of the current 
trial will be compared. This cohort contains 91 progression events with 1-, 2- and 5- year 
PFS estimates (±se) given as 42.6% (±4.6%), 22.2% (±4.2%), and 12.5% (±4.6%), 
respectively.   
 
Using the approach proposed by Korn and Freidlin which was further refined by Wu and 
Xiong, we will employ a group sequential approach based on a 1-sided log rank test to 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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estimate the sample size and monitor for futility in this stratum.52, 53 Using the methodology 
described in Wu and Xiong and the empirical Kaplan-Meier estimate to model the EFS 
distribution, the design proposed here requires 65 patients to detect a HR=0.55 with 5% 
type I error and 90% power. HR=0.55 translates to approximately 20% improvement in 
PFS at 1 and 2 years. The design also stipulates that all patients will be followed for at least 
1 year post-accrual completion with an estimated accrual duration of approximately 
3 years. Interim monitoring for futility only will be done using an alpha-spending approach 
based on the gamma family with =-. The expected number of PFS events (total 
information) during the entire duration of the trial is 35 and we will conduct the first interim 
analysis starting with the 10th failure, which is expected to occur approximately 2 years 
after accrual initiation. Subsequently, interim analyses will be conducted approximately 
annually corresponding with the DSMC reports. We expect to conduct no more than 
3 interim analyses. 
 
Stratum 2: 
Stratum 2 will enroll patients with IDH mutant tumors. Of note, IDH mutations are 
generally mutually exclusive with H3 K27M and BRAF mutations. Given the fact that IDH 
mutations generally occur in patients who are in their teenage or early 20s, eligibility is 
extended to 25 years in this stratum. Due to the rarity of these tumors, historical data are 
somewhat sparse. In the Heidelberg cohort, only 10 (7.1%) patients had IDH mutations 
among the 140 patients who were aged 3 years and older, had tumors outside the brainstem 
and had non-disseminated disease. In the ACNS0822 cohort, 8/62 (12.9%) had IDH 
mutations. IDH information was also available from a subset of patients treated on the 
ACNS0423 study. ACNS0423 was a phase 2 study which preceded ACNS0822. This study 
enrolled 108 eligible patients with similar eligibility criteria and treated them with 
temozolomide + RT followed by 6 cycles of temozolomide + lomustine. Among these, 
IDH mutations were assessed in 43 patients and 7 (16.3%) were identified as IDH positive. 
We were also able to obtain data from 6 additional IDH patients included in the recent Cell 
meta-analysis paper and 4 patients from the HERBY study (personal communication, Chris 
Jones). The PFS distributions of IDH mutated patients from these 5 studies are given in the 
Kaplan-Meier (KM) plot below. While there is some variability, these PFS distributions 
are not statistically different from each other (logrank p-value=0.325). Similarly here as 
well, PFS and EFS distributions are the same. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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We will use the combined group from these 5 cohorts as our historical control. This cohort 
includes 35 patients and 18 PFS events for patients whose median age is 16.9 years (range 
11.728). The KM plot of the combined cohort is given below. The estimated 1, 2, and 
5 year PFS estimates (±se) are 85.4% (±6.05%), 61.1% (±8.5%), and 35.8% (±11.4%), 
respectively. 
 
Using the same methodology as in Stratum 1, we will employ a group sequential approach 
based on a 1-sided logrank test to estimate the sample size and monitor for futility in this 
stratum. Using the methodology described in Wu and Xiong and the KM estimate to model 
the PFS distribution, the design proposed here requires 30 patients to detect a HR=0.45 with 
10% type I error and 80% power. HR=0.45 translates to approximately 8% improvement in 
PFS at 1 year and 19% at 2 years. The design also stipulates that all patients will be followed 
for at least 3 years post-accrual completion with an estimated accrual duration of 23 years. 
Interim monitoring for futility only will be done using an alpha-spending approach based on 
the gamma family with γ = -4. The expected number of PFS events (total information) during 
the entire duration of the trial is 13 and we will conduct the first interim analysis starting with 
the 5th failure which is expected to occur at the end of accrual if the treatment is effective. 
Otherwise if the treatment has the same efficacy as historical controls, we expect to observe 
6 events 22.5 years after actual initiation. Subsequently, interim analyses will be conducted 
approximately annually corresponding with the DSMC reports. We expect to conduct 
approximately 3 interim analyses. 
 
9.3 
Methods of Analysis 
For both strata, the primary analysis for EFS will be based on a 2-sample, 1 sided logrank test. 
For each stratum we will also consider Cox models that incorporate known prognostic factors 
as feasible including resection status (GTR vs. < GTR) and tumor grade (Grade 3 vs. 4), etc. 
to ensure that these variables do not have undue influence on the overall outcome. For patients 
with measurable disease at baseline, we will also report the objective response rate. 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

  
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4. Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be 
measured accurately. Presence and location of leptomeningeal tumor spread should be 
noted and change in extent/thickness assessed on follow up studies. Note that patients 
with leptomeningeal disease are not eligible for enrollment on this study. 
 
5. Overall Response Assessment 
The overall response assessment takes into account response in both target and non-
target lesion, and the appearance of new lesions, where applicable, according to the 
criteria described in the table below.  The overall response assessment is shown in the 
last column, and depends on the assessments of target, non-target, and new lesions in 
the preceding columns. 
 
 
Target Lesions 
 
Non-target 
Lesions 
 
New Lesions 
 
Overall Response 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR 
PR 
CR, IR/SD 
No 
PR 
SD 
CR, IR/SD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR – Complete Response  
 
PR – Partial Response 
 
 
SD – Stable Disease 
PD – Progressive Disease 
IR – Incomplete Response 
 
The sections that follow discuss the selection and evaluation of each of these types of lesions. 
 
10.3 
Selection of Target and Non-Target Lesions 
a. 
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. Note 
that patients with M+ disease are not eligible for enrollment on this study. 
b. 
If multiple measurable lesions are present, up to 3 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.   
c. 
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). 
d. 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
 
 

  
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10.4 
Response Criteria for Target Lesions 
1. Response criteria are assessed in 2 dimensions – the product of W x T.  
 
2. To assess response/progression, the ratio is calculated: 
 
 W x T (current scan)       
 W x T (reference scan) 
 
3. 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. 
 
4. Response Criteria for target lesions: 
 
Complete Response (CR): Disappearance of all target lesions.  
 
Partial response (PR): ≥ 50% decrease in the sum of the products of the two 
perpendicular diameters of target lesions, compared to baseline measurement. 
 
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 (taking as reference the 
initial baseline measurements), nor sufficient increase in a single target lesion to 
qualify for PD, (taking as reference the smallest disease measurement since the 
treatment started). 
 
Progressive Disease (PD): ≥ 25% increase in the product of perpendicular diameters 
of ANY target lesion, taking as reference the smallest product observed since the start 
of treatment (see exception below); OR the appearance of one or more new lesions, 
OR worsening neurologic status not explained by causes unrelated to tumor 
progression (e.g., anticonvulsant or corticosteroid toxicity, electrolyte disturbances, 
sepsis, hyperglycemia, presumed post-therapy swelling, etc.) PLUS any increase in 
tumor cross-sectional area (or tumor volume).  
 
However, because radiotherapy may be associated with transient, reversible swelling 
during or within the first 3 months after completion of RT, there may be a lag time 
between the initiation of therapy and maximal anti-tumor effect. Removing a patient 
from protocol therapy as soon as tumor area increases by 25% may result in the 
treatment being terminated prematurely. It is quite possible that if these patients were 
maintained on protocol therapy, their disease might eventually stabilize and even 
regress.  
 
Therefore, patients will not be considered to have progressive disease and will not 
be removed from protocol therapy for radiographic worsening secondary to local 
tumor enlargement (LTE), defined as increase in maximal bi-dimensional tumor 
area of 25% or more but less than 50%, and with no new lesions on any MRI 
performed within 3 months from completion of RT (i.e., on the required MRI 
4  weeks after completing RT, or the scan performed prior to Cycle 3 of the 
Maintenance). Thus, during and for 3 months after completion of RT, patients should 
only be removed from protocol therapy for progressive disease if there is 50% or more 
 
 

  
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increase in tumor area (with or without neurological worsening), OR if there is the 
appearance of one or more new lesions on the MRI outside the radiation port. 
 
The criteria for progressive disease as defined above will commence with the required 
brain MRI scans done more than 3 months after completion of RT (i.e., prior to  
Cycle 3 of therapy, or scans done for suspected progression more than 3 months after 
completion of RT). Patients whose tumors meet these criteria will be removed from 
protocol therapy.  
 
Local progression is defined as progression of known residual tumor or the appearance 
of tumor at known prior sites of disease that were at some point without evidence of 
disease. Distant progression is defined as the appearance of tumor at sites other than 
known prior sites of disease. Distant progression most often occurs in the subarachnoid 
space and may occur at any point within the neuraxis. Although rare, extra-CNS 
metastasis represents distant failure. Combined local and distant progression is defined 
when evaluation of the entire neuraxis reveals local and distant progression. 
 
10.5 
Response Criteria for Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions.  
 
Incomplete Response/Stable Disease (IR/SD):  The persistence of one or more non-target 
lesions.  
 
Progressive Disease (PD): The appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
11.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Certain adverse events must be 
reported in an expedited manner to allow for timelier monitoring of patient safety and care. 
The following sections provide information about expedited reporting. 
 
11.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was associated 
with the event.  
 
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.  
 
 
 

  
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Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply. 
 
Concurrent administration: When an investigational agent is used in 
combination with a commercial agent, the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
 
Sequential administration: When a study includes an investigational agent and 
a commercial agent on the same study arm, but the commercial agent is given 
for a period of time prior to starting the investigational agent, expedited 
reporting of adverse events that occur prior to starting the investigational agent 
would follow the guidelines for commercial agents. Once therapy with the 
investigational agent is initiated, all expedited reporting of adverse events 
follow the investigational agent reporting guidelines. 
 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI 
requires that AEs be submitted according to the timeframes in the AE reporting tables 
assigned to the protocol, using the CTEP Adverse Event Reporting System (CTEP-AERS). 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug experience 
when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
11.4 
Special Situations for Expedited Reporting  
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of a 
possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting tables in this protocol.  
 
 
 

  
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11.4.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it 
occurs at any time following treatment with an agent under a NCI IND/IDE since 
these are considered to be serious AEs. 
 
11.4.3 Death 
 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: A disorder characterized by cessation of life during the first 
28 days of life.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
o Death due to progressive disease should be reported as Grade 5 “Disease 
Progression” in the system organ class (SOC) “General disorders and 
administration site conditions.” Evidence that the death was a manifestation 
of underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) 
should be submitted.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours.  
 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.4.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
 
The NCI requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
 
Leukemia secondary to oncology chemotherapy  
 
Myelodysplastic syndrome  
 
Treatment related secondary malignancy  
 
 

  
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Any malignancy possibly related to cancer treatment (including AML/MDS) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
11.4.5 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 
11.4.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form, available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to (301) 897-7404. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.4.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents that may be teratogenic. For this reason, pregnancy needs 
to be reported in an expedited manner via CTEP-AERS as Grade 3 
“Pregnancy, 
puerperium 
and 
perinatal 
conditions 
- 
Other 
(pregnancy)” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. 
 
Pregnancy needs to be followed until the outcome is known. If the baby 
is born with a birth defect or anomaly, then a second CTEP-AERS report 
is required. 
 
11.4.6.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any 
Pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a Pregnancy loss as a Grade 5 event 
since CTEP-AERs recognizes any Grade 5 event as a patient death.  
 
11.4.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring during 
the first 28 days after birth”, should be reported expeditiously as  
Grade 4 “Death neonatal” under the “General disorders and 
administration” SOC, when the death is the result of a patient 
pregnancy or pregnancy in partners of men on study. Do NOT report 
a neonatal death resulting from a patient pregnancy or pregnancy in 
partners of men on study as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death.  
 
 
 

  
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11.5 
Reporting Requirements for Specialized AEs 
 
11.5.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (e.g., elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
 
a. If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event 
to determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.5.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
 
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 
 
11.5.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.6 
Exceptions to Expedited Reporting 
 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and 
Potential Risks (CAEPR) that contains a list of events that are considered expected 
for CTEP-AERS reporting purposes. (Formerly referred to as the Agent Specific 
Adverse Event List [ASAEL].)  
 
AEs listed on the SPEER should be reported expeditiously by investigators to the 
NCI via CTEP-AERS ONLY if they exceed the grade of the event listed in 
parentheses after the event. If the CAEPR is part of a combination IND using 
 
 

  
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multiple investigational agents and has an SAE listed on different SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
 
11.6.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed under the 
CTEP-AERS reporting Table A for this protocol. 
 
11.7 
Reporting Requirements  Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports 
in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database.   
 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website  
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted electronically to NCI via CTEP-AERS at: 
https://eapps-ctep.nci.nih.gov/ctepaers.  
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to 
be made to the NCI for agents supplied under a CTEP IND by telephone call to (301) 897-
7497.  
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of the 
report at the site.   
 
 
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days  The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days  A complete expedited report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event.  
 
 
Any event that results in a persistent or significant incapacity/substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect, or is 
 
 

  
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an IME, which based upon the medical judgment of the investigator may jeopardize 
the patient and require intervention to prevent a serious AE, must be reported via 
CTEP-AERS if the event occurs following investigational agent administration.  
 
 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 
24  hours.  
 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE requires 
expedited reporting within 24 hours.  
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  
 
Any medical documentation supporting an expedited report (e.g., H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to 
the NCI. NOTE: English is required for supporting documentation submitted to the 
numbers listed below in order for the NCI to meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents supplied under 
a CTEP IND to: (301) 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. 
 
 
 
 
 

  
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12.0 
STUDY REPORTING AND MONITORING  
The Case Report Forms and the submission schedule are posted on the COG web site with each 
protocol under “Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted quarterly to CTEP 
by electronic means. Reports are due January 31, April 30, July 31 and October 31. CDUS 
reporting is not a responsibility of institutions participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (e.g., termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released prior to the release of study results at the time specified 
in the protocol document. 
 
12.3 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing Agents contain confidential information and should 
not be shared or distributed without the permission of the NCI. If a copy of this 
protocol is requested by a patient or patient’s family member participating on the 
study, the individual should sign a confidentiality agreement. A suitable model 
agreement can be downloaded from: http://ctep.cancer.gov. 
 
 

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

  
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protected. Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting 
or publication in the proceedings. Press releases and other media presentations 
must also be forwarded to CTEP prior to release. Copies of any manuscript, 
abstract and/or press release/media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
13.0 
SURGICAL GUIDELINES 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
13.1 
Neurosurgical Procedures 
There are no standard neurosurgical procedures for high-grade astrocytomas. An attempt 
should be made to perform maximal safe surgical resection. The extent of surgical resection 
will depend upon the location and growth features of the tumor. It is suggested that 
navigational guidance (stereotaxy, intra-operative MRI, ultrasound) be used in an effort to 
guide surgical resection. Patients potentially eligible for this study must undergo at least 
tissue sampling that results in a pathologic interpretation. No patient will be eligible for 
this study without a pathological diagnosis. 
 
13.2 
Definitions of Extent of Resection 
Note: An attempt should be made to estimate the volume of the residual tumor in cm3. 
 
13.2.1 Biopsy Only 
An open surgical removal or close (e.g., needle) removal of tissue for the sole 
purpose of making a pathologic diagnosis. If tumor removal is less than 10% of 
the total tumor mass, this will be considered a biopsy only. 
 
13.2.2 Partial Resection 
The surgical removal of greater than 10% but less than 50% of the tumor mass. 
 
13.2.3 Subtotal Resection 
The surgical removal of greater than or equal to 50% but less than 90% of the 
tumor mass. 
 
 
 

  
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13.2.4 Near Total Resection (Extensive Subtotal Resection) 
Resection of greater than or equal to 90% of the tumor mass, but residual disease 
apparent on inspection. 
 
13.2.5 Gross Total Resection 
Resection of all visible tumor. 
 
13.3 
Imaging Confirmation of Extent of Resection 
See Section 16.0 for Neuroimaging Guidelines. All patients must have confirmation of the 
neurosurgical staging of the extent of resection with a post-operative MRI with and without 
contrast. It is strongly encouraged that the post-operative imaging of the brain be done 
within 48 hours of surgery if possible, but if unable to be done at that time (or post-
operative changes obscure potential residual tumor) must be done prior to enrollment. The 
requirement for a post-operative MRI is waived for patients who undergo biopsy only. 
 
13.4 
Peri-operative Corticosteroids 
Some patients with large tumors may require initiation of corticosteroid therapy pre-
operatively to reduce associated cerebral edema or improve neurologic function. 
 
Usual corticosteroid dosage is 0.25 to 1 mg/kg/day of dexamethasone in divided doses 
every 6–12 hours. Corticosteroids may be discontinued during the peri-operative period; 
however, every attempt should be made to taper and discontinue corticosteroid therapy as 
soon as clinically feasible (7 days). 
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
Before entering patients on this trial, clinicians should discuss this protocol with their 
pathologist and provide them with the APEC14B1 protocol and list of the required materials 
that will need to be submitted for the rapid central pathology screening review.  
 
It is the responsibility of the Principal Investigator at the institution to ensure that the pathologist 
is informed and to request that all HGG patient specimens be forwarded to the COG Biopathology 
Center (BPC), as required. The BPC will NOT request materials. 
 
14.1 
Required Rapid Central Pathology Review  
See APEC14B1 and Section 3.1 for required materials for the Rapid Central 
Screening Review.  
 
The pathologic classification of tumors is becoming increasingly complex since there is 
considerable variation in the histological features of patients. Central review is therefore 
critical to ensuring that the diagnosis is accurate and that patients are treated appropriately. 
Central pathologic review will be performed on all diagnostic specimens (whether resected 
or biopsied). The classification and grading of the tumors will be performed according to 
the 2016 WHO Central Nervous System (CNS) criteria. The submission of pathology 
material shall be made directly from the participating institutions. Results of the review 
will be given to the treating institution.  
 
 

  
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If there is a discrepancy between the institutional diagnosis and the diagnosis on the rapid 
screening central review of a patient, then a discussion between the local and study 
pathologists will take place to attempt to reach a consensus, however, the decision of the 
study pathologists will be used to confirm eligibility. At least ONE of the central review 
pathologists will need to confirm eligibility prior to enrollment. Slides will be stored at the 
COG BPC for quality control purposes. 
 
 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
15.1 
Required Studies 
 
15.1.1 Rapid Central Molecular Screening Review 
In patients who have pathology confirmed by central pathology review, Rapid 
Central Molecular Screening Review will be performed on genomic DNA 
extracted from FFPE tissue. See Section 3.1.1.4 for details. These specimens are 
submitted via APEC14B1. 
 
15.2 
Optional Studies 
 
15.2.1 Genomic Analysis of Germline DNA 
Genomic analysis of germline DNA will be performed in consenting patients. If a 
patient has consented to optional banking on APEC14B1, we will request use of 
some of the banked blood sample to study germline DNA on ACNS1721. If a 
patient has not submitted a banked blood sample on APEC14B1 but consents 
to correlative biology studies on ACNS1721, please collect a peripheral blood 
sample before treatment begins. Leftover samples will be banked at the COG 
Biopathology Center. 
 
15.2.1.1 Specimen Requirements 
At pre-treatment, please collect 4–10 mL of peripheral blood, preferably 
in a 10 mL Streck Cell Free DNA tube. Purple top EDTA tubes may be 
used if Streck tubes are not available at the institution. Please note that 
Streck tubes will not be provided for ACNS1721 correlative studies. 
Samples should be collected prior to beginning protocol therapy, but can 
be collected within the first 5 days of treatment if needed. 
 
Note: A minimum of 5 mL of blood is required if using Streck tubes to 
maintain sample integrity. 
 
15.2.1.2 Specimen Processing 
The blood should be shipped whole and unprocessed to the BPC on the 
day of collection. If a specimen cannot be shipped the day of collection, 
then blood in EDTA tubes should be kept at 4°C while blood in Streck 
tubes must be kept at room temperature. Ship blood on the next working 
day. 
 
 
 

  
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15.2.2.2 Specimen Preparation 
Note: Frozen samples (tissue, plasma, buffy coat) may be stored for up 
to 6 months at -80°C. Samples should not be batched. 
 
15.2.2.2.1 
Peripheral Blood 
Whole blood should be collected preferably in 10 mL 
Streck tubes (Cell-Free DNA BCT®). If Streck tubes are not 
available at the institution, K2 EDTA (BD Vacutainer®) 
tubes can be used and the same centrifugation steps 
followed. Please note that Streck tubes will not be provided 
for ACNS1721.  
Whole blood should be separated into plasma and blood 
cells by two consecutive centrifugations: 
 
1. Centrifuge at 800g (2900 rpm) at +4°C for 
10 minutes to separate blood, buffy coat, and 
plasma.  
 
2. Remove the top layer of plasma and place in an 
Eppendorf tube in 1.5 mL aliquots for subsequent 
centrifugation (Step 5). 
 
3. Remove “buffy coat” (concentrated leukocyte 
band) and store in plastic screw-cap (cryo)vial or 
Eppendorf tube at -80°C. 
 
4. Store the lower layer of blood in a separate plastic 
screw-cap (cryo)vial or Eppendorf tube at -80°C. 
 
5. For the second centrifugation step, centrifuge the 
supernatant (plasma) from Step 2 at 21000g 
(15,000 rpm or the maximum speed available) at 
+4°C for 10 minutes. 
 
6. Remove the resulting supernatant (plasma) and 
store in a cryovial in 2 mL aliquots at -80°C. 
 
Optional: The pellet from the centrifugation at Step 
5 can be combined with the buffy coat from Step 3. 
 
15.2.2.2.2 
Frozen Tumor Sample 
Frozen tumor samples should be stored in a cryovial or 
Eppendorf tube, without media.  
 
15.2.2.3 Specimen Labeling and Shipping  
Please contact the Jabado Lab at 
 
before specimens are shipped to obtain a FedEx account number. 
Specimens should be labeled with the patient ID, tumor location (if 
applicable), and date and time of collection. For plasma, please note the 
 
 

  
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16.0 
NEUROIMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
 
16.1 
Timing of MRIs and Retrospective Central Imaging Review 
Sites are required to submit imaging scans for retrospective central imaging review. To 
document the initial extent and degree of residual tumor, standard whole brain MRI with 
and without contrast (gadolinium) must be performed at the following time points: 
1. 
Brain MRI: Pre- and post-operative* MRIs should be performed prior to 
enrollment onto the study 
2. 
Brain MRI: Prior to each odd-numbered cycle of Maintenance chemotherapy 
3. 
Brain MRI: At the end of therapy 
4. 
Brain MRI: Every 3 months for Year 1 in follow-up (3, 6, 9, 12 months) 
5. 
Brain MRI: Every 4 months for Year 2 in follow-up (16, 20, 24 months) 
6. 
Brain MRI: Every 6 months for Year 3 in follow-up (30, 36 months) 
7. 
Brain MRI: Once yearly for Years 4–10 in follow-up 
8. 
Brain MRI: At progression/relapse (if outside the timepoints noted above) 
 
*It is strongly encouraged that the post-operative brain MRI be done within 48 hours of 
surgery if possible, but if unable to be done at that time (or post-operative changes obscure 
potential residual tumor) must be done prior to enrollment. The requirement for a post-
operative MRI is waived for patients who undergo biopsy only. 
 
Tumor response assessment will be performed at each site. For all patients, submit all MRI 
studies with their corresponding reports to the address in Section 16.5. Please note that 
results from the retrospective central imaging review will not be returned to the site. 
 
16.2 
Whole Brain MRI With and Without Contrast 
Pre- and post-operative brain MRIs with and without contrast (gadolinium) are required to 
document the degree of residual tumor. It is strongly encouraged that the post-operative 
brain MRI be done within 48 hours of surgery if possible, but if unable to be done at that 
time must be done prior to enrollment. The requirement for a post-operative MRI is waived 
for patients who undergo biopsy only. 
 
16.2.1 Required Sequences on 1.5T or 3T machine 
Pre-contrast: 
1. Loc 
2. Sagittal T1; 5 mm skip 0  
3. Axial T2 FLAIR; 5 mm skip 0 
4. Axial DWI; 5 mm skip 0 
5. Axial GRE; 2.5 mm skip 0 
6. Axial T1; 5 mm skip 0 
 
 

  
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7. Axial FSE T2; 5 mm skip 0 
8. Strongly recommended if available: 3D isovolumetric Axial T2 Flair 
Post-contrast: 
9. Coronal T1 post contrast; 5 mm skip 0 
10. Sagittal T1 post contrast; 5 mm skip 0 
11. Axial T1 post contrast; 5 mm skip 0  
12. Strongly recommended if available: 3D isovolumetric T1 post-contrast  
 
16.2.2 Optional Sequences (depending on tumor) 
Pre-contrast: 
1. Sagittal or coronal FSE T2; 5 mm skip 0 
2. Axial DTI 
3. Susceptibility weighted imaging (SWI, mIP SWI, filtered phase, 
magnitude) 
Post-contrast: 
4. Axial T1 (DSC) or T2* (DCE) perfusion  
 
Notes: 
- 
No fat saturation 
- 
Flow compensation not used on coronal and sagittal T1 post contrast 
 
16.3 
Tumor Response Assessment 
For the response assessment, MRI scans obtained prior to each odd numbered Maintenance 
cycle will be compared to the baseline MRI scan. Exception: In cases of progressive 
disease, the reference scan should be the MRI with the smallest product observed since the 
start of treatment (not necessarily at Week 8). 
 
16.4 
Extracranial Disease Progression 
If imaging obtained for a clinical indication reveals extracranial disease progression (e.g., 
spinal cord or other organs), submission of diagnostic scans is required. 
 
16.5 
Submitting Scans 
Submission of Diagnostic Imaging data in digital format is required. Submission of the 
digital files and reports via TRIAD is preferred; however, if TRIAD has not been enabled 
at your site, to avoid delays in imaging submission, alternative submission methods are 
available. Instructions for TRIAD setup can be found in Section 17.0. The files can be 
submitted via sFTP. Information to obtain an sFTP account and submission instructions 
can be found at www.QARC.org. Follow the link labeled digital data. Sites using 
Dicommunicator@QARC.org may submit imaging via that application.  
 
Questions regarding the submission of imaging studies and reports should be sent to: 
DataSubmission@qarc.org. 
 
 
 
 

  
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17.0 
RADIATION THERAPY GUIDELINES 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
Radiation therapy (RT) for patients on COG protocols can only be delivered at approved 
COG RT facilities.  
 
To view the ACNS1721 HGG Contouring Atlas, please visit www.qarc.org and under NCI Groups, 
select COG and follow the link titled “COG Contouring Atlases.” 
 
Submission of the radiation therapy treatment plan in digital format as DICOM RT is 
required. Submission of the digital files and reports via TRIAD is preferred. Instructions for 
TRIAD setup are provided below. See the IROC Rhode Island website (https://irocri.qarc.org/) for 
digital data submission information. 
 
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, DICOM RT and 
other non-DICOM digital files. TRIAD anonymizes and validates the DICOM and DICOM RT 
images as they are transferred. 
 
TRIAD Access Requirements: 
 
Site staff who 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 user must be on the site’s membership roster in RSS/CTSU 
and be assigned the 'TRIAD site user' role.  Users should contact their site’s CTSU 
Administrator or Data Administrator to request assignment of the TRIAD site user role.  
CRAs are able to submit standard of care imaging through the same method. 
 
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 will facilitate the central reviews. 
 
 

  
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Submission of imaging and RT data via TRIAD is preferred; however, if TRIAD has not been enabled 
at your site, to avoid delays in imaging submission, alternative submission methods are available.  The 
files can be submitted via sFTP. Information to obtain an sFTP account and submission instructions 
can be found at www.qarc.org. Follow the link labeled digital data. Sites using 
Dicommunicator@QARC.org may submit imaging via that application. Submit the Diagnostic 
imaging scans, along with their corresponding reports, to the address listed in Section 17.9.5.3. 
 
Contact IROC Rhode Island with questions or for additional information. 
 
17.1 
Radiation Therapy Timing 
Radiation therapy (RT) is to start within 31 days of the definitive surgical procedure  
(Day 0). To ensure compliance with this requirement, practitioners should not await central 
pathology review or confirmation of eligibility to initiate RT planning. 
 
Diagnostic MRIs may be used for RT treatment planning if additional MRIs in the 
treatment position cannot be obtained or if repeating an MRI is likely to result in excessive 
cost to the patient's family without insurance reimbursement. A separate CT scan is 
required for all RT planning. 
 
17.2 
Radiation Therapy Credentialing 
 
17.2.1 All therapy units used on this protocol must have their calibrations verified by IROC 
Houston (Radiologic Physics Center). The table in Section 17.3 indicates allowable 
modes of treatment delivery. 
 
17.2.2 IMRT/VMAT 
Institutions treating with intensity-modulated or volumetric-modulated arc therapy 
(IMRT/VMAT) and not previously credentialed for use of IMRT in COG trials 
must irradiate IROC Houston’s head and neck phantom. Contact IROC Houston 
(http://irochouston.mdanderson.org) for information about their phantoms. 
 
17.2.3 Proton Therapy 
Each beam line used to treat patients on this study must be approved for clinical 
use by the IROC Houston QA Center. The proton therapy method may be 
scattering, uniform scanning, or pencil beam scanning depending on institutional 
availability and approval status for that mode of operation. Investigators using 
proton beam radiation must comply with current NCI proton therapy guidelines as 
outlined in the Guidelines for the Use of Proton Radiation Therapy in NCI 
Sponsored 
Cooperative 
Group 
Clinical 
Trials, 
available 
at 
http://rpc.mdanderson.org/RPC/home page/Proton guidelines.htm. Irradiation 
of the proton head and neck phantom is required as well as baseline proton 
credentialing. 
 
 
 

  
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16.2.1). Isovolumetric sequences should be used whenever possible (see Section 
16.2.1, #11 and #12). The following sequences are needed to evaluate the full-
extent of tumor: T1-weighted (T1W) without contrast, T1-weighted (T1W) with 
contrast, T2-weighted (T2W) without contrast, and T2W FLAIR. 
 
17.4.2 Post-Operative Imaging (if resection was performed) 
17.4.2.1 A post-operative MRI scan (unless only a biopsy was performed) with 
and without contrast is required for trial entry. A slice thickness less than 
or equal to 3 mm in the cranial caudal dimension is recommended. The 
following sequences are needed to evaluate the full-extent of tumor: 
T1W without contrast, T1W with contrast, T2W without contrast, and 
T2W FLAIR. 
 
17.4.2.2 Additional sequences which improve the delineation of the operative bed 
include susceptibility weighted-imaging, T2*, and/or GRE sequences. 
Diffusion weighted (DWI) and perfusion imaging (Perf) may be useful 
for delineating residual tumor and these sequences are encouraged. 
Diffusion tensor imaging (DTI) may be useful for illustrating proximal 
white matter tracts at risk for tumor spread. 
 
17.4.3 Planning CT Scan 
All patients will undergo CT treatment planning for this protocol. Slices of 
≤ 0.3 cm thick shall be taken throughout the extent of the irradiated volume. CT 
(volumetric)-based planning is required to optimize dose to the target volume 
while protecting normal tissues. In the event that a patient must start emergently 
with a non-volumetric treatment plan, a volumetric plan must be started within 
three fractions of the treatment start and the previously utilized beams must be 
incorporated into the composite plan. 
 
17.4.4 Imaging Registration 
Use of fusion image registration software is required.  
 
17.5 
Treatment Delivery Verification Imaging 
 
17.5.1 Photons 
Weekly orthogonal planar imaging or volumetric cone-beam CT (CBCT) imaging 
is required for verification of correct patient positioning. Daily CBCT or 
orthogonal planar images are required if a PTV margin of 3 mm is used (see 
Section 17.9.5.2). If daily CBCT is not possible, then documentation of the use of 
a head fixation system or verification system is required. Orthogonal AP and lateral 
images should be used to verify isocenter relative to simulation scans. 
 
17.5.2 Protons 
When proton radiation is employed, daily image guidance with either 2-D or 
volumetric imaging is required. Volumetric imaging for position verification may 
be in-room kV or MV cone beam or conventional CT imaging. When volumetric 
 
 

  
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imaging is available for daily treatment verification, a tolerance of no more than  
5 mm tissue discrepancy along the beam path within the 20% isodose line is 
suggested prior to re-planning although this threshold may be relaxed if the patient 
has been planned with conservative robustness planning parameters. Evaluation of 
a QA plan based on repeat CT sim is strongly suggested when there is any concern 
for suspected or visualized changes in anatomy (ventricular shift, changes in body 
circumference, changes in size or position of the resection cavity, etc.).   
 
17.6 
Radiotherapy Target Volumes 
International Commission on Radiation Units and Measurements (ICRU) Reports 50, 62 
and 78 (www.icru.org) define prescription methods and nomenclature that will be utilized 
for this study. Treatment planning will be based on the following definitions. Radiotherapy 
(RT) volumes for this study will be determined by the collective information (operative 
note, MRI, CT) that delineates the extent of disease both prior to and following surgical 
resection or biopsy. Representative cases with pictures and further detail can be found at 
https://www.qarc.org/cog protocol resources.htm. 
 
17.6.1 Photons 
17.6.1.1 Gross tumor volume (GTV) is the volume occupied at diagnosis by 
disease. 
 
17.6.1.2 Clinical target volume (CTV) includes the GTV and sites with potential 
occult tumor involvement adjacent to the GTV that may be clinically 
involved. 
 
17.6.1.3 Planning target volume (PTV) is the CTV surrounded by a geometric 
margin to account for variability in setup, or motion during treatment. 
 
17.6.2 Protons 
17.6.2.1 GTV is the same for protons and photons.  
 
17.6.2.2 CTV is the same for protons and photons. 
 
17.6.2.1 PTV is the same for protons and photons. 
 
The planning target volume (PTV) for proton therapy will include a 
margin which is added to the CTV in 3-dimensions. The margin should 
be consistent with the motion control and setup accuracy for the 
particular type of treatment (scattered versus scanning) at the treating 
proton center. When proton therapy is used, the PTV will be used for 
dose reporting and not specifically for treatment planning. The goal of 
treatment planning will be CTV coverage at 100% directly with 
specific measures taken for each specific uncertainty. 
 
 
 

  
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When passive scattering techniques are used, additional beam specific 
PTVs may be required for planning as the PTV will vary with each 
individual field and will require additional adjustment including (1) the 
lateral margins, (2) smearing of compensator for scattered beams, (3) 
range of beam (depth of penetration) and, (4) modulation (number of 
required Bragg peaks). Adjustments to any of the aforementioned 
parameters (usually 2–7 mm) will be based on the range uncertainty, CT 
number uncertainty, internal motion, and set up error determined for the 
particular body site at the individual proton institution. The following 
parameters must be explicitly reported for each beam: range, modulation, 
smearing radius of the compensator for scattered beams, setup margin 
(SM) and PTV margin. The specifics of dose reporting for the proton 
PTV and recommendations regarding the PTV margin are discussed in 
Section 17.7.6. 
 
When pencil beam scanning techniques are used with scenario-based 
optimization (also known as robust optimization), the plan may be 
optimized to CTV as described in Section 17.7.6.2.2. The above defined 
PTV should be reviewed in either case to confirm sufficient coverage. 
 
17.6.3 Recommended Target Volumes 
17.6.3.1 GTV_PreOp: This is the full extent of initially involved tissue apparent 
on review of the CT, and MR imaging prior to resection. This volume is 
only defined for resected cases. 
 
17.6.3.2 GTV_Cavity: This is the CSF space that fills the area where parenchymal 
normal brain resided prior to resection. The resection cavity is best 
delineated using T2, T2*, and Susceptibility Weighted Imaging (SWI). 
GTV_Cavity will only be delineated as a target volume in cases where a 
subtotal resection has been performed. 
 
17.6.4 Required Target Volumes 
17.6.4.1 Gross Target Volumes (GTV) 
 
17.6.4.1.1 
GTV1 
- Definition: GTV1 will include all the tissues initially 
involved with disease and the entire residual tumor 
defined by the post-operative MRI scans. 
- Imaging used for target volume delineation: The 
GTV1 will include both enhancing and non-enhancing 
areas of the tumor. The GTV1 will take into account 
any changes in brain anatomy that have occurred as a 
result of tumor resection and/or CSF shunt placement. 
T1W, T2W, and FLAIR sequences of the MRI scans 
should all be reviewed and the sequence that best 
defines the extent of initial disease should be used to 
determine the GTV1.  
 
 
 

  
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Note – Large Resection Cavities: Portions of the 
surgical cavity may represent areas cut due to surgical 
approach and not in contact with tumor. Coverage of the 
entire surgical cavity may result in excessively large 
treatment volumes which do not reflect an at risk region 
for tumor spread. The inclusion of GTV cavity in GTV1 
is at the discretion of the treating radiation oncologist. 
 
Note – Surgical Tract: In deep seated brain tumors 
where a substantial amount of normal brain parenchyma 
is traversed in the surgical approach, the treating radiation 
oncologist may consider the exclusion of the surgical tract 
if the surgical tract extends beyond the pre-operative 
tumor volume defined by GTV PreOp delineated on the 
pre-operative brain MRI. 
 
17.6.4.1.2 
GTV2 
- 
Definition: GTV2 will include only the area of 
residual disease based on the post-operative MRI 
scans. The GTV2 should exclude regions of residual 
tumor which are within 5 mm proximal to either the 
brainstem or optic chiasm. This volume is not defined 
for cases that are completely resected as GTV1 would 
be equivalent to GTV2.  
- 
Imaging used for target volume delineation: The 
GTV2 will include both enhancing and non-
enhancing areas of the tumor. The GTV2 will take 
into account any changes in brain anatomy that have 
occurred as a result of tumor resection and/or CSF 
shunt placement. T1W, T2W, T2W FLAIR, DWI and 
Perf sequences of the MRI scans should all be 
reviewed and the sequence that best defines the extent 
of residual disease should be used to determine the 
GTV2.  
 
Note: A 3 mm isotropic expansion of the brainstem is 
useful for exclusion of the GTV2 volume. Areas of 
restricted diffusion or increased perfusion should be 
considered highly likely to harbor residual tumor and 
should be included in the GTV2 volume. 
 
17.6.4.2 Clinical Target Volume (CTV) 
- 
Definition: The CTV includes the GTV with an added margin that 
is intended to treat subclinical microscopic disease and is 
anatomically confined. Anatomically confined that the CTV may 
exclude the inner table of the bony calvarium,or the operative cavity 
(GTV_Cavity). 
 
 
 

  
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17.6.4.2.1 CTV1 
- 
Primary supratentorial tumors: CTV1 will be 
expanded in an anisotropic fashion by 1–1.5 cm. A 1 
cm expansion is recommended. A 1.5 cm expansion is 
appropriate when GTV1 is in close proximity to a 
major white matter tract and this area is at increased 
risk. When white matter tracts are deemed at risk, the 
CTV1 
may 
be 
anisotropic 
to 
illustrate 
the 
directionality of that tract. For example, if a deep 
seated temporal lobe tumor is in close proximity to the 
medial longitudinal fasciculus, the CTV1 would 
extend 1.5 cm in the anterior posterior direction and 
would be more conservative in areas of grey matter 
greater than 1 cm distal to GTV1. 
- 
Primary infratentorial tumors (cerebellar, non-
brainstem): CTV1 will be expanded in an 
anatomically constrained anisotropic fashion by  
1–1.5 cm. Care should be taken to include the middle 
cerebellar peduncles when the primary tumor is in 
close proximity. 
 
Note – Large Resection Cavities: CTV1 may exclude the 
volume created by a 3 mm contraction of the GTV Cavity 
volume when the conditions specified above in Section 
17.6.4.1.1 are met. The exclusion of the operative cavity in 
cases with extensive surgical resections is at the discretion 
of the treating radiation oncologist. In cases where the at-
risk region is unclear, please contact the radiation oncology 
PIs. 
 
Note – Surgical Tract: The CTV should be allowed to 
extend into the proximal aspect of the surgical tract to allow 
for potential inaccuracies in registration, brain shift, or 
distortions in brain anatomy following resection. The CTV 
should not extend beyond the bony margins of the 
calvarium. 
 
17.6.4.2.2 CTV2 
- 
Definition: CTV2 will include the GTV2 plus a 
0.5 cm margin in all dimensions. The CVT2 should 
exclude regions of residual tumor which are within  
5 mm proximal to either the brainstem or optic chiasm. 
- 
This volume is not defined for cases that are 
completely resected. 
- 
Primary supratentorial tumors: CTV2 will be 
expanded in the cranial and caudal directions by  
0.5–1 cm. For residual disease abutting major white 
matter tracts, a 1 cm expansion may be appropriate. 
When GTV2 is not adjacent major white matter tracts, 
a 0.5 cm is recommended. For example, if an 
 
 

  
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incompletely resected occipital lobe tumor is in close 
proximity to the corpus callosum, the residual disease 
should be expanded 1 cm along the callosum but only 
0.5 cm into adjacent grey matter >0.5 cm distal from 
residual disease. 
- 
Primary infratentorial tumors (cerebellar, non-
brainstem): CTV2 will be expanded in an 
anatomically constrained anisotropic fashion by  
0.5–1 cm. CTV2 should not extend within 5 mm of the 
brainstem even when residual disease is noted. 
 
Note – Defining Anisotropic CTV Margins: DTI may aid 
the definition of CTV1 and CTV2 as it will nicely delineate 
the major white matter tracts. Major white matter tracts 
include but are not limited to arcuate fasciculus (superior 
longitudinal fasciculus), superior and inferior occipito-
frontal 
fasciculi, 
cingulum, 
uncinate 
and 
inferior 
longitudinal bundle, callosal tracts and corona radiata. 
 
17.6.4.3 Planning Target Volume (PTV) 
- 
Definition: The PTV includes the CTV with an added margin that is 
intended to account for patient movement and setup variability. 
While beam specific PTVs may be required for passive scatter 
technique plans, the PTV used for dose reporting (PTV1 and PTV2) 
should be created based on isotropic expansions as defined below. 
 
17.6.4.3.1 
PTV1 
- 
PTV1 will include the CTV1 plus a 3–5 mm margin 
in all dimensions. The PTV will extend beyond bone 
margins, but shall not extend 3 mm beyond the 
proximal skin surface. A 3 mm expansion from CTV1 
is recommended for all intracranial targets (supra- 
and infratentorial).  
 
17.6.4.3.2 
PTV2 
- 
PTV2 will include the CTV2 plus a 3–5 mm margin 
in all dimensions. The PTV may extend beyond bone 
margins, but shall not extend beyond the skin surface. 
A PTV2 is not defined for gross totally resected 
intracranial tumors (i.e., if there is not a CTV2, there 
will not be a PTV2). 
 
17.7 
Radiation Therapy Dose 
17.7.1 Prescription 
All radiotherapy plans should be prescribed to a prescription isodose line 
encompassing the relevant target volume. Integrated boost radiotherapy plans are 
not permitted. 
 
 
 

  
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17.7.2 Dose Definition 
Photon dose is specified in Gray (Gy)-to-muscle. For proton beams, the absorbed 
dose, ICRU 78’s DRBE, is specified in Gy (RBE), using a standard RBE of 1.1 
with respect to Cobalt-60. Cobalt-Gray-Equivalents are equal to Gy RBE when an 
RBE factor of 1.1 is used. 
 
17.7.3 Fractionation 
The protocol-specified dose per fraction is 1.8 Gy. The treatment should be limited 
to one fraction per day. Five fractions should be given per week. There may be an 
exception if a department is closed on a major holiday but an effort should be made 
to minimize days missed. Efforts should be made to minimize the occurrence of 
orphan fractions (one fraction at treatment start at the end of a week or a solitary 
fraction the last week of therapy). 
 
17.7.4 Tissue Heterogeneity 
Calculations that take into account tissue heterogeneity are required for CT-based 
planning techniques to generate dose distributions and treatment calculations from 
CT densities. When protons are used, tissue heterogeneity calculations should be 
performed with the CT-based treatment planning system to generate dose 
distributions from the proton relative stopping power. Proton therapy should be 
used with extreme caution when any of the treatment beams traverse critical 
structures such as the brainstem or optic apparatus. 
 
17.7.5 Target Prescription Dose Guidelines 
Supratentorial and infratentorial primary brain malignant gliomas will receive a 
total dose of between 54.0 and 59.4 Gy in 30–33 fractions over 6–7 weeks. 
 
17.7.5.1 Gross Total Resection: The total dose will be 54.0 Gy if a gross total 
resection has been performed. 
 
17.7.5.2 Incomplete Resection: If the tumor has not been completely resected, 
the residual disease will be boosted to a total dose of 59.4 Gy. 
 
17.7.5.3 Dose to PTV1 and PTV2: All patients receive a total dose of 54.0 Gy 
to PTV1. Patients with an incomplete resection receive an additional 
dose of 5.4 Gy to PTV2. 
 
17.7.6 Coverage Goals 
17.7.6.1 Photon Planning: At least 95% of the protocol-specified dose should 
encompass 100% of the PTV1, and the maximum dose to PTV1 in the 
absence of PTV2 should be no greater than 110% of the protocol dose 
for PTV1 as evaluated by DVH. When optic nerve and chiasm 
constraints are at risk of being exceeded secondary to attempts to cover 
PTV2 with 5940 cGy, relaxed coverage of PTV2 is permitted such that 
 
 

  
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at least 95% of the protocol specified dose should encompass 95% of 
PTV2. 
 
17.7.6.2 Proton Planning: At least 95% of the protocol-specified dose should 
encompass 100% of the CTV1, and the maximum dose to PTV1 in the 
absence of PTV2 should be no greater than 110% of the protocol dose 
for PTV1 as evaluated by DVH. When optic nerve and chiasm 
constraints are at risk of being exceeded secondary to attempts to cover 
CTV2 and PTV2 with 5940 cGy, relaxed coverage of CTV2 and PTV2 
is permitted. For protons, the PTV should be used to confirm appropriate 
coverage regardless of planning technique utilized. Two methods are 
acceptable for evaluating sufficient coverage according to various 
treatment delivery uncertainties. The same criteria for coverage will be 
used for proton and photon plans. 
 
 
17.7.6.2.1 Geometric 
margins 
with 
static 
dose 
cloud 
approximations: For scattered and uniform scanning 
beams, the aperture margin must include the appropriate 
beam penumbra for the selected beam energy, and setup and 
internal margins (SM and IM). These margins depend on 
the patient setup techniques used at the treating proton 
center. The aperture margin may be expanded further if a 
cold spot occurs near the edge of CTV due to insufficient 
lateral scatter. The smearing radius for the range 
compensator must be equal to the setup and internal margins 
(SM and IM). The beam range should be equal to the 
maximum water equivalent depth of the CTV plus a range 
margin. Most proton centers use 3.5% of the maximum 
water-equivalent depth of the CTV to account for CT HU 
uncertainty and then add another 3 mm to account for 
uncertainties in beam range calibration and compensator 
fabrication. Additional range margin should be applied if 
internal motion could increase the water equivalent depth of 
the CTV. The modulation width should ensure proximal 
coverage of the target volume. A PTV should be created by 
a uniform expansion from CTV for reporting purposes. The 
expansion margin should be consistent with SM and IM and 
is typically 3 mm for a static target volume when daily 
imaging is performed. 
 
17.7.6.2.2 Scenario-based robust planning: Scenario-based margins 
are a method for robust planning under setup uncertainty 
where the plan is optimized using a sum of a plan evaluation 
criterion over a set of scenarios simulating various 
geometric perturbations and changes in tissue density 
within a predefined range. Penalties in the voxel-wise 
summands are weighted by a distribution of coefficients 
defined such that the method is mathematically equivalent 
  

  
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to the use of conventional geometric margins if the scenario 
doses are calculated using the static dose cloud 
approximation. Scenarios are typically discretized into 
variations in setup and range uncertainty. Setup uncertainty 
scenarios should mirror the expected variations in setup  
(3–5 mm for this study) that would be accounted for using 
the PTV concept. Specifically, if the expected setup 
uncertainty is 3 mm, then 3 mm variations in the 
anterior/posterior, left/right and cranial/caudal dimension 
should be evaluated across all combinations. Likewise, 
variations in proton range are accounted for across a range 
of values for tissue density expected within normal clinical 
practice to account for organ motion, particle range 
uncertainty and tissue density heterogeneity variations. 
Range error variations have been suggested to vary by 3–
5% and should be considered for the nominal case and 
undershoot/overshoot scenarios.  
 
17.7.6.3 When targets are superficial the PTV is often modified to not come 
within 3 mm of the skin. As a result, shallow planning target volumes 
may come within close proximity to clinical or gross tumor volumes. A 
potential exception is when the range margin is smaller than the PTV 
expansion (e.g., 3 mm). As a result, the beam may not penetrate deep 
enough to sufficiently cover the distal portion of the PTV. This may 
occur for shallow target volumes where the maximum depth of the CTV 
is small and the range margin is small. This scenario is not expected for 
this protocol; however, such incomplete coverage of the PTV will not 
constitute a planning deviation because the plan should be sufficiently 
robust to cover the CTV with the protocol specified dose accounting for 
all uncertainties. 
 
17.7.7 Treatment Delays and/or Interruptions 
No treatment breaks in the radiation therapy component of this combined modality 
treatment are recommended or anticipated. Skin reactions should be treated 
supportively. Low blood counts are generally related to systemic therapy and are 
not caused or worsened by local field brain RT. In the case of severe or unusual 
toxicities, the radiation oncology co-PI or study chair should be notified. The 
reason for any interruptions greater than 3 treatment days should be recorded in 
the patient’s treatment chart and submitted with the QA documentation (RT-2 form 
– see Section 17.9.4). 
 
17.7.8 Treatment Technique 
17.7.8.1 Two-dimensional planning is not allowed in this study and, as such, a 
volumetric 3DCRT, IMRT, or proton plan should be used at therapy 
initiation. 
 
 
 

  
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17.7.8.2 Patient Position and Immobilization 
Reproducible setups are critical and the use of immobilization devices 
such as a short mask are recommended for all pediatric patients and 
required for patients being treated with IMRT or proton therapy. 
 
17.7.8.3 Beam Configuration 
- 
Every attempt should be made to minimize dose to organs at risk 
without compromising coverage of the target volume. Three-
dimensional conformal therapy (coplanar or non-coplanar) or IMRT 
are often required to minimize dose to normal tissue.  
- 
When protons are used, efforts should be made to limit the distal 
edge of multiple beams from ranging out within the same geometric 
region adjacent a critical structure (brainstem, optic apparatus). 
Multi-field arrangements which have hinge angles > 60 degrees 
between each beam may limit the potential for distal edge 
convergence on critical structures such as the brainstem.54 
- 
Scenario based plan optimization strategies (see Section 17.7.6.2.2) 
may be useful in evaluating beam position for the most robust beam 
arrangement to expected setup variations.  
- 
When post-operative epidural fluid collections or large air cavities 
are present, photon treatment is recommended as large variations in 
range uncertainty may preclude target coverage or result in excess 
radiation dose to at risk critical structures.  
 
17.7.8.4 Beam Modifiers 
- 
Field Shaping: Multi-leaf collimators are to be used for beam 
shaping. Apertures for protons will be done with either brass or 
cerrobend apertures or proton-specific multi-leaf collimation for 
scattered and uniform scanning beams. Pencil beam scanning does 
not require additional accessories for field shaping although 
apertures to further refine beam penumbra are allowed when critical 
structures are at risk.  
- 
Means of obtaining a more uniform photon dose distribution are 
encouraged (i.e., wedges used with 3D conformal radiotherapy, 
compensators with non-MLC based IMRT, etc.). 
- 
Special considerations: Anesthesia or sedation may be required in 
certain patients, such as very young patients, to prevent movement 
during simulation and daily treatments.  
 
 

  
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17.7.9 Treatment Planning Procedures  
Treatment Planning CT 
-see Section 17.4.3 
Section thickness: ≤3 mm 
Volume: thoracic inlet-top of head 
↓ 
Register MR Imaging 
-see Section 17.4 
Pre-op (T1W with contrast and/or T2W) 
Post-op (T1W with contrast and/or T2W) 
↓ 
Required Contours 
-see Section 17.6 
GTV1, CTV1, PTV1 
GTV2, CTV2, PTV2, GTV_Cavity (pending extent of resection) 
Normal Tissue Contours 
↓ 
Radiation Treatment Planning 
-see Section 17.6 and Section 17.8 
Target Volume Coverage 
Normal Tissue Dose Recommendations 
↓ 
Data Submission to IROC RI 
-see Section 17.9 
Due Day 3 and End of Treatment 
Electronic Data 
 
 
17.8 
Organs at Risk  
The organs at risk guidelines in this section are recommendations. If the recommended 
doses to the organs at risk are exceeded because of target volume coverage requirements 
or other conditions, an explanation should be included in the quality assurance 
documentation (see Section 17.9.4). In some cases, photon IMRT may be the preferred 
treatment method to meet these recommendations and the required target volume coverage 
guidelines. 
 
 
 

  
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17.8.1 Cochleae  
 
D50% < 3500 cGy – Goal (single cochlea)  
 
D50% < 2000 cGy – Preferred (single cochlea)  
o Comment – There is no dose limit for the cochleae.  
o Structure definition - Each cochlea will be contoured on the treatment 
planning CT as a circular structure within the petrous portion of the 
temporal bone. The contour should appear on at least two successive CT 
images.  
 
17.8.2 Optic Globes  
 
D50% < 1000 cGy and D10% < 3500 cGy – Goal  
 
D50% < 2000 cGy and D10% < 5400 cGy – Maximum  
o Comment – Effort should be made to avoid direct treatment of the anterior 
chamber of the eye and minimize dose to the entire eye without 
compromising target volume coverage during treatment of PTV1. In the 
event that the recommended maximum dose constraints provided in this 
section would be exceeded as a result of treatment of PTV2, the treating 
radiation oncologist may use their discretion to reduce target volume 
coverage.  
o Structure definition - Each eye should be separately contoured on the 
treatment planning CT or MR as a circular structure from the most superior 
to inferior aspect.  
 
17.8.3 Spinal Cord  
 
D0.1cc < 5400 cGy – Maximum  
o Comment – Effort should be made to minimize dose to the spinal cord 
without compromising target volume coverage during treatment of PTV1.  
o Structure Definition - For the purposes of this study, the upper aspect of the 
spinal cord begins at the inferior border of the foramen magnum and should 
be contoured on the treatment planning CT. For purposes of comparison 
and consistency with dose volume data, the spinal cord should be contoured 
on a number of images to be determined by the image section thickness (CT 
section thickness, n=number of images; 2 mm, n=30; 2.5 mm, n=24; 3 mm, 
n=20). Using these guidelines, only the superior-most 6 cm of anatomic 
spinal cord is contoured.  
 
17.8.4 Optic Nerves and Chiasm  
 
D50% < 5400 cGy and D0.1cc < 5600 cGy – Maximum  
o Comment – Effort should be made to avoid direct treatment of the optic 
nerves and chiasm without compromising target volume coverage during 
treatment of PTV1. In the event that the recommended maximum dose 
constraints provided in this section would be exceeded as a result of 
treatment of PTV2, the coverage may be relaxed. Recall that tumor 
components within 5 mm of the optic apparatus should be excluded from 
GTV2 (see Section 17.7.6.1).  
o Structure definition – The optic nerve may be contoured on CT or MR. The 
contour should appear on at least two successive CT or MR images. A T1 
 
 

  
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17.9.4 Quality Assurance Documentation  
Institutions are required to submit the treatment plan as DICOM RT. Radiation 
therapy planning digital data submissions must include the treatment planning CT 
and MRI, structures, plan, and dose files. MRI time points and sequences required 
for digital data submission include the pre-operative T1W, T1W with contrast, 
T2W and T2 FLAIR sequences while the post-operative sequences should include 
T1W, T1W with contrast, T2W, and T2 FLAIR.  
 
Submission by TRIAD is preferred (see Section 17.0). Alternatively, sites may 
submit data sFTP. Instructions for data submission by sFTP are on the IROC 
Rhode Island web site at http://irocri.qarc.org/ under "Digital Data." All items on 
the list below that are not part of the digital submission may be included with the 
transmission of the digital RT data or submitted separately.  
 
Please submit the following data within 3 days of the start of radiation therapy, 
detailed treatment data shall be submitted for on treatment review.  
 
17.9.5 Submissions  
17.9.5.1 External beam Treatment Planning System  
 
RT treatment plan including CT, structures, dose, and plan files. 
These items are included in the digital plan.  
 
Treatment planning system summary report that includes the 
monitor unit calculations, beam parameters, calculation algorithm, 
and volume of interest dose statistics.  
 
MRI studies that have been fused with the planning CT are required 
to be submitted along with the digital RT data. The corresponding 
spatial registration files should also be submitted, if available. 
 
17.9.5.2 Supportive Data  
 
All diagnostic imaging and reports used to plan the target volume. 
This includes CT or MRI PRIOR to attempted surgical resection of 
the primary tumor.  
 
For protons, a description of the rationale for the PTV margins.  
 
If the recommended doses to the organs at risk are exceeded, an 
explanation should be included for review by the IROC RI and the 
radiation oncology reviewers.  
 
If a PTV margin of 3 mm is used, written documentation that image-
guided radiation therapy (IGRT) methods are used on a daily basis 
or alternatively that a head fixation system or verification system 
was used with weekly or more frequent imaging.   
 
RT-1/IMRT Dosimetry Summary Form; or Proton Reporting Form 
(whichever is applicable).  
 
17.9.5.3 Within 1 week of the completion of radiotherapy, the following data 
shall be submitted for all patients:  
 
The RT-2 Radiotherapy Total Dose Record form.  
 
 

  
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evaluation of the neuraxis, radiotherapy isodose lines, timing, and imaging appearance at 
failure relative to the first post-RT baseline MRI. The monitoring of EFS will assess the 
rate of failure. Local failure is defined as progression of known residual tumor or the 
appearance of tumor at known prior sites of disease that were at some point without 
evidence of disease. Determining the patterns of failure will require an assessment of tumor 
recurrence with respect to targeting and dosimetry. Failure may be described as in-field, 
marginal or out-of-field when focal irradiation techniques are used. Out-of-field failure is 
recurrence that occurs entirely outside of the CTV and is synonymous with distant failure. 
In-field failure is recurrence that originated entirely within the volume that was targeted to 
receive the prescription dose (CTV). Marginal failure is recurrence originating on the 
margin of the volume targeted to receive the prescription dose (CTV) and may be described 
in terms of location or the dose received. There is no universally accepted analytical 
method to assess pattern of failure and to determine whether failure is in-field, marginal or 
out-of-field. The pattern of failure will be assessed qualitatively and quantitatively by 
registering MR data obtained at the time of failure to the dosimetry from the original 
treatment plan. Failures will be determined qualitatively to be “in-field” when the 
recurrence appears to have originated from within and remains confined to the CTV, 
“marginal” when a portion of the recurrence is within the CTV but the majority of the 
recurrence is outside of the CTV, “distant” when the recurrence does not involve the CTV. 
Recurrences will be quantitatively categorized as in-field, marginal, or out-of-field based 
on the proportion of the recurrence that received at least 95% of the prescription dose. This 
requires contouring of the recurrence and computation of the dose-volume histogram. 
Marginal failure occurs when between 20 and 80% of the recurrence volume receives more 
than 95% of the prescription dose, thus, in-field failure occurs when more than 80% of the 
recurrence volume receives more than 95% of the prescription dose and out-of-field failure 
occurs when less than 20% of the volume received more than 95% of the prescription dose. 
Any method has significant limitations, however, since the point of origin for tumor 
recurrence cannot be ascertained with absolute certainty and does not explicitly determine 
marginal failure. 
 
Imaging appearance at local failure will be classified as to whether the failure was called 
due to a new area of enhancement on T1W post contrast MRI outside of the treatment field, 
enlargement of a previously contrast enhancing mass lesion greater than 25% of the product 
of the perpendicular diameters (or sum of the product of the perpendicular diameters if 
multiple contrast enhancing areas are present on the post-RT baseline scan), increasing 
steroid requirements with stable/smaller tumor size, clinical deterioration not due to 
treatment, pathologically proven treatment failure with residual viable tumor (greater than 
70% of biopsied specimen), or other undefined reason for calling treatment failure. The 
timing of treatment failure should be classified as either less than 12 weeks or greater than 
12 weeks following radiotherapy completion.  
 
Distant failure is defined as the appearance of tumor at sites other than known prior sites 
of disease. Distant failure most often occurs in the subarachnoid space and may occur at 
any point within the neuraxis. Although rare, extra-CNS metastasis represents distant 
failure. Distant failures may be further classified according to the type (leptomeningeal, 
nodular, and/or infiltrative flair abnormalities in areas beyond the 20% isodose line) not 
attributable to treatment effect. Combined local and distant failure is defined when 
evaluation of the entire neuraxis reveals local and distant failure.  
 
 
 
  

  
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CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all physicians 
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in 
the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and annual re-
registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP 
Investigator Registration Procedures above for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials 
Support Unit) websites and applications, including the CTSU members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate registration.htm>. For questions, please contact 
the CTEP Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements for ACNS1721 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted) 
• 
IROC Credentialing Status Inquiry (CSI) Form 
Note: For studies with a radiation and/or imaging (RTI) component, the enrolling site must be 
aligned to a RTI provider.  To manage provider associations access the Provider Association 
tab on the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or 
remove associated providers.  Sites must be linked to at least one IROC credentialed provider 
to participate on trials with an RT component.   
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab 
Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
 

  
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Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory 
Office immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
Data Submission / Data Reporting 
 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave 
via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab 
Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum 
of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered 
as an NPIVR or IVR. Associates can hold read-only roles in Rave. If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on the 
DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on 
the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner of the 
iMedidata page. Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
 
 
 

  
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APPENDIX II:  YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY 
(for children from 7 through 12 years of age) 
 
ACNS1721 
A Study of the Drug Veliparib with Radiation Therapy in Patients with Newly-Diagnosed  
High-Grade Glioma 
 
 
1. We have been talking with you about your cancer. The type of cancer you have is called high-grade 
glioma. High-grade glioma (HGG) is a type of cancer that grows in the brain. After doing tests, we 
have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have HGG. A research study is 
when doctors work together to try out new ways to help people who are sick. This study will see if 
a certain type of treatment will help to keep your cancer away for a longer length of time than the 
normal treatment for this disease. 
 
3. Patients who are part of this study will be treated with radiation (X-rays) followed by anti-cancer 
medicines. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is that you get a 
treatment that works better to get rid of the cancer than the normal treatment. But we don’t know 
for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad things 
are called “risks.” A risk to you in this study is bad health problems from the anti-cancer medicines. 
If this happens you may need treatment for the problems. There is the risk that the cancer may grow 
back while you are taking the anti-cancer medicines. There is also a risk that the cancer may spread 
into other areas of your brain or spine. Other things may happen to you that we don’t yet know 
about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect extra blood and tumor tissue. We want to see if there are 
ways to tell how the cancer will react to treatment. These samples would be taken when other 
standard blood tests are being done, so there would be no extra blood draws. You can still take part 
in this study even if you don't allow us to collect the extra blood samples for research. 
 
 
 
 
 

  
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INFORMATION SHEET REGARDING RESEARCH STUDY 
(for teens from 13 through 17 years of age) 
 
ACNS1721 
A Study of the Drug Veliparib with Radiation Therapy in Patients with Newly-Diagnosed  
High-Grade Glioma 
 
1. We have been talking with you about your cancer. The type of cancer you have is called high-grade 
glioma. High-grade glioma (HGG) is a type of cancer that grows in the brain. The words “high-
grade” mean that the tumor is growing and spreading quickly. After doing tests, we have found that 
you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have HGG. A research study is 
when doctors work together to try out new ways to help people who are sick. This study will see if 
a certain type of treatment will help to keep your cancer away for a longer length of time than the 
normal treatment for this disease. 
 
3. Patients who are part of this study will be treated with radiation (X-rays) followed by anti-cancer 
medicines. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is that you get a 
treatment that works better to get rid of the tumor than the normal treatment. But we don’t know 
for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” A risk to you in this study is bad health problems from the anti-cancer medicines. 
If this happens you may need treatment for the problems. There is the risk that the tumor may grow 
back while you are taking the anti-cancer medicines. There is also a risk that the tumor may spread 
into other areas of your brain or spine. Other things may happen to you that we don’t yet know 
about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have.  
 
7. We are asking your permission to collect extra blood and tumor tissue. We want to see if there are 
ways to tell how the cancer will respond to treatment. These samples would be taken when other 
standard blood tests are being performed, so there would be no extra procedures. You can still take 
part in this study even if you don't allow us to collect the extra blood samples for research. 
 
 
 
 
 

  
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APPENDIX III:  DETAILS OF RAPID CENTRAL PATHOLOGY AND MOLECULAR CENTRAL 
PATHOLOGY REVIEW 
 
Central Pathology Review 
Consistent with all prior COG HGG studies, patient eligibility for this trial will be limited to tumor histology 
consistent with anaplastic astrocytoma or glioblastoma according to the current 2016 World Health 
Organization (WHO) classification.38  
 
The coordination of the central pathology review will be performed by the Children’s Oncology (COG) 
Biopathology Center (BPC), at the Research Institute of Nationwide Children's Hospital, in Columbus, 
Ohio. The BPC is a CAP certified biorepository and has affiliated CAP/CLIA-certified Histology, 
Anatomic Pathology, and Cytogenetic/Molecular Genetics laboratories within the Department of Pathology 
and Laboratory Medicine at Nationwide Children’s Hospital. The BPC already performs centralized testing 
for COG Acute Lymphoblastic Leukemia, Neuroblastoma, and Central Nervous System (CNS) committees. 
The Biopathology Center serves as the COG effector arm of the COG Pathology Discipline Committee and 
the biorepository for COG solid and liquid tumors. The BPC is directed by Dr. Nilsa Ramirez, while 
centralized laboratory testing for the BPC is directed by Dr. Julie Gastier-Foster.  
 
Patients diagnosed with HGG locally will be required to consent to the COG Every Child protocol 
(APEC14B1) to allow for the pre-screening part of the protocol prior to enrolling on the treatment protocol. 
After consent is obtained, formalin-fixed paraffin embedded (FFPE) material and, if available, fresh tumor 
tissue will be submitted directly to the COG Biopathology Center. Patients will also have the option of 
submitting additional material for biology studies via ACNS1721 or consenting to the banking of any 
leftover material from the specimens collected for the required studies for tumor banking and research 
studies through the Every Child Protocol.  
 
Details of required specimens for submission can be found in Section 3.1.1.4. Required samples should be 
shipped with the corresponding pathology report for central neuropathology review by the treating 
institution. Central Neuropathology review will be performed by Dr. Chris Fuller, State University of New 
York Upstate Medical University (SUNY Upstate), with Dr. Chris Pierson, Neuropathologist at Nationwide 
Children's Hospital in Columbus, Dr. Bonnie Cole at Seattle Children’s Hospital in Seattle, or their 
designees acting as backup reviewers.  
 
Slides will be reviewed to confirm the presence of histological features consistent with anaplastic 
astrocytoma or glioblastoma according to the current 2016 World Health Organization (WHO) 
classification. Consistent with all prior COG HGG trials, only patients with a histological diagnosis 
compatible with anaplastic astrocytoma or glioblastoma are eligible for this trial. Difficult cases will be 
discussed among the study neuropathologists so as to achieve a consensus review diagnosis. 
 
Histone H3 K27M immunohistochemistry 
The testing for Histone H3 K27M IHC will be performed by the Department of Pathology and Laboratory 
Medicine at the Cincinnati Children’s Hospital Medical Center (CCHMC) in Cincinnati, OH. Under the 
direction of Dr. Sarangarajan Ranganathan, the Pathology Department houses Histology/Anatomic 
Pathology and Clinical Pathology laboratories, which are CAP/CLIA certified (CLIA ID number: 
36D0656333; CAP Laboratory number: 1667801; Cincinnati BioBank CAP Biorepository number: 
8678477; Date of validation: 01/27/2016). Dr. Christine Fuller at SUNY Upstate will review the H3 K27M 
immunohistochemistry results in conjunction with H&E images (to confirm tumor content for all testing). 
The CCHMC Pathology Department routinely performs H3 K27M immunohistochemistry for clinical 
 
 

  
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diagnostic purposes, as well as for molecular classification of samples for the Diffuse Intrinsic Pontine 
Glioma (DIPG) Registry.  
 
IHC using a Histone H3 K27M mutant-specific antibody will be undertaken on 5 µm sections of formalin-
fixed paraffin-embedded (FFPE) tumor tissue as previously described.1 With Amendment 3A, a 
commercially available primary monoclonal antibody to Histone H3 K27M (EPR18340, Abcam, 
Cambridge, MA, USA; catalog # ab190631, or subsequent equivalent) will be applied at a concentration of 
1:1000 with diaminobenzidine (Ultraview DAB) as the chromogen to reveal antigen-antibody complexes. 
The assay is performed on the Ventana Benchmark Ultra (Tucson, AZ). Appropriate positive and negative 
controls will be used. 
 
H3 K27M IHC sections will be scored for tumor cell nuclear positivity, as this represents the presence of 
H3 K27M mutation within the respective tumor sample. Cytoplasmic and membranous staining of tumor 
cells is not specific and will not constitute an H3 K27M-mutated tumor. In H3 K27M mutant gliomas, the 
mutation is generally present in all tumor cells; therefore tumors with scattered nuclei comprising 5% or 
fewer of tumor nuclei are not regarded as positive. 
 
Results will be presented to treating institutions as positive (H3 K27M mutant) or negative (H3 K27M 
wildtype) by Medidata RAVE notification. In addition, the report will include the histopathological 
diagnosis (glioblastoma, anaplastic astrocytoma) according to the World Health Organization (WHO) 2016 
CNS Tumor Classification. The treating physician will communicate results to patients. 
 
The H3 K27M immunohistochemistry assay was previously optimized and validated in the 
Histology/Anatomic Pathology laboratory in the Department of Pathology and Laboratory Medicine at 
Cincinnati Children’s Hospital Medical Center for physician ordering and testing following College of 
American Pathologists (CAP)/CLIA standards. The laboratory follows all criteria required for the set-up 
and validation of antibodies as established by the CAP and CLIA. The anti-H3 K27M antibody was 
validated according to CAP/CLIA guidelines using a range of dilutions and pretreatment conditions on a 
Ventana Benchmark Ultra immunostainer. DIPG and other HGG tissue samples with previously 
documented H3 K27M mutant positive status (inclusive of cases with documented mutations of H3.3, H3.1, 
and H3.2) served as positive controls while the secondary antibody was omitted for negative controls. Upon 
completion of the optimization runs EDTA pretreatment and an antibody dilution of 1:1000 were 
considered optimal. Individual FFPE slides from 20 HGG samples (with known H3 K27M status) were 
stained under the optimized conditions. All known H3 K27M mutant positive cases showed diffuse strong 
nuclear positivity with H3 K27M IHC (11 out of 11 cases with majority of tumor cell nuclei staining 
positive), while all known H3 K27M wildtype cases show absent nuclear positivity for this same IHC 
(9 out of 9 with 5% or fewer tumor cell nuclei staining positive). Note that the validation of this H3 K27M 
mutant-specific monoclonal antibody (EPR18340, Abcam, Cambridge, MA, USA) was essentially identical 
to that performed for the previously-used H3 K27M monoclonal antibody (SAB5600095, Sigma-Aldrich, 
St Louis, MO, USA); with Amendment 3A, the former antibody is replacing the latter, as SAB5600096 
manufacturing has been discontinued. It is not completely uncommon for IHC antibodies to be discontinued 
and replaced by an equivalent antibody. Therefore, with Amendment 3A, a commercially available primary 
monoclonal antibody to Histone H3 K27M, EPR18340, Abcam, Cambridge, MA, USA; catalog 
# ab190631, or subsequent equivalent, will be utilized for the H3 K27M IHC assay. 
 
Central pathology review on all samples will initially only include histopathological review and H3 K27M 
IHC. The results will be reported to the clinical PI within 7 days of receipt of all required tissue. Patients 
will receive results from the treating physician. Histopathologically confirmed HGG samples that are 
negative for nuclear H3 K27M staining will proceed to further molecular characterization (Mutational 
Analysis of BRAF and IDH1/2 by Next-Generation DNA Sequencing) as described below.  
  

  
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Mutational Analysis of BRAF and IDH1/2 by Targeted Next-Generation DNA Sequencing 
Mutational testing of BRAF codon 600 and IDH1 codon 132/IDH2 codon 172 will be performed by the 
Precision Medicine Laboratory at Cincinnati Children’s Hospital Medical Center (CCHMC) in Cincinnati, 
OH. This is a CAP/CLIA-certified Genetics laboratory within the Department of Human Genetics at 
CCHMC, under the direction of Dr. D. Brian Dawson. The Department of Pathology and Laboratory 
Medicine at CCHMC houses the affiliated CAP/CLIA-certified Histology/Anatomic Pathology and 
Clinical Pathology laboratories. Dr. Christine Fuller, Neuropathologist at SUNY Upstate, will examine 
H&E slides/images (to confirm tumor content for all testing) and coordinate specimen submission to this 
laboratory. 
 
With Amendment 2, testing for both IDH1 codon 132/IDH2 codon 172 and BRAF will be performed on the 
AmpliSeq 50 gene Focus Center Hotspot Panel V2 assay (Illumina, San Diego, CA). The Focus Cancer 
Panel (FCP) is a curated targeted resequencing assay for identifying somatic mutations in 50 clinically 
relevant cancer genes. Genomic DNA is isolated from FFPE tissue and is PCR amplified using 
oligonucleotide primers predesigned for ~2800 COSMIC mutations. Prepared libraries are sequenced on 
the Illumina MiSeqDx. The raw sequence data is aligned to the reference genome (HG19) and variants are 
annotated and reported using GenomOncology (Cleveland, OH). The minimum required sequencing depth 
is 500x. The analytical sensitivity is 5% variant allele frequency (VAF) for detection of SNVs and indels. 
SNV and indel variants in IDH1 codon 132, IDH2 codon 172, and BRAF will be reported. Miscellaneous 
findings (mutations) detected in the other 47 genes covered by this panel will be recorded under the heading 
“Miscellaneous molecular findings,” though will not factor in directly relative to patient stratification for 
this COG study.  
 
The FCP at CCHMC has been previously optimized and validated in accordance with current CAP and 
CLIA standards for molecular testing, and it is routinely utilized as a reportable clinical test at CCHMC. 
The assay has been validated for FFPE samples. For the purposes of the study, genomic DNA extracted 
from FFPE tissue will be run on the Illumina Ampliseq NGS platform as of Amendment 2. Note that the 
validation of the Focus Cancer Panel (AmpliSeq Cancer Hotspot Panel v2, Illumina, San Diego, CA, USA) 
corresponds to that performed for the previously-used dual NGS platforms using both the Ion Ampliseq 
Cancer Hotspot Panel (Life Technologies, Carlsbad, CA, USA) and the Illumina TruSeq Cancer Hotspot 
Panel (Illumina, San Diego, CA, USA); with Amendment 2, the former Focus Cancer Panel is replacing 
the latter due to obsolescence of the TruSeq Custom Amplicon platform. 
 
Upon completion of sequencing, the data undergoes three tiers of data analysis: 
 
Primary analysis: Independent to the biological meaning of the sequence 
a. Converting raw cycle data to raw intensities which are then normalized resulting in per base 
sequence and quality information which is then output as a FASTQ file. 
b. Alignment to the reference (HG19, GRCh37) resulting in a BAM File. 
c. Removal of sequencing duplicates. 
d. Variant calling resulting in a Variant Call File (VCF). 
 
Secondary analysis: 
a. Variant annotation using several curated databases (dbSNP, COSMIC, 1000 Genome). Secondary 
analysis is performed by GenomOncology (GO) Workbench – a sequencing data analysis and 
reporting software suite customized by the vendor to i) pull together sequencing data from the 
MiSeqDx, ii) assess run/sample/variant quality based on thresholds determined during validation, 
and iii) following tertiary analysis, output results into a physician-ready final report. 
 
 
 

  
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Tertiary analysis: 
a. Independent and combined review by a Genomic Analyst and either an Oncologist and/or 
Molecular Geneticist and/or Molecular Pathologist. Combining sequencing metric data with 
biological relevance (actionability) to determine variant status. 
b. Final report generation. 
 
During test validation, patient samples, cell lines and commercial samples were sequenced, including inter- 
and intra-platform repeats. Only samples with one or more gold standard (GS) or concordant variants in 
genomic regions covered by our test were included in the validation (GS included Foundation Medicine 
(for patient samples) and Acrometrix Hotspot Frequency Ladder, HD200 and HD730 (commercial 
samples)). 
 
Reportable Range: For NGS applications, the reportable range can be defined as the portion of the genome 
for which sequence information can be reliably derived for a defined test system. This is defined by the 
combined BED files for the two platform specific panels, plus flanking regions meeting or exceeding 
variant level quality metrics as defined above. 
 
Reference Range: For NGS applications, the reference range can be defined as the range of normal sequence 
variations that the assay is designed to detect within a defined population. Our test looks at over 
20,000 bases and, as such, it is not possible to identify every possible variant that might appear in the normal 
population within that range. However, we classify variants as normal variation or clinically significant as 
they are identified using focused Oncologist/Molecular Director review as well as dbSNP, COSMIC, CIViC 
database, St. Jude PeCan Data Portal and 1000 Genome data through the GO Workbench in order to 
determine variant significance within the defined population, i.e., based on the patient’s diagnosis. 
Furthermore, the GO Workbench tracks the final decision for each specific variant, showing whether or not 
it has been identified before and how it was previously classified. 
 
Precision – Repeatability: > 98% concordance and Reproducibility: > 97% concordance 
 
Interfering Substances: Prior comparison of variant cells between DNA extracted from matched 
fresh/frozen samples and FFPE samples indicated excellent concordance. 
 
Inherent Error Rate of Platform: The platform error rate was reported in 'A tale of three next generation 
sequencing platforms: comparison of Ion Torrent, Pacific Biosciences and Illumina MiSeqDX sequencers’ 
by Quail, MA et al. in BMC Genomics. 
 
MiSeq- 0.8% 
 
Repetitive regions overlapping target regions in both assays were identified using the UCSC Table Browser 
found at http://genome.ucsc.edu/cgi-bin/hgTables. The panel target definition files (BED files) for each 
panel were uploaded to the table browser. The target definitions were used to intersect to RepeatMasker, 
Interrupted Repeats, and Simple Repeats tables to identify repeat elements overlapping the target regions. 
The table browser was also used to determine regions of homology and G/C content. 
 
 
 
 
 

  
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APPENDIX VI:  PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD  
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions 
with Other Drugs and Herbal Supplements  
 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to the patient at the 
time of enrollment.  Use or modify the text as appropriate for the study agent, so that the patient is aware 
of the risks and can communicate with their regular prescriber(s) and pharmacist.  A convenient wallet-
sized information card is also included for the patient to clip out and retain at all times.  If you choose to 
use them, please note that the information sheet and wallet card will require IRB approval before 
distribution to patients.] 
 
 
The patient ____________________________ is enrolled on a clinical trial using the experimental study 
drug veliparib (ABT-888).  This clinical trial is sponsored by the National Cancer Institute.  This form is 
addressed to the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
 
Veliparib may interact with certain transporter proteins that help move drugs in and out of cells. 
 
 The proteins in question are OCT1/2, OATPs, MATE1, MATE2K, and P-gp. Veliparib is a 
substrate of P-gp, OCT2, and MATE1/2K and may be affected by other drugs that inhibit these 
protein transporters. Veliparib is an inhibitor of OATPs, OCT1/2, and MATE1/2K, and may 
affect transport of other drugs in and out of cells.  
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Veliparib may interact with other drugs which can cause side effects.  For this reason, it is very important 
to tell your study doctors of any medicines you are taking before you enroll onto this clinical trial.  It is also 
very important to tell your doctors if you stop taking any regular medicines, or if you start taking a new 
medicine while you take part in this study.  When you talk about your current medications with your doctors, 
include medicine you buy without a prescription (over-the-counter remedy), or herbal supplements such as 
St. John’s Wort.  It is helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
 
Use caution when administering veliparib with other medicines that need certain transport protein to be 
effective or to be cleared from your system.  Before you enroll onto the clinical trial, your study doctor 
will work with your regular health care providers to review any medicines and herbal supplements.  
 
  Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
  Your regular health care provider should check a frequently updated medical reference or call 
  

  
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your study doctor before prescribing any new medicine or discontinuing any medicine.  Your 
study doctor’s name is  
 
_____________________________________ and he or she can be contacted at  
 
_____________________________________.                                                                                     June 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
 
You are enrolled on a clinical trial using the experimental study drug 
veliparib  (ABT‐888).    This  clinical  trial  is  sponsored  by  the  NCI.    
Veliparib  (ABT‐888)  may  interact  with  drugs  that  need  certain 
transport proteins in your body.  Because of this, it is very important 
to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over‐the‐counter medicine or herbal supplement. 
Use caution as veliparib (ABT‐888) may interact with medicines that 
stop transport proteins MATE1/2K, OCT2, and P‐gp to process further 
in the body.  
 
Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements. 
 Do NOT drink orange juice, other citrus based juice, or grapefruit 
juice on the days you take veliparib oral solution. 
 Before prescribing new medicines, your regular prescribers 
should go to a frequently‐updated medical reference for a list of 
drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is ________________________  
and can be contacted at _________________________.  
 
 

  
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APPENDIX IX: POSSIBLE DRUG INTERACTIONS  
Temozolomide 
 
Some drugs, food, and supplements may interact with temozolomide.  Examples include: 
 
Drugs that may interact with temozolomide* 
 Clozapine, leflunomide, natalizumab, tofacitinib, valproate products 
 
Food and supplements that may interact with temozolomide** 
 Echinacea 
 
*Sometimes these drugs are used with temozolomide on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
The list above does not include everything that may interact with your chemotherapy. Talk to your doctor 
before starting any new medications, over-the-counter medicines, or herbal supplements and before 
making a significant change in your diet. 
 
 
 
 

  
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