Clinical trial NCT01189266
Conditions: Anaplastic Astrocytoma Anaplastic Oligoastrocytoma Diffuse Intrinsic Pontine Glioma Gliosarcoma
Sponsor: National Cancer Institute (NCI)
Start date: 2010-08-09; Completion date: 2021-09-30
Enrollment: 79 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects and best dose of vorinostat and to see how well it works when given together with radiation therapy followed by maintenance therapy with vorinostat in treating younger patients with newly diagnosed diffuse intrinsic pontine glioma (a brainstem tumor). Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vorinostat together with radiation therapy may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

l. To estimate the maximum tolerated dose (MTD) or recommend a phase 2 dose of vorinostat given concurrently with radiation in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

II. To define and describe the toxicities of vorinostat given concurrently with radiation in children with newly diagnosed DIPG.

III. To determine, in the context of this phase I/II trial, the anti-tumor activity of combining vorinostat with radiation, followed by maintenance vorinostat for twelve courses, in children with newly diagnosed DIPG, as measured by 12-month event-free survival (EFS) and overall survival (OS).

IV. To determine the toxicities of vorinostat for 12 additional courses after completion of vorinostat and radiation.

SECONDARY OBJECTIVES:

I. To measure non-homologous end-joining (NHEJ) activity in peripheral blood mononuclear cells (PBMCs) before treatment, at 2 weeks after starting vorinostat and radiation, and at the end of radiation.

II. To measure histone deacetylase 2 (HDAC2) levels and assess histone acetylation in PBMCs before treatment, at 2 weeks after starting vorinostat and radiation, and at the end of radiation.

III. To quantify deoxyribonucleic acid (DNA) repair proteins from the NHEJ and homologous recombination repair (HHR) pathways in tumors by either Western analysis or immunohistochemistry, if paraffin-embedded tumor is available.

OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study.

Patients receive vorinostat orally (PO) on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients undergo 3-dimensional (3D) conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. Patients then receive maintenance therapy comprising vorinostat PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months.

Arms: arm 1: Patients in phase I received vorinostat at 180 mg/m\^2/day PO on Monday through Friday weekly for the duration of radiation therapy (6-7 weeks). Patients underwent 3D conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. After completing concurrent vorinostat and radiation therapy, patients then received maintenance therapy comprising of vorinostat at 230 mg/m\^2/day PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients received a higher dose of vorinostat at 230 mg/m\^2/day PO on Monday through Friday weekly for the duration of radiation therapy (6-7 weeks). Patients underwent 3D conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. After completing concurrent vorinostat and radiation therapy, patients then received maintenance therapy comprising of vorinostat at 230 mg/m\^2/day PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. arm 3: Patients received a higher dose of vorinostat at 230 mg/m\^2/day PO on Monday through Friday weekly for the duration of radiation therapy (6-7 weeks). Patients underwent 3D conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. After completing concurrent vorinostat and radiation therapy, patients then received maintenance therapy comprising of vorinostat at 230 mg/m\^2/ day PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: 3-Dimensional Conformal Radiation Therapy intervention 2: Intensity-Modulated Radiation Therapy intervention 3: Laboratory Biomarker Analysis intervention 4: Vorinostat
Intervention descriptions: intervention 1: Undergo 3D conformal radiation therapy intervention 2: Undergo intensity-modulated radiation therapy intervention 3: Correlative studies intervention 4: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
 
ACNS0927 
 
 
 i 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Chief Administrative Officer 
Maria Hendricks, M.S.N, R.N. 
C.C.R.P. 
hendricksm@email.chop.edu  
 
Group Statistician 
Meenakshi Devidas, Ph.D. 
mdevidas@cog.ufl.ed 
 
Associate Group  
Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
P 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
A National Cancer Institute  
supported clinical cooperative 
group and Equal Opportunity 
Affirmative Action Institutions 
 
 
 
 
 
 
 
 
 
August 6, 2014 
 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
 
Dear Ms. Kruhm, 
 
 
The study committee for ACNS0927, A Phase 1/2 Study of Suberoylanilide Hydroxamic 
Acid (Saha, Vorinostat) and Local Irradiation, Followed by Maintenance Saha in 
Children with Newly Diagnosed Diffuse Intrinsic Pontine Gliomas (DIPG) has provided 
Amendment #3A, dated 08/06/2014 for CTEP review. This amendment is being submitted 
in response to a Request for Amendment (RA) from Dr. Richard L. Piekarz 
(rpiekarz@nih.gov) received on April 3, 2014. 
 
In this amendment, the vorinostat monograph has been modified to reflect the 
incorporation of the revised Comprehensive Adverse Events and Potential Risks (CAEPR) 
list for vorinostat provided by the NCI. The changes made due to this request are detailed 
below. Administrative updates have also been made throughout the protocol and are 
tracked. 
 
The ACNS0927 study committee looks forward to approval of this amendment. 
 
Sincerely, 
 
Meg Stahlman, Protocol Coordinator (for) 
Jack Su, MD, MS, Study Chair, ACNS0927 
 


 
 
ACNS0927 
 
 
 ii 
 
SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the protocol. Additions 
are in boldfaced font and deletions in strikethrough font. 
# 
Section 
Page(s) 
Change 
1.  
 
Reference to the “Adverse Event Expedited Reporting System 
(AdEERS)” have been changed to “CTEP Adverse Event Reporting 
System (CTEP-AERS)” throughout the protocol. 
2. Title Page 
1 
The Version date and Amendment number have been updated with 
this amendment. 
3. Table of 
Contents 
2-5 
The table of contents has been updated. 
4. Study 
Committee 
6-8 
The contact information for multiple members has been updated 
Ashish Mark Ingle and Gencie Turner have been removed, Mehek 
Hasija has been replaced by Sung Tse as Research Coordinator, and 
Mark Krailo has replaced Baojiang Chen as Phase 2 Senior 
Statistician.  
5. 9.1 
37-42 
• The SPEER grades have been updated. 
 
Added New Risk:   
• 
Also Reported on Vorinostat Trials But With the 
Relationship to Vorinostat Still Undetermined:  Abducens 
nerve disorder; Cardiac disorders - Other (supraventricular 
arrhythmia); Euphoria; Eye disorders - Other (retinal tear); 
Gastroesophageal reflux disease; Gastrointestinal 
disorders - Other (duodenitis); Hyperuricemia; Irregular 
menstruation; Metabolism and nutrition disorders - Other 
(decreased total protein); Musculoskeletal and connective 
tissue disorders – Other (myositis); Oral pain; Skin and 
subcutaneous disorders – other (brittle nails); Somnolence; 
Stroke; Vaginal hemorrhage; Visceral arterial ischemia 
 
Decrease in Risk Attribution: 
• 
Changed to Reported But Undetermined from Less 
Likely:  Alkaline phosphatase increased; 
Hypoalbuminemia; Hyponatremia; Musculoskeletal and 
connective tissue disorders - Other (muscle spasms) 
 
Provided Further Clarification: 
• 
General disorders and administration site conditions – 
Other (angioedema) is now reported as Immune system 
disorders – Other (angioedema). 
• 
Infections and infestations – Other (Herpes zoster) is now 
included in the previously reported risk “Infection”. 


 
 
ACNS0927 
 
 
 iii 
# 
Section 
Page(s) 
Change 
 
Deleted Risk:  
• 
Deleted from Reported But Undetermined:  Arthralgia; 
Death NOS; Gingival pain; Hypernatremia; 
Hypoglycemia; Hypomagnesemia; Insomnia; Nasal 
congestion; Pharyngolaryngeal pain; Pruritus; Vascular 
disorders - Other (arterial thrombosis); Vasculitis 
 
The following COG template update has been made: 
Active 
CTEP-registered 
investigators 
and 
investigator-designated 
shipping 
designees 
and 
ordering designees can must submit agent requests 
through the PMB Online Agent Order Processing 
(OAOP) 
application 
< 
https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  >.  Access to 
OAOP requires the establishment of a CTEP Identity 
and 
Access 
Management 
(IAM) 
account 
< 
https://eapps-ctep.nci.nih.gov/iam/ 
> 
and 
the 
maintenance of an “active” account status and a 
“current” password.  Alternatively, site personnel can 
fax completed Clinical Drug Requests (NIH-986) to 
the Pharmaceutical Management Branch at (301) 480-
4612.  For questions about drug orders, transfers, 
returns, or accountability, call (301240) 496276-5725 
6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) or email PMBAfterHours@mail.nih.gov 
anytime. 
 
The current version of the protocol contained Version 2.6 of the 
CAEPR. The following changes represent the changes from Version 
2.6 to 2.7 of the CAEPR: 
• 
Vorinostat (SAHA, Zolinza, NSC 701852) 
• 
Below is the CAEPR for vorinostat (SAHA, Zolinza). 
• 
Version number and date updated 
• 
Relationship to Vorinostat (SAHA, Zolinza) 
• 
Specific Protocol Exceptions to Expedited Reporting 
(SPEER) (formerly known as ASAEL) 
• 
Also reported on vorinostat (SAHA, Zolinza) trials 
but with the relationship to vorinostat (SAHA, 
Zolinza) still undetermined: 
• 
Note: Vorinostat (SAHA, Zolinza) 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. 
6. 11.3.1 
46-47 
The statistical section for Part B has been expanded to clarify the 
evaluable patients as follows: 
Efficacy Endpoints  


 
 
ACNS0927 
 
 
 iv 
# 
Section 
Page(s) 
Change 
The primary endpoint for the evaluation of treatment efficacy 
will be event-free survival (EFS), defined as the time to 
disease progression, disease relapse, occurrence of a second 
neoplasm, or death from any cause, or date of last follow-up 
measured from the time of study enrollment. 
 
Definitions of Evaluable 
 
Part B:  
Evaluable for Adverse Events and Efficacy 
Patients will be considered evaluable for adverse events 
and efficacy if they meet the following criteria: (1) the 
patient is eligible; (2) the patient receives one dose of 
vorinostat at the MTD determined in Phase 1 (230 
mg/m2/day) per protocol guidelines, and (3) if central 
review is required, the patient is confirmed to have eligible 
diagnosis. 
 


 
 
ACNS0927 
 
 
 v 
 
SUMMARY OF CHANGES: INFORMED CONSENT DOCUMENT A AND B 
 
In accordance with the above discussion, the following specific revisions have been made to the Informed Consent 
Document(s). Additions are in boldfaced font and deletions in strikethrough font. 
# 
Section 
Page(s) 
Change 
1.  
 
The version dates have been updated. 
2. 
ICD A: 
During the 
study 
ICD B: 
Research 
study tests 
and 
procedures 
4 
The following statement has been added to the ICD A section 
“During the Study” and ICD B section “Research Study Tests 
and Procedures”: 
The drugs used in this study may affect how 
different parts of your body work such as your liver, 
kidneys, heart, and blood. The study doctor will be 
testing your blood and will let you know if changes 
occur that may affect your health. You may develop 
high or low levels of certain salts in the body which 
may require you to take another medicine to correct 
the salt level. 
3. 
What side 
effects or 
risks can I 
expect from 
being in the 
study? 
6-7 
The risks table has been revised and now reflects the risk profile 
provided by CTEP in the “patient-friendly” condensed format. 
 
As noted by CTEP in the Request for Amendment the following 
Decrease in Risk Attribution:  
• 
Changed to Reported But Undetermined from 
Occasional: Muscle spasms 
 
The following statement has been added below the risk insert: 
Some drugs or supplements may interact with your 
treatment plan. Talk to your doctor, pharmacist, or 
study team before starting any new prescription or 
over-the-counter drugs, herbals, or supplements and 
before making a significant change in your diet.  
Supplements may come in many forms, such as teas, 
drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. 
4. 
What are 
the costs of 
taking part 
in this 
study? 
10 
The following COG template update has been made: 
For more information on clinical trials and insurance 
coverage, you can visit the National Cancer Institute’s 
Web 
site 
at 
http://www.cancer.gov/clinicaltrials/learningabout.htt
p://cancer.gov/clinicaltrials/learning/insurance-
coverage/.  You can print a copy of the “Clinical Trials 
and Insurance Coverage” information from this Web 
site. 
 


 
 
ACNS0927 
 
 
 vi 
# 
Section 
Page(s) 
Change 
5. 
What are 
my rights if 
I take part 
in this 
study? 
10 
The following COG template update has been made: 
During your follow-up visits, you may ask to be given 
a summary of the study results, which will only be 
available after the study is fully completed. A 
summary of the study results will also be posted on 
the 
Children’s 
Oncology 
Group 
website 
(http://www.childrensoncologygroup.org/). 
To 
receive the results, you may either (1) go to the COG 
website to check if results are available or (2) register 
your information with the COG on its web site and 
have an email sent to you when the results are 
available. Your pediatric oncology team from your 
hospital can give you additional instructions on how 
to do this. Please note, that the summary of results 
may not be available until several years after 
treatment for all children on the study is completed, 
and not only when your child completes treatment. 
6. 
Where can I 
get more 
information
? 
11 
The following COG template updates have been made: 
The COG Family Handbook for Children with Cancer 
has information about specific cancers, tests, treatment 
side effects and their management, adjusting to cancer, 
and resources.  Your doctor can get you this Handbook, 
or 
you 
can 
get 
it 
at 
www.curesearch.comhttp:///www.childrensoncologygroup
.org/familyhandbook.   
 
A description of this clinical trial will be available at: 
http://www.ClinicalTrials.gov, as required by U.S. 
Law. This web site will not include information that 
can identify you. At most, the web site will include a 
summary of the results. You can search this web site 
at any time. 
 
 
 
 
 
 
 


 
 
ACNS0927 
 
 
Page 1 
Activated: 
August 9, 2010 
Version Date: 
8/06/14 
Closed: 
 
Amendment #: 
3A 
 
 
 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
ACNS0927 
 
A PHASE 1/2 STUDY OF SUBEROYLANILIDE HYDROXAMIC ACID (SAHA, VORINOSTAT) 
AND LOCAL IRRADIATION, FOLLOWED BY MAINTENANCE SAHA IN CHILDREN WITH 
NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG) 
 
Phase 1: Initial Participation Limited to the COG Phase 1 Consortium 
 
Phase 2: Open to COG Institutions in the United States, Canada, Australia and New Zealand  
 
 
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 
 
Jack Su, MD, MS 
Texas Children’s Cancer Center 
Baylor College of Medicine 
6701 Fannin Street, CC 1410 
 
 
 
 
 
Houston, Texas 77030 
Phone: 832 822-4306 
Fax: 832 825-1503 
E-mail: jmsu@txch.org 
 
For Group Operations and Statistics & Data Center Contacts See: http://members.childrensoncologygroup.org 


 
 
ACNS0927 
 
 
Page 2 
TABLE OF CONTENTS 
SECTION 
PAGE 
STUDY COMMITTEE 
5 
ABSTRACT 
8 
EXPERIMENTAL DESIGN SCHEMA 
9 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
10 
1.1 
Primary Aims 
10 
1.2 
Secondary Aims 
10 
2.0 
BACKGROUND 
10 
2.1 
Introduction/Rationale for Development 
10 
2.2 
Preclinical Studies 
12 
2.3 
Adult Studies of Vorinostat 
13 
2.4 
ADVL0416, A Pediatric Phase 1 Study of Vorinostat 
14 
2.5 
Overview of Proposed Pediatric Study 
15 
3.0 
STUDY ENROLLMENT 
17 
3.1 
Patient Registration 
17 
3.2 
IRB Approval 
17 
3.3 
Reservation Requirements 
17 
3.4 
Institutional Pathology Report 
18 
3.5 
Study Enrollment 
18 
3.6 
Timing 
18 
4.0 
PATIENT ELIGIBILITY 
18 
4.1 
Inclusion Criteria 
19 
4.2 
Exclusion Criteria 
20 
4.3 
Regulatory 
21 
5.0 
TREATMENT PROGRAM 
22 
5.1 
Overview of Treatment Plan 
22 
5.2 
Criteria for Starting Subsequent Cycles (Part A and B) 
24 
5.3 
Dose Escalation Schema 
25 
5.4 
Vorinostat Maintenance Therapy (Parts A and B) 
26 
5.5 
Grading of Adverse Events 
26 
5.6 
Definition of Dose-Limiting Toxicity (DLT) 
26 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
27 
6.1 
Dose Modification for DLT During Vorinostat and Concurrent Radiation                    
(Parts A and B) 
27 
6.2 
Dose Modification During Maintenance Phase (Parts A and B) 
28 
6.3 
DSMB Monitoring of Toxicities During Maintenance 
29 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
29 
7.1 
Concurrent Anticancer Therapy 
29 
7.2 
Investigational Agents 
29 
7.3 
Supportive Care 
29 
7.4 
Growth Factors 
29 
7.5 
Concomitant Medications 
29 
7.6 
Management of Diarrhea 
29 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
31 


 
 
ACNS0927 
 
 
Page 3 
8.1 
Required Clinical, Laboratory and Disease Evaluations 
31 
8.2 
Required Observations Following Completion of Protocol Therapy 
33 
8.3 
Correlative Studies 
33 
8.4 
Tumor Specimens 
34 
9.0 
AGENT INFORMATION 
36 
9.1 
VORINOSTAT 
36 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY       
CRITERIA 
42 
10.1 
Criteria for Removal from Protocol Therapy 
42 
10.2 
Off Study Criteria 
42 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
43 
11.1 
Sample Size and Study Duration 
43 
11.2 
Part A of the Study 
43 
11.3 
Part B of the Study 
45 
11.4 
Gender and Minority Accrual Estimates 
49 
11.5 
Correlative Studies 
49 
12.0  
EVALUATION CRITERIA 
50 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
50 
12.2 
Methodology to Determine Tumor Measurement 
50 
12.3 
Selection of Target and Non-Target Lesions 
52 
12.4 
Response Criteria for Target Lesions 
52 
12.5 
Overall Response Assessment 
52 
12.6 
Best Response 
53 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
53 
13.1 
Purpose 
53 
13.2 
Determination of reporting requirements 
53 
13.3 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
54 
13.4 
Reporting methods 
54 
13.5 
When to report an event in an expedited manner 
55 
13.6 
Other recipients of adverse event reports 
55 
13.7 
Reporting of Adverse Events for investigational agents 
55 
13.8 
Routine Adverse Event Reporting 
59 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
60 
14.1 
Categories of Research Records 
60 
14.2 
CDUS 
60 
14.3 
CRADA/CTA 
60 
14.4 
Data and Safety Monitoring Plan 
62 
15.0 
RADIATION THERAPY GUIDELINES 
63 
15.1 
Indications for Radiation Therapy 
64 
15.2 
Timing 
64 
15.3 
Emergency Irradiation 
64 
15.4 
Equipment and Methods of Delivery and Verification 
64 
15.5 
Target Volumes 
65 
15.6 
Target Dose 
66 
15.7 
Treatment Technique 
67 
15.8 
Organs at Risk 
68 
15.9 
Dose Calculations and Reporting 
69 


 
 
ACNS0927 
 
 
Page 4 
15.10 Quality Assurance Documentation 
69 
15.11 Definitions of Deviations in Protocol Performance 
71 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
72 
APPENDIX II:  ENZYME INDUCING AND NON-ENZYME INDUCING ANTICONVULSANTS 
73 
APPENDIX III: VORINOSTAT DOSING NOMOGRAM FOR CAPSULE FORMULATION 
74 
APPENDIX IV-A: PATIENT DIARY FOR VORINOSTAT CAPSULE ADMINISTRATION      
DURING CHEMORADIOTHERAPY (Part A only) 
75 
APPENDIX IV-B: PATIENT DIARY FOR VORINOSTAT PEDIATRIC SUSPENSION DURING 
CHEMORADIOTHERAPY (Part A only) 
78 
APPENDIX IV-C: PATIENT DIARY FOR VORINOSTAT (CAPSULE OR PEDIATRIC 
SUSPENSION) DURING MAINTENANCE THERAPY (PART A ONLY) 
81 
APPENDIX V: BLOOD SAMPLE COLLECTION GUIDE FOR CORRELATIVE BIOLOGY      
STUDIES  (PART A AND PART B OF STUDY) 
83 
APPENDIX VI: CORRELATIVE STUDY FORM (PART A AND PART B OF STUDY, DURING 
RADIATION THERAPY) 
84 
APPENDIX VII: YOUTH INFORMATION SHEETS (PART B ONLY) 
85 
APPENDIX VIII: TUMOR SPECIMEN (PART A AND PART B OF STUDY) 
87 
APPENDIX IX: ACNS0927 CHEMORADIOTHERAPY ROADMAP (PART B) 
88 
APPENDIX X: ACNS0927 MAINTENANCE ROADMAP (PART A AND B) 
90 
REFERENCES 
91 
 


 
 
ACNS0927 
 
 
Page 5 
STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Jack Meng-Fen Su, MD 
Susan Blaney, MD 
Hematology/Oncology 
Chair, Developmental Therapeutics 
Baylor College of Medicine 
Hematology/Oncology  
6621 Fannin Street 
Baylor College of Medicine 
MC3-3320 
Clinical Care Center 
Houston, TX  77030 
6621 Fannin Street, Suite 1410 
Phone:  
(832) 822-4306 
CC1410.00 
Fax: 
(832) 825-1503 
Houston, TX  77030-2399 
E-mail: 
jmsu@txch.org 
Phone: (832) 822-4586 
 
Fax: 
(832) 825-4299 
STUDY VICE CHAIR 
E-mail: smblaney@txch.org 
Lindsay Baker Kilburn, MD 
 
Hematology/Oncology 
Brenda Weigel, MD 
Children’s National Medical Center 
Vice Chair, Developmental Therapeutics 
Center for Cancer & Blood Disorders  
Hematology/Oncology 
111 Michigan Avenue NW 
University of Minnesota Medical Center - Fairview 
Washington, District of Columbia, 20010 
Department of Pediatrics, Hem/Onc/BMT 
Phone: 
(202) 476-2800 
420 Delaware Street, SE 
Fax: 
(202) 476-5685 
MMC 366 
E-mail: 
lkilburn@cnmc.org 
Minneapolis, MN 55455 
 
Phone: (612) 626-5501 
 
Fax: 
(612) 624-3913 
SENIOR STATISTICIAN (Phase 1) 
E-mail: weige007@umn.edu 
Charlotte Hsieh Ahern, PhD 
 
Statistics 
Regina Irene Jakacki, MD  
Baylor College of Medicine 
Hematology/Oncology 
One Baylor Plaza, BCM 600 
Children’s Hospital of Pittsburgh of UPMC  
Houston, TX  77030 
One Children’s Hospital Drive 
Phone: 
(713) 798-1630 
4401 Penn Ave  
Fax: 
(713) 798-1642 
Faculty Pavillion Bldg, 8th Floor  
E-mail: 
chahern@bcm.edu 
Pittsburgh, PA  15224 
 
Phone: (412) 692-7056 
SENIOR STATISTICIAN (Phase 2) 
Fax: 
(412) 692-3412 
Mark Krailo, Ph.D. 
E-mail: Regina.Jakacki@chp.edu 
Statistics 
 
Children's Oncology Group - Operations Center 
Amar Gajjar, MD 
Statistics 
Hematology/Oncology 
222 E. Huntington Drive 
St. Jude Children's Research Hospital Memphis 
Monrovia, CA  91106 
Hematology/Oncology 
Phone: 
(626) 241-1529 
262 Danny Thomas Place 
Fax: 
(626) 445-4334 
MS 260 
E-mail: 
mkrailo@childrensoncologygroup.org 
Memphis, TN, 38105-3678 
 
Phone: (901) 595-2615 
 
Fax: 
(901) 521-9005 
 
E-mail: amar.gajjar@stjude.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Page 6 
 
STUDY COMMITTEE MEMBERS  
Patricia A. Baxter, MD 
Xiao-Nan Li, MD, PhD 
Hematology/Oncology 
Laboratory Science  
Baylor College of Medicine 
Baylor College of Medicine 
Pediatric Oncology 
Pediatrics 
6621 Fannin St 
6621 Fannin Street 
CCC 1500.00 
MC 3-3320 
Houston, TX  77030-2399 
Houston, TX  77030 
Phone: (832) 822-4200 
Phone: 
(832) 822-4277 
Fax: 
(832) 825-1453 
Fax: 
(832) 824-4038 
E-mail: pabaxter@txch.org 
E-mail: 
xxli@txch.org 
 
 
STUDY NURSE 
Adekunle Michael Adesina, MD, PhD 
Kathryn Cameron, BSN 
Pathology 
Childrens Hospital of Orange County 
Baylor College of Medicine 
Research Oncology 
Department of Pathology 
455 S. Main Street 
One Baylor Plaza 
Orange, California  92868 
Houston, TX  77030 
Phone: 714 532-8646 
Phone: 
(832) 824-5859 
Fax: 714 516-4365 
Fax: 
(832) 825-1032 
E-mail: kcameron@choc.org 
E-mail: 
aadesina@bcm.tmc.edu 
  
 
STUDY CRA 
 
Susan Burlingame, BS 
David Bruce Mansur, MD 
Pediatrics 
Radiation Oncology 
Baylor College of Medicine 
Washington University School of Medicine 
1102 Bates, MC3-3320 
Radiation/Oncology 
Houston, TX 77030 
4939 Children's Place 
Phone:   (832) 824-1532 
Suite #5500, Box 8224 
Fax:  
 (832) 825-1198 
St. Louis, MO  63110 
E-mail: susanb@bcm.edu  
Phone: 
(314) 362-8516 
 
Fax: 
(314) 362-8521 
RESEARCH COORDINATOR PHASE 2 
E-mail: 
mansur@radonc.wustl.edu  
Sung Tse 
  
Children's Oncology Group - Operations Center 
Daphne Haas-Kogan, MD 
222 E. Huntington Drive  
Radiation Oncology 
Monrovia, CA  91106 
UCSF Medical Center - Parnassus 
Phone: (626) 241-1663 
Radiation Oncology 
Fax: 
(626) 445-4334 
2356 Sutter St., 1st Floor 
E-mail: stse@childrensoncologygroup.org 
San Francisco, CA  94115-0226 
 
Phone: 
(415) 353-8900 
 
Fax: 
(415) 353-8679 
 
E-mail: 
hkogan@radonc17.ucsf.edu  
 
 
 
Thomas Merchant, DO, PhD 
 
Radiation Oncology 
 
St. Jude Children’s Research Hospital Memphis 
 
Radiological Sciences 
 
262 Danny Thomas Place MS 220 
 
Memphis, Tennessee  38105-3678 
 
Phone: (901) 595-3604 
 
Fax: (901) 595-3113 
 
E-mail: Thomas.merchant@stjude.org 
 
 
 


 
 
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Page 7 
 
 
PROTOCOL COORDINATOR PHASE 1 
 
Catalina Martinez, BA 
 
Children's Oncology Group - Operations Center 
 
Study Development Office 
 
440 E. Huntington Drive, 4th Floor 
 
Arcadia, CA  91006 
 
Phone: (626) 241-1543 
 
Fax: 
(626) 445-4334 
 
E-mail: cmartinez@childrensoncologygroup.org  
 
 
 
PROTOCOL COORDINATOR PHASE 2 
 
Chris Williams-Hughes   
 
Children's Oncology Group - Operations Center 
 
222 E. Huntington Drive 
 
Monrovia, CA  91106 
For Group Operations (GOC) and 
Phone: (660) 553-5049 
Statistics & Data Center (SDC) contacts see: 
Fax: 
(626) 445-4334 
http:members.childrensoncologygroup.org  
E-mail: cwilliams@childrensoncologygroup.org 
 
 
AGENT NSC# AND IND#’s  
 
Vorinostat (SAHA) NSC# 701852 IND# 71976 
 
 
SEE SECTION 8.3.6 AND 8.4.4 FOR SPECIMEN SHIPPING ADDRESSES 
 


 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects.  The Certificate protects 
against the involuntary release of information about subjects collected during the course of our covered 
studies.  The researchers involved in the studies cannot be forced to disclose the identity or any 
information collected in the study in any legal proceedings at the federal, state, or local level, regardless 
of whether they are criminal, administrative, or legislative proceedings.  However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain circumstances.  For 
example, if the subject or his/her guardian requests the release of information in writing, the Certificate 
does not protect against that voluntary disclosure.  Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program evaluation 
or an FDA request under the Food, Drug and Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm 
to self or others. 
 
ABSTRACT 
 
This is a phase 1/2 study to determine the maximum tolerated dose (MTD) of suberoylanilide hydroxamic 
acid (SAHA; vorinostat) in combination with radiation therapy and the efficacy of administering 
vorinostat concurrently with radiation therapy, followed by maintenance therapy with vorinostat, in 
patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG).  
 
This study consists of two parts: Part A, which is the phase 1 dose-finding study to define the MTD of 
vorinostat in combination with radiation therapy, and Part B, which is the phase 2 portion of the study to 
measure the efficacy of continuing vorinostat as maintenance therapy after radiation. Part A of the study 
will be completed within the COG Phase 1 Consortium. After completion of radiation and vorinostat, 
patients in Part A will continue to receive vorinostat as maintenance therapy at the MTD defined in 
ADVL0416. For Part B of the study, patients will receive vorinostat, at 230 mg/m2/day (the MTD 
determined in Part A of the study), with concurrent radiation, and then continue maintenance therapy with 
vorinostat at the MTD defined in ADVL0416, for a maximum of 12 courses. Part B of the study will take 
place at member COG institutions, group wide. 
 
The primary endpoints for toxicity and safety monitoring of vorinostat in combination with radiation 
therapy include DLTs and toxic death. Toxicities for maintenance therapy will also be determined. The 
primary endpoint for the evaluation of treatment efficacy will be 1-year event-free survival (EFS), and a 
secondary endpoint will be overall survival (OS). EFS and OS outcomes will be compared to historical 
control data from ACNS0126 and CCG-9941. 
 
Assessment of histone acetylation, HDAC2 level, and non-homologous end-joining (NHEJ) activity from 
peripheral blood mononuclear cells (PBMC) will be performed pre-treatment, at 2 weeks after starting 
vorinostat and radiation treatment, and at completion of vorinostat and radiation treatment. If paraffin-
embedded tumor samples are available, then HDAC 2 level, NHEJ activity, and/or protein levels of key 
repair proteins in the NHEJ and homologous recombination repair (HRR) pathways will be determined. 
Any correlation between these biologic studies and clinical outcome will be explored. 
 


 
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EXPERIMENTAL DESIGN SCHEMA 
 
Part A (Phase 1 Consortium) 
 
As of Amendment #2, Part A was completed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part B (Phase 2 Open to COG Institutions in the United States, Canada, Australia and New 
Zealand) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Each Maintenance therapy cycle is 28 days. 
 
 
* Cycles will continue in the absence of disease progression or excessive toxicity. 
 
+ Response evaluation per section 8.1 and section 12.4. 
Study Entry 
Chemoradiotherapy (Table 1, section 5.3.1): 
Dose escalation and determination of vorinostat MTD 
when administered concurrently with RT 
(54 Gy total dose in 1.8 Gy daily fractions)  
Maintenance Therapy (Table 2, section 5.4): 
 
Vorinostat (230 mg/m2/day by mouth continuously) 
for a maximum of 12 cycles*+ 
Study Entry 
Chemoradiotherapy: 
 
Vorinostat 230 mg/m2/day Monday through Friday (at 
the MTD determined on Part A) 
concurrently with RT 
Maintenance Therapy (Table 2, section 5.4): 
 
Vorinostat (Dose Level 1: 230 mg/m2/day, continuously)  
for a maximum of 12 cycles*+ 


 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To estimate the maximum tolerated dose (MTD) or recommend a Phase 2 dose of 
vorinostat given concurrently with radiation in children with newly diagnosed 
diffuse intrinsic pontine glioma (DIPG). 
 
1.1.2 
To define and describe the toxicities of vorinostat given concurrently with 
radiation in children with newly diagnosed DIPG. 
 
1.1.3 
To determine, in the context of this phase I/II trial, the anti-tumor activity of 
combining vorinostat with radiation, followed by maintenance vorinostat for 
twelve courses, in children with newly diagnosed DIPG, as measured by 
12-month event-free survival (EFS) and overall survival (OS). 
 
1.1.4 
To determine the toxicities of vorinostat for 12 additional courses after 
completion of vorinostat and radiation. 
 
1.2 
Secondary Aims 
 
1.2.1 
To measure NHEJ activity in PBMCs before treatment, at 2 weeks after starting 
vorinostat and radiation, and at end of radiation therapy. 
 
1.2.2 
To measure HDAC2 levels and assess histone acetylation in PBMCs before 
treatment, at 2 weeks after starting vorinostat and radiation, and at end of 
radiation therapy. 
 
1.2.3 
To quantify DNA repair proteins from the NHEJ and HHR pathways in tumors 
by either Western analysis or immunohistochemistry, if paraffin-embedded tumor 
is available. 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
 
2.1.1 
Diffuse Intrinsic Pontine Gliomas in Children 
Diffuse intrinsic pontine gliomas (DIPGs) in children remain essentially 
incurable. A recent review of 22 clinical trials of pediatric diffuse brainstem 
gliomas showed that only 92 out of 940 children survived, with identical 
progression free (PFS) or overall survival (OS) in recent trials compared to older 
series.1 In children whose tumors were biopsied, the majority (153 out of 229 
samples; 67%) were high-grade gliomas.1 Clinical trials of hyperfractionated 
radiation, delivering up to 72 Gy radiation, showed no benefit over conventional 
(54-58 Gy) radiation.2-8 Chemotherapy or biologic agents, whether given pre-
irradiation,2,8-10 
with 
radiation, 
and/or 
after 
radiation,3-7,9-18 
including 
myeloablative regimen with stem cell rescue,19,20 have also failed to improve PFS 
or OS. Collectively, these series showed dismal median PFS (5-8.8 months), 
median OS (8-12 months), and 2-year survival (5-15%).1 


 
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Because radiation often induces a temporary response and symptomatic 
improvement for children with DIPGs, concurrent administration of an agent 
with both an anti-glioma and a radiosensitizing effect may potentially improve 
outcome. Pre-clinical studies have shown that vorinostat (suberoylanilide 
hydroxamic acid, SAHA), an orally bioavailable histone deacetylase (HDAC) 
inhibitor, inhibits growth of malignant gliomas and enhances radiation sensitivity 
of these tumors. The maximum tolerated dose (MTD) of vorinostat as a single 
agent has been defined in a pediatric phase 1 study (ADVL0416). We therefore 
propose a phase I/II trial for children with newly diagnosed DIPG to study: 1) the 
MTD or recommended phase 2 dose of vorinostat given concurrently with 
radiation; and 2) the efficacy of vorinostat, given concurrently with radiation and 
then continued as maintenance therapy after radiation, as measured by 12-month 
and 18-month EFS and OS.  
 
2.1.2 
Vorinostat and Other Histone Deacetylase Inhibitors 
Nucleosomes, the basal unit of chromatin, are composed of DNA wrapped 
around histones with lysine-rich amino terminal tails. The positive charge of the 
amino tails attracts the negatively-charged DNA, and this interaction partly 
regulates the chromatin structure and gene expression.21 Histone acetyltransferase 
(HAT) transfers an acetyl moiety to the lysines on the amino tails and neutralizes 
the positive charge of the histones, leading to decreased affinity for DNA, 
relaxation of chromatin, and transcriptional activation.21,22 HDACs remove the 
acetyl groups and restore the negative charge, leading to chromatin compaction 
and transcriptional repression.22,23 Dysregulation of histone acetylation has been 
implicated in the development of human cancers.21,24 It is hypothesized that 
aberrant histone acetylation leads to inappropriate transcriptional repression and 
maintenance of the transformed state in human tumors. HDAC inhibitors are 
hypothesized to reactivate gene expression of critical pathways that are 
abnormally silenced in tumorigenesis, and indeed treatment of human tumor cells 
with HDAC inhibitors results in cell cycle arrest, apoptosis, and 
differentiation.21,25 There are several classes of HDAC inhibitors, including 
butyric acid derivative (phenylbutyrate and AN-9), short-chain fatty acid 
(valproic acid), hydroxamic acids, benzamides (MS-275), and cyclic peptides 
(depsipeptide).26,27 Vorinostat is one of the hydroxamic acid-based HDAC 
inhibitors. In contrast to depsipeptide and MS-275 which only inhibit selective 
members of class I HDAC (HDAC 1, 2, 3, and 8) or valproic acid which inhibits 
class I and class IIa HDACs (HDAC 4, 5, 7, and 9), vorinostat inhibits all classes 
of HDAC, including class IIb (HDAC 6 and 10) and IV (HDAC 11).27,28 Whether 
a pan-HDAC inhibitor such as vorinostat has more potent or a broader range of 
anti-tumor efficacy versus a selective HDAC inhibitor such as MS-275 is 
unproven. 
 


 
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2.2 
Preclinical Studies 
 
2.2.1 
Pre-Clinical Activity of Vorinostat in CNS Tumors  
There have been several pre-clinical studies documenting vorinostat’s in vitro 
and in vivo inhibition of malignant gliomas. Ugur et al.29, Chinnaiyan et al.30,Yin 
et al.31, and Eyupoglu et al.32 demonstrated that the concentration of vorinostat 
required for 50% growth inhibition (IC50) of multiple malignant glioma cell lines 
and primary GBM explants were approximately 1-2 µM (264-528 ng/ml), and 
these concentrations were comparable to the safely achieved Cmax in adult and 
pediatric clinical trials (see discussion below). Recently, it was also shown that in 
vitro vorinostat treatment inhibited growth of stem-like GBM cells in 
neurospheres equally effectively as it inhibited non-stem GBM tumor cells.33 In 
vivo studies also confirmed that administration of vorinostat to mice with 
intracranial malignant glioma xenografts significantly prolonged their survival 
versus control animals.29,31,32   
 
In addition to its documented activity in malignant gliomas, vorinostat also 
inhibits growth of other CNS tumors such as medulloblastoma34,35 and 
supratentorial primitive neuroectodermal tumor.36 Although there has not been 
any formal study of the CNS pharmacokinetics of vorinostat, two investigators 
demonstrated increased levels of acetylated histones in normal mouse brains and 
intracranial xenografts after vorinostat treatment.35,37 In addition, it has recently 
been shown that in adults with GBM post-vorinostat treatment tumors had 
increased histone acetylation as well.38 These studies provide indirect evidence 
that vorinostat crossed the blood-brain barrier and induced biological changes in 
normal brain and intracranial tumors. 
 
2.2.2 
HDAC Inhibitors Enhances Radiation Sensitivity of Malignant Gliomas 
Several studies have shown that various HDAC inhibitors, including 
phenylbutyrate,39 TSA,40 AN-9,41 MS-275,42 and valproic acid43,44 enhanced in 
vitro and in vivo radiosensitivity of malignant glioma cell lines. Chinnaiyan et 
al.30 showed that pre-treating U373, a malignant glioma cell line, with 0.75-1 µM 
of vorinostat for 48-72 hours, and continuing vorinostat with radiation 
significantly increased its radiosensitivity. Additional studies similarly 
demonstrated that vorinostat treatment enhanced radiation sensitivity of other 
solid tumors, 45-48 including intracranial breast cancer xenografts.49 In most of the 
pre-clinical studies, optimal radiation enhancement was observed when HDAC 
inhibition preceded radiation by 24-72 hours and was continued concurrently 
with radiation.  
 
Pre-clinical studies of vorinostat prior to radiation treatment demonstrate 
significantly reduced levels of DNA repair proteins in the non-homologous end-
joining (NHEJ; Ku70, Ku80, DNA-PK) and homologous recombination repair 
(HRR; BRCA 1 and 2, ATM, and Rad51) pathways.30,46 Since radiation is 
thought to exert its anti-tumor effect by inducing double-stranded DNA (dsDNA) 
breaks, and dsDNA breaks are repaired by the NHEJ and HRR pathways, it has 
been hypothesized that radiation-enhancement by vorinostat and other HDAC 
inhibitors is in part mediated by decreased DNA repair proteins and impaired 
dsDNA break repair. Additional pre-clinical studies of the radiation potentiation 
by other HDAC inhibitors have also shown that expression of key DNA repair 


 
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proteins in the NHEJ and HRR pathways is significantly reduced50-53 and dsDNA 
break repair is inhibited.43,44 
 
2.2.3 
NHEJ and HRR Possibly Mediating Radiation Resistance in Malignant Gliomas 
Several pre-clinical studies have documented elevated expression of DNA repair 
proteins in the NHEJ and HRR pathway in radiation resistant glioma cell 
lines54,55 or in response to irradiation,54,56 and inhibition of these DNA repair 
proteins restored the radiation sensitivity of tumor cells.57-60 Most recently, two 
functional studies demonstrated that expression of EGFRvIII, one of the most 
common mutations in adult GBM, enhanced glioma cell survival after radiation 
by accelerating repair of dsDNA breaks.61,62 This enhanced survival after 
radiation was associated with elevated expression of DNA-PK, ATM, and Rad51 
and abrogated by their respective inhibitors. Taken together, these pre-clinical 
data suggest that enhanced dsDNA break repair may mediate radiation resistance 
of malignant gliomas, and inhibition of NHEJ and HRR pathways may potentiate 
the sensitivity of these tumors to radiation. As vorinostat treatment has been 
associated with decreased expression of key DNA repair proteins in both the 
NHEJ and HRR pathways, it is a promising agent for radiation potentiation, and 
its clinical efficacy may correlate with inhibition of dsDNA break repair. 
 
2.2.4 
Clinical Significance of HDAC expression in Human Tumors 
Although multiple studies have documented HDAC over-expression in various 
solid tumors63-66 and correlated such over-expression with aggressive tumor 
biology and decreased survival,67-69 HDAC expression in CNS tumors has been 
poorly and inconsistently documented.70-73 Several pre-clinical studies, however, 
have shown that inhibition of HDAC2 appears to be critical for various aspects of 
HDAC inhibitors’ anti-tumor effect, including chromatin decondensation and 
remodeling, transcriptional activation, and induced histone acetylation.74-77 A 
clinical trial correlated HDAC2 expression in cutaneous T-cell lymphoma 
(CTCL) with biological aggressiveness and unfavorable clinical outcome.69 
Furthermore, several clinical trials have confirmed that baseline expression of 
HDAC2 in PBMCs (as surrogates for tumor specimens) correlated directly with 
increases in histone H3 and H4 acetylation after HDAC inhibitor 
treatment.69,75,78,79 Therefore, baseline and post-treatment HDAC2 level in 
PBMCs may be an additional surrogate marker for measuring vorinostat’s 
biologic effect in tumors. 
 
2.3 
Adult Studies of Vorinostat 
 
2.3.1 
Phase 1 and 2 Studies of Vorinostat 
Early phase I trials of vorinostat in adults showed encouraging objective 
responses in various solid tumors80,81 and hematologic malignancies,80-82 with an 
impressive response rate up to 30% in patients with CTCL.83,84 Subsequent phase 
1 and 2 clinical trials of vorinostat as a single agent in adults with hematologic 
malignancies85,86 and solid tumors,87-91 however have yielded somewhat 
disappointing results, with few objective responses and stable disease being the 
most common outcome. Most recently, a phase 2 study of vorinostat in adults 
with recurrent glioblastoma multiforme demonstrated only 2 objective responses 
in 66 patients.38  
 


 
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The most common vorinostat regimen is 400 mg orally, once daily or 200 mg 
orally, bid continuously;80,82-84,88,90,91 but alternative schedules (e.g. 200-400 mg 
bid x 14 days every 21 days) have also been evaluated.38,85-87,89 The oral 
bioavailability is 43%, with an apparent half-life of 91-127 minutes.80 Observed 
Cmax in the 400 mg q day regimen averaged 658 +/- 439 ng/mL, exceeding the 
IC50 (264-528 ng/mL) required in pre-clinical studies to inhibit growth of 
malignant gliomas, either as a single agent29-32 or to enhance the effect of 
radiation.30 
 
Vorinostat was reasonably well tolerated in the adult trials. The most common 
grade 3 and 4 toxicities were fatigue, gastrointestinal (nausea/vomiting, anorexia, 
diarrhea, 
dehydration), 
hematologic 
(thrombocytopenia, 
lymphopenia, 
neutropenia, anemia), and metabolic (hypernatremia, hypokalemia). Grade 3 and 
4 thrombocytopenia, the most common hematologic toxicity, occurred in 5-22% 
of patients.38,80,82,83,85,87,89-91  However, the platelet count usually recovered to 
normal within 3-7 days after drug discontinuation.28,80,82,85  
 
In earlier adult clinical trials, increased acetylation of H3 and H4 histones in 
PBMC was essentially observed in all patients across all dose levels.80-82,85 Peak 
hyperacetylation of PBMC histones was observed 2-4 hours after a dose of 
vorinostat and generally returned to baseline level after 6-8 hours. Persistent 
hyperacetylation of PBMC histones was observed after 3 weeks on continuous 
dosing.80 However, hyperacetylation of histones in tumors was less consistent, as 
Kelly et al.80 and Galanis et al.38 showed that only three out of five post-
vorinostat tumor samples demonstrated increased histone H3 acetylation. 
 
2.4 
ADVL0416, A Pediatric Phase 1 Study of Vorinostat 
 
2.4.1 
Phase 1 Study of Vorinostat in Children (Fouladi et al., unpublished results) 
In the recently completed COG phase 1 study of vorinostat (ADVL0416) in 
children with refractory solid tumors, vorinostat was administered orally once 
daily starting at 180 mg/m2/day continuously, with dose escalations in 30% 
increments. The MTD for pediatric patients in ADVL0416 has been defined as 
230 mg/m2/day. At one dose level (300 mg/m2/day) above the MTD, 4 out of 12 
patients experienced DLTs (2 thrombocytopenia, 1 neutropenia, 1 hypokalemia). 
No dose-limiting thrombocytopenia or neutropenia were observed at the MTD 
(230 mg/m2/day) or one dose level below (180 mg/m2/day).  
 
No objective response was observed with vorinostat as a single agent, although 
prolonged stable disease (median of 4 cycles, range 4-8 cycles) was observed in 
six patients, including a patient with a DIPG and another with a low-grade 
glioma. Two additional patients treated with vorinostat and 13-cis-retinoic acid 
(one medulloblastoma, one pineoblastoma) also had stable disease for 5 and 7 
cycles. 
 
There was wide interpatient variability in vorinostat pharmacokinetic, with no 
clear linear relationship between drug exposure (as measured by area-under 
concentration-time curve, AUC) and dose. Vorinostat exposure following a 
capsule formulation versus an oral suspension, at 230 mg/m2/day, as measured by 
AUC0->inf, was roughly similar (range 1415-9291 ng/ml*hr versus 1186-4780 


 
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ng/ml*hr, respectively). The observed Cmax across all dose levels (range 269-780 
ng/ml) was within or exceeded the IC50 range (264-528 ng/ml) required for 
inhibiting malignant gliomas in pre-clinical studies.29-32 
 
A significant increase in PBMC histone H3 acetylation was not consistently 
observed in children who received vorinostat at 180 mg/m2/day, whereas 15 out 
of 18 patients who received either 230 mg/m2/day or 300 mg/m2/day 
demonstrated more than a 2-fold increase in PBMC histone H3 acetylation. 
 
2.5 
Overview of Proposed Pediatric Study 
This study is comprised of two parts. Part A is a phase 1 dose-finding study employing 
the rolling six phase 1 trial design, to define the MTD or recommended phase 2 dose of 
vorinostat in combination with radiation therapy, for children with newly diagnosed 
DIPG. Although the MTD of vorinostat as determined in ADVL0416 was 230 
mg/m2/day, given the expansive nature of DIPG and proximity to pons and medulla, it 
would be prudent to ensure that there is no synergistic toxicity when vorinostat is 
combined with radiation. Therefore, the starting dose of vorinostat for Part A of this trial 
will be 180 mg/m2/day, Monday through Friday during radiation (Dose Level 1; Table 1, 
section 5.3.1). This starting dose is one dose level below the MTD (230 mg/m2/day) 
determined in ADVL0416. One dose de-escalation (Dose Level 0, vorinostat 180 
mg/m2/day, 3 days a week during radiation therapy) will be studied if Dose Level 1 is not 
well tolerated. The phase 1 dose-finding study will conclude if Dose Level 2 (vorinostat 
230 mg/m2/day, Monday through Friday during radiation therapy) is well tolerated (Table 
1, section 5.3.1). Part A of the study will only be open for enrollment to the institutions in 
the COG Phase 1 Consortium.  
 
After completion of radiation and vorinostat, patients enrolled on Part A of the study will 
continue on maintenance therapy with vorinostat, provided that they meet all the on-study 
criteria and have no contraindication for continuing vorinostat. Patients will continue 
vorinostat at 230 mg/m2/day continuously (Dose Level 1; Table 2, section 5.4), which 
was the MTD as determined in ADVL0416. Patients will continue vorinostat 
maintenance therapy for a maximum of 12 courses. Two dose de-escalations will be 
allowed in the event a patient experiences a DLT during maintenance (post RT) therapy.  
 
Six patients were enrolled on Dose Level 1 (vorinostat 180 mg/m2/day Monday through 
Friday during radiation treatment). None of these six patients had DLTs during course 1 
of chemoradiotherapy. Six additional patients were then enrolled onto Dose Level 2 
(vorinostat 230 mg/m2/day Monday through Friday during radiation therapy), and none 
of these six patients experienced DLTs. According to the rolling-six study design, dose 
level 2 is determined to be the recommended Phase 2 dose during chemoradiation. Part B 
of the study will now be open to group-wide participation, and all future patients will 
receive vorinostat 230 mg/m2/day, Monday through Friday, during the chemo-radiation 
phase. 
 
Of the twelve patients who have received maintenance therapy (course 2 and beyond), 
two patients experienced grade 3 thrombocytopenia requiring dose de-escalation of 
vorinostat. No recurrent dose-limiting thrombocytopenia was observed after the dose 
reduction. One of these 2 patients who experienced grade 3 thrombocytopenia also 
experienced grade 4 neutropenia, and despite a dose reduction, this patient's grade 4 
neutropenia recurred, necessitating discontinuation of maintenance protocol therapy. No 


 
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other dose limiting toxicities have been observed thus far in the 12 patients who have 
received maintenance therapy. Dose-limiting toxicities during the maintenance phase will 
continue to be monitored closely on a weekly basis, per toxicity monitoring rule specified 
in section 11.3.6, when PART B of the study opens for group-wide participation. 
 
It appears that thus far, at least with chronic dosing on this trial, hematologic DLT may 
be more prevalent than previously observed in the pediatric Phase I study (ADVL0416), 
in which patients most commonly received only 1 course of vorinostat. It is however 
worth noting that, due to the concern for intra-tumoral hemorrhage for our patient 
population, the definition for a dose-limiting thrombocytopenia (grade 3 < 50,000/µL), 
was intentionally defined more stringently than the typical definition of a dose-limiting 
thrombocytopenia (grade 4 < 25,000/µL) for a phase I study such as ADVL0416. We 
observed 2 out of 12 patients who experienced grade-3 thrombocytopenia with 
maintenance vorinostat, but it has been reassuring that recurrent grade-3 
thrombocytopenia has not been observed after dose-reduction of vorinostat. Moving 
forward with conduct of PART B of the study, it is our expectation that repeated dosing 
of vorinostat during maintenance therapy may result in more patients experiencing dose-
limiting thrombocytopenia than originally anticipated, but based on clinical observations 
from PART A of the study, we do not anticipate that discontinuation of maintenance 
vorinostat due to recurrent hematologic DLT will be a common occurrence. We have 
therefore modified the toxicity monitoring rule in Section 11.3.6 such that vorinostat 
dosing during maintenance will only be modified using the rule outlined in the Section 
11.3.6. 
 
Part B, the phase 2 portion of the trial, will be performed group-wide once the MTD of 
vorinostat during radiation is defined. Patients enrolling onto the phase 2 portion of the 
study will be enrolled at 230 mg/m2/day, the MTD for vorinostat during radiation and 
continue on maintenance therapy as described above. The primary aim of Part B of the 
study is to determine the effect of administering vorinostat concurrently with radiation, 
followed by maintenance vorinostat for up to 12 courses, as measured by 1-year EFS and 
OS in children with newly diagnosed DIPG. Data collected from any patients enrolled at 
the MTD from Part A of the trial will be included in analyzing the outcome from Part B 
of the study.  
 
Based on pre-clinical studies described in sections 2.2.2 through 2.2.4, we hypothesize 
that levels of HDAC2 and histone acetylation in PBMCs may be appropriate surrogate 
markers for vorinostat’s biologic effect in tumor, and that vorinostat’s inhibition of 
dsDNA break repair and NHEJ activity may correlate with its radiation potentiation. 
Therefore, we propose to study these biological parameters in PBMCs before and at 2 
weeks after starting vorinostat and radiation therapy, and at completion of vorinostat and 
radiation. In addition, when DIPG tumor samples (paraffin embedded tissue blocks) are 
available, we also propose to determine levels of DNA repair proteins from the NHEJ 
(Ku70, Ku80, DNA-PK) and HRR (BRCA 1 and 2, Rad51) pathways by Western 
analysis or immunohistochemistry. Any correlation between these biological parameters 
and clinical outcome will be explored. 


 
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3.0 
STUDY ENROLLMENT 
 
3.1 
Patient Registration  
Prior to enrollment on this study, patients must be assigned a COG patient ID number. 
This number is obtained via the eRDE system 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.   
 
In order for an institution to maintain COG membership requirements, every newly 
diagnosed patient needs to be offered participation in ACCRN07, Protocol for the 
Enrollment on the Official COG Registry, The Childhood Cancer Research Network 
(CCRN).  
 
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.  
 
3.2 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling 
patients. Sites must submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit 
(CTSU) Regulatory Office and allow 3 business days for processing. The submission 
must include a fax coversheet (or optional CTSU IRB Transmittal Sheet) and the IRB 
approval document(s).  The CTSU IRB Certification Form may be submitted in lieu of 
the signed IRB approval letter.  All CTSU forms can be located on the CTSU web page 
(https://www.ctsu.org). Any other regulatory documents needed for access to the study 
enrollment screens will be listed for the study on the CTSU Member’s Website under the 
RSS Tab.   
 
IRB/REB approval documents may be faxed (1-215-569-0206), 
Emailed (CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.   
 
When a site has a pending patient enrollment within the next 24 hours, this is considered 
a “Time of Need” registration.  For Time of Need registrations, in addition to marking 
your submissions as ‘URGENT’ and faxing the regulatory documents, call the CTSU 
Regulatory Helpdesk  at: 1-866-651-CTSU. For general (non-regulatory) questions call 
the CTSU General Helpdesk at: 1-888-823-5923. 
 
3.3 
Reservation Requirements 
Investigators should refer to the COG website to determine if the study is currently open 
for accrual. If the study is listed as active, investigators should then access the Studies 
Requiring Reservations page to ensure that a reservation for the study is available. To 
access the Studies Requiring Reservations page:  
1. Log in to https://members.childrensoncologygroup.org.  
2. From the menu bar, click eRDES. The eRDES sub-menu appears. 
3. Click Reservation. The Studies requiring Reservations page appears. 
 
Prior to obtaining informed consent and enrolling a patient, a reservation must be made 


 
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with the Statistical and Data Center through the eRDE system. 
 
Reservations may be obtained 24-hours a day through the COG website. Please refer to 
the Reservation System eRDES User Guide that can be downloaded from:  
https://members.childrensoncologygroup.org/_files/Help/eRDES_ReservationSystem_Us
erGuide.pdf 
 
 
3.4 
Institutional Pathology Report 
Because DIPGs are often not biopsied, enrollment of patients with typical-appearing 
DIPG (see section 4.1.2) without an institutional pathology report is allowed. For patients 
with brainstem tumors not considered typical DIPG as defined in section 4.1.2, they will 
only be eligible if their tumors are biopsied and meet the eligibility criteria as defined in 
section 4.1.2. Immediately following enrollment, the institutional pathology report for the 
diagnosis under which the patient is being enrolled must be faxed, with the corresponding 
shuttle sheet, to the Operations Center at (626) 447-2204. The fax should be sent to the 
attention of the study research coordinator and must include the associated study number 
and COG patient registration and accession numbers. Personal identifiers, including the 
patient’s name and initials must be removed from the institutional pathology report prior 
to submission to COG. 
 
 
3.5 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have 
been met. Study enrollment is accomplished by going to the Enrollment application in the 
RDE system.  If you have problems with enrollment, refer to online help in the 
Applications area of the COG website.  
 
3.6 
Timing 
Patients must be enrolled before treatment begins.  The date protocol therapy is projected 
to start must be no later than seven (7) calendar days after the date of study enrollment. 
Patients must not receive any protocol therapy prior to enrollment. 
 
 
 
4.0 
PATIENT ELIGIBILITY  
 
All clinical and laboratory studies to determine eligibility must be performed within 7 
days prior to enrollment unless otherwise indicated.  If more than 7 calendar days elapse 
between the date eligibility studies outlined in section 4.1.5 were obtained and the start 
date of treatment, then the following studies must be repeated prior to treatment: CBC 
with differential, bilirubin, ALT (SGPT) and serum creatinine.  If any of these repeat 
laboratory studies are outside the parameters required for eligibility (labs may again be 
repeated within 48-72 hours), then the patient is off protocol therapy.  Imaging studies 
are required within 2 weeks prior to start of protocol therapy. 
 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived (per COG policy posted 5/11/01).  All clinical and laboratory data 
required for determining eligibility of a patient enrolled on this trial must be 
available in the patient’s medical or research record which will serve as the source 
document for verification at the time of audit. 


 
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4.1 
Inclusion Criteria 
 
4.1.1 
Age:  Patients must be > 36 months and  21 years of age at the time of study 
enrollment. 
 
4.1.2 
Diagnosis: Patients with newly diagnosed diffuse intrinsic pontine gliomas 
(DIPGs), defined as tumors with a pontine epicenter and diffuse involvement of 
at least 2/3 of the pons, are eligible without histologic confirmation. Patients with 
brainstem tumors that do not meet these criteria or not considered to be typical 
intrinsic pontine gliomas will only be eligible if the tumors are biopsied and 
proven to be an anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, or 
anaplastic mixed glioma. Patients with juvenile pilocytic astrocytoma, fibrillary 
astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not 
eligible. Patients with disseminated disease are not eligible, and MRI of spine 
must be performed if disseminated disease is suspected by the treating physician. 
 
4.1.3 
Performance Level:  Karnofsky  50% for patients > 16 years of age and Lansky 
 50 for patients  16 years of age (See Appendix I). Patients who are unable to 
walk because of paralysis, but who are up in a wheelchair, will be considered 
ambulatory for the purpose of assessing the performance score. 
 
4.1.4 
Prior Therapy 
Patients must not have received any prior treatment except dexamethasone and/or 
surgery. 
 
4.1.5 
Organ Function Requirements 
 
4.1.5.1 Adequate Bone Marrow Function Defined as: 
- 
Peripheral absolute neutrophil count (ANC)  1000/µL 
- 
Platelet count  100,000/µL (transfusion independent, defined as 
not receiving platelet transfusions within a 7 day period prior to 
enrollment) 
- 
Hemoglobin  8.0 g/dL (may receive RBC transfusions) 


 
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4.1.5.2 Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR  70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
3 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the 
Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 
106:522, 1985) utilizing child length and stature data published by the 
CDC. 
 
4.1.5.3 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated)  1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT)  110 U/L.  For the purpose of this study, the ULN for 
SGPT (ALT) is 45 U/L.  
- 
Serum albumin  2 g/dL. 
 
 
 
 
4.1.5.4 Central Nervous System Function Defined as: 
- 
Patients with seizure disorder may be enrolled if on non-enzyme 
inducing anticonvulsants (with the exception of valproic acid; see 
Section 4.2.2.5) and seizures are well controlled. 
 
4.1.6 
Patients must be able to swallow capsules or liquids. Patients dependent on NG 
tube feeding are not permitted to receive protocol therapy. 
 
4.1.7 
Timing 
Enrollment must be no later than 28 days after the date of radiographic diagnosis 
or surgery, whichever is the later date.  
 
4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study due to risks 
of fetal and teratogenic adverse events as seen in animal/human studies. 
Pregnancy tests must be obtained in girls who are post-menarchal. Males or 
females of reproductive potential may not participate unless they have agreed to 
use an effective contraceptive method. 
 
4.2.2 
Concomitant Medications 
 
4.2.2.1 Growth factor(s): Growth factors that support platelet or white cell 
number or function must not have been administered within the 7 days 
prior to enrollment.  
 


 
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4.2.2.2 Investigational Drugs: Patients who are currently receiving another 
investigational drug are not eligible. 
 
4.2.2.3 Anti-cancer Agents: Patients who are currently receiving other anti-
cancer agents are not eligible. 
 
4.2.2.4 Anticonvulsants: Patients must not currently be receiving enzyme 
inducing anticonvulsants (see Appendix II for a list of enzyme inducing 
and non-enzyme inducing anticonvulsants). 
 
4.2.2.5 Valproic Acid: Patients on valproic acid must discontinue valproic acid 
for at least 2 weeks before starting protocol therapy. 
 
4.2.2.6 Anti-coagulant: Patients receiving coumadin, heparin, low-molecular 
weight heparin, or any other anti-coagulants are not eligible for study 
entry.  
 
4.2.2.7 Anti-platelet agents: Patients receiving ASA (> 81 mg/day), non-
steroidal anti-inflammatory drugs, clopidogrel (Plavix), dipyridamole 
(Persantine), or any other drug that inhibits platelet function are not 
eligible for study entry. 
 
4.2.3 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
4.2.4 
Patients who in the opinion of the investigator may not be able to comply with 
the safety monitoring requirements of the study are not eligible. 
 
4.3 
Regulatory 
 
4.3.1 
All patients and/or their parents or legal guardians must sign a written informed 
consent. 
 
4.3.2 
All institutional, FDA, and NCI requirements for human studies must be met. 


 
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5.0 
TREATMENT PROGRAM 
 
 
5.1 
Overview of Treatment Plan 
 
All patients must begin therapy no later than 7 days after study enrollment. Enrollment 
must be no later than 28 days after the date of radiographic diagnosis or surgery, 
whichever is the later date. Radiation therapy (RT) will be administered in single daily 
fractions of 1.8 Gy for 30 treatments over 6-7 weeks.  The total dose of radiation will be 
54 Gy (see section 15.0). During radiation, patients on Part A of the study will receive 
vorinostat as per Table 1, section 5.3.1, for the duration of radiation treatment. Following 
completion of radiation therapy, patients will immediately begin maintenance therapy 
with vorinostat (see guidelines in section 5.4) for a maximum of 12 cycles. 
 
Note:   It is recommended but not required that Day 1 of the first cycle of protocol 
therapy begin on a Monday in order to extend the duration of radiation therapy in 
the first week. 
 
Patients' doses are to be prescribed based on dosing nomogram in Appendix III.   
 
Vorinostat is available as a 100-mg capsule or a 50 mg/mL pediatric suspension. The 
dosing for pediatric suspension should be rounded to the nearest 5 mg. Dosing for 
vorinostat capsule should be determined according to the nomogram provided in 
Appendix III, in which vorinostat doses have been rounded to the nearest 100 mg. 
Please note that the absolute daily dose of vorinostat should not exceed 500 mg. 
Patients with a BSA < 1.25 m2 should be given the pediatric suspension, since using 
capsules can lead to more than a 15% deviation in intended dosing.  Patients ≥ 1.25 
m2  should receive either capsules per the nomogram or suspension, but may not receive a 
combination of both. Vorinostat capsules should not be opened or crushed. Vorinostat 
should be taken with food whenever possible. If a patient vomits within 30 minutes after 
the dose of vorinostat is administered, that dose should be repeated. If a patient vomits 
after 30 minutes, the dose will not be repeated.  
 
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 per COG administrative 
Policy 5.14 (except where explicitly prohibited within the protocol).  


 
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PART A: Phase 1 dose-finding study (Phase 1 Consortium institutions only) 
 
As of Amendment #2, Part A was completed. 
 
Part A of this study is the phase 1 dose-finding study to define the MTD or recommended 
phase 2 dose of vorinostat in combination with radiation therapy. Part A of the study will 
be completed within the COG Phase 1 Consortium institutions. Patients will start 
vorinostat on the first day of radiation therapy at the assigned dose level and schedule. 
Refer to Table 1, Section 5.3.1 for the dose escalation schema. Following completion of 
radiation therapy, patients enrolled in Part A of the study will continue maintenance 
vorinostat therapy per guidelines in Section 5.4. 
 
Patients or their guardians will keep a diary to document the intake of each dose of 
vorinostat and potential side effects (see Appendices IV-A, IV-B, and IV-C). Please 
instruct patient/parents to record each dose on the diary immediately rather than waiting 
until a later time. Errors on the diary should be crossed out and initialed. The patient 
diary should be reviewed weekly with the patient and family during radiation treatment 
and at the completion of each treatment cycle during maintenance therapy, and drug 
should be accounted for at this time. These diaries should also be faxed to the COG 
Statistics and Data Center, with the corresponding shuttle sheet, at (626) 447-2204 after 
each treatment cycle. 
 
PART B: Phase 2 component of the study (COG Groupwide) 
Part B is the phase 2 portion of the study to determine the efficacy of combining 
vorinostat with radiation and then continuing vorinostat as maintenance therapy in 
children newly diagnosed with DIPG. Part B of the study will begin enrollment once the 
MTD for Part A has been determined. For Part B of the study, patients will receive 
vorinostat, at 230 mg/m2/day Monday through Friday (the MTD determined in Part A of 
the study), with concurrent radiation, and then continue maintenance therapy with 
vorinostat (per guidelines in section 5.4) for a maximum of 12 courses. Part B of the 
study will take place at member COG institutions, group wide. 
 
5.1.1 
Vorinostat Administration During Radiation Therapy 
 
As of Amendment #2, Part A was completed. 
 
PART A: Patients on Part A of the study will start vorinostat on the first day of 
radiation therapy at the dose level assigned at enrollment. Refer to Table 1, section 
5.3.1 for the Dose Escalation Schema.  
 
PART B: Once the MTD of vorinostat for Part A of the study has been determined, 
patients on Part B of the study will start vorinostat on the first day of radiation 
therapy at 230 mg/m2/day as determined on Part A of the study. See Appendix IX 
for Chemoradiotherapy Roadmap. 
 
Vorinostat dosing during and throughout the radiation component of therapy 
should be based on BSA determined from height and weight at the start of 
radiation therapy. The absolute daily dose of should not exceed 500 mg.   


 
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Vorinostat should be given 60-120 minutes prior to radiation therapy, whenever 
feasible. For patients who must remain NPO for sedation prior to RT therapy, 
vorinostat should be given immediately prior to bedtime on the evening preceding 
the RT.  
 
 
See Section 5.6 for definition of DLTs encountered during radiation therapy and 
Section 6.0 for vorinostat dose modifications. 
 
If radiation is omitted because of holiday or other logistical reasons, patients should 
still continue their scheduled vorinostat without interruption. 
 
5.1.2  Vorinostat Administration During Maintenance Therapy (Part A and B)  
All patients (on Part A or Part B), upon completion of radiation therapy, will 
immediately continue vorinostat as maintenance therapy, provided that they 
continue to meet all on-study criteria and have not experienced toxicities 
necessitating interruption or discontinuation of vorinostat.  
 
Dosing of vorinostat during maintenance therapy will be determined per guidelines 
in Section 5.4. See Appendix X for Maintenance Roadmap. 
 
Vorinostat doses during the maintenance phase of therapy should be adjusted 
based on the BSA determined from height and weight obtained within one 
week prior to the beginning of each cycle. The absolute daily dose of 
vorinostat should not exceed 500 mg.  
 
A cycle of maintenance therapy is defined as 28 days. Maintenance therapy may be 
continued for a maximum of 12 cycles in the absence of disease progression and/or 
excessive toxicities.  
 
See section 5.6 for definition of DLTs encountered during maintenance therapy and 
section 6.0 for vorinostat dose modification.  
 
5.2 
Criteria for Starting Subsequent Cycles (Part A and B) 
 
5.2.1 
Chemoradiotherapy 
Radiation therapy should not be interrupted for vorinostat-related DLTs 
unless clinically indicated. 
 
5.2.2 
Vorinostat Maintenance Therapy 
A complete cycle of maintenance therapy is defined as 28 days. Cycles of 
maintenance therapy should not commence unless the ANC is ≥ 1,000/µL and 
platelet count is ≥ 100,000/µL. Missed doses of vorinostat during a cycle will 
not be made up.  Maintenance therapy may be continued in the absence of 
disease progression (see section 5.4). 


 
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5.3 
Dose Escalation Schema 
 
5.3.1 
Inter-Patient Escalation (Part A Chemoradiotherapy) 
 
As of Amendment #2 Part A was completed. 
 
 
Table 1:  Oral Vorinostat Dosing During Radiation Therapy  
(Part A of Study) 
Dose 
Level 
Vorinostat Dose  
Vorinostat Schedule 
0 
180 mg/m2/dose 
Monday, Wednesday, and Friday 
during radiation therapy 
1* 
180 mg/m2/dose 
Monday through Friday 
during radiation therapy 
2 
230 mg/m2/dose 
Monday through Friday 
during radiation therapy 
*starting dose level 
 
The starting dose of vorinostat for Part A of the study will be Dose Level 1, 
180 mg/m2/day, Monday through Friday weekly during the duration of radiation 
therapy (on Days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40). If radiation 
continues into Days 43-48 then vorinostat should continue at the same dose and 
schedule until RT is completed. 
 
The starting dose is one dose level below the MTD (230 mg/m2/day) determined 
in ADVL0416. One dose de-escalation (Dose Level 0, 180 mg/m2/day, Monday, 
Wednesday, and Friday weekly during radiation therapy) will be evaluated if 
Dose Level 1 is not well tolerated. The phase 1 dose-finding study will conclude 
if Dose Level 2 (230 mg/m2/day, Monday-Friday weekly, during radiation 
therapy) is well tolerated.  
 
Note: 
It is recommended but not required that Day 1 of the first cycle of 
protocol therapy begin on a Monday in order to extend the duration of 
radiation therapy in the first week. 
 
If Dose Level 0 is not well tolerated, all subsequent patients will receive radiation 
without vorinostat.  
 
Patients enrolled in Part A of the study, upon completion of vorinostat and 
radiation therapy, will continue vorinostat as maintenance therapy, per section 
5.4, provided that they continue to meet the criteria to start subsequent cycles of 
therapy. 


 
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5.3.2 
Part B Chemoradiotherapy  
Once the MTD of vorinostat for Part A of the study has been determined, Part B of 
the study will begin enrollment, and subsequent patients will receive vorinostat at 
230 mg/m2/day as determined in Part A of the study. See Appendix IX for 
Chemoradiotherapy Roadmap. 
 
5.3.3 
Intra-Patient Escalation 
Intra-patient dose escalation is not allowed in either Part A or Part B of the study.  
 
5.4 
Vorinostat Maintenance Therapy (Parts A and B) 
At the conclusion of chemoradiotherapy, all patients will continue vorinostat 
maintenance therapy at Dose Level 1 (230 mg/m2/day, continuously; Table 2) including 
those patients who had discontinued vorinostat during chemoradiotherapy because of 
DLTs. 
 
Table 2: Oral Vorinostat Dosing During Maintenance Therapy 
Dose Level 
Vorinostat Dose  
Vorinostat Schedule 
-1 
230 mg/m2/dose 
Monday, Wednesday, and Friday, every week 
0 
230 mg/m2/dose 
Monday through Friday, every week 
  1* 
230 mg/m2/dose 
Daily without interruption 
* Initial dose level for all patients post-XRT.  This dose was the single agent MTD of 
vorinostat defined in ADVL0416. 
 
See Section 5.6 for definition of DLTs encountered during maintenance therapy and 
Section 6.0 for vorinostat dose modification. See Appendix X for Maintenance Roadmap. 
 
5.5 
Grading of Adverse Events 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).Any suspected or confirmed dose-limiting toxicity should be 
reported immediately (within 24 hours) to the Study Chair. 
 
5.6 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are at least possibly, probably or 
definitely attributable to vorinostat. For Part A of the study, the observation period for the 
purpose of dose-escalation will be the entire duration of radiation therapy (approximately 
6 to 7 weeks). For Part B of the study, DLTs observed at any time during protocol 
therapy will be documented. 
 
Dose limiting hematological and non-hematological toxicities are defined separately, as 
detailed below.   
 
5.6.1 
Interruption of Radiation Therapy 
 
The interruption of planned radiation for 5 consecutive days or 10 days total. 
 
5.6.2 
Non-hematological dose-limiting toxicity 
• 
Any Grade 4 non-hematological toxicity 


 
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• 
Any Grade 3 non-hematological toxicity with the specific exclusion of: 
- 
Grade 3 nausea and vomiting of < 5 days duration 
- 
Grade 3 elevation of ALT/AST that returns to levels meeting initial 
eligibility criteria within 7 days of study drug interruption and does not 
recur upon study drug re-challenge. Note: For the purposes of this study 
the ULN for ALT/AST is defined as 45 U/L. 
- 
Grade 3 fever or infection < 5 days duration. 
- 
Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to oral supplementation 
- 
Grade 3 diarrhea that improves to grade 1 or better within 48 hours of 
starting anti-diarrhea treatment  
• 
Any Grade 2 non-hematological toxicity that persists for > 7 days and is 
considered medically significant or sufficiently intolerable by patients that it 
requires treatment interruption 
 
5.6.3 
Hematological dose limiting toxicity  
• 
Grade 3 thrombocytopenia (platelet count < 50,000/µL) 
• 
Grade 4 neutropenia 
• 
A delay of > 14 days in starting the subsequent cycle of vorinostat due to 
ANC < 1,000/µL and/or platelet < 100,000/µL (definition of this DLT 
applicable only during maintenance therapy) 
 
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dose modification or use of Filgrastim. 
 
6.1 
Dose Modification for DLT During Vorinostat and Concurrent Radiation (Parts A 
and B) 
For vorinostat-related non-hematologic DLTs during radiation therapy, vorinostat will be 
withheld until the toxicity resolves to meet on study parameters, and the patient will 
restart vorinostat at one dose level lower (see Table 1 below), if not already at Dose 
Level 0.  
 
 
Table 1:  Oral Vorinostat Dosing During Radiation Therapy  
 
Dose Level 
Vorinostat Dose  
Vorinostat Schedule 
0 
180 mg/m2/dose 
Monday, Wednesday, and Friday 
during radiation therapy 
1 
180 mg/m2/dose 
Monday through Friday 
during radiation therapy 
2  
(Starting Dose) 
230 mg/m2/dose 
Monday through Friday 
during radiation therapy 
 
For vorinostat-related hematologic DLTs, vorinostat will be withheld until criteria in 
6.1.1 and 6.1.2 are met, and vorinostat will be restarted at one dose level lower, if not 
already at Dose Level 0. If the same DLT is experienced at the lower dose level then 
vorinostat should be discontinued.  If a different DLT is encountered, then the patient 
may restart vorinostat at the next lower dose level, if not already at Dose Level 0. 


 
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In the event of hematological DLT, a CBC should be checked twice weekly until 
recovery of ANC ≥ 1,000/µL and platelet ≥ 100,000/µL. A patient who experiences any 
DLT despite being treated on Dose Level 0 will then complete radiation therapy without 
vorinostat. Radiation should be continued despite vorinostat-related DLT, unless 
there is a strong clinical contraindication.  
 
6.1.1 
Platelet transfusion is permissible and strongly encouraged for patients with 
dose-limiting thrombocytopenia (platelet count < 50,000/µL) to minimize risk of 
intra-tumoral hemorrhage. Vorinostat should not be restarted until platelet count 
has recovered to ≥ 100,000/µL (transfusion independent). Radiation should not 
be interrupted unless clinically indicated. 
 
6.1.2 
Patients with grade 4 neutropenia may receive filgrastim (G-CSF) support but 
should re-start vorinostat at the next lower dose level (See Table in Section 6.1). 
Vorinostat should not be restarted until the ANC is ≥ 1,000/µL and for at least 48 
hours without G-CSF support. Radiation should not be interrupted unless 
clinically indicated. 
 
Patients who experience vorinostat-related DLTs during radiation will continue 
vorinostat dosing during maintenance therapy (per guidelines in section 5.4), provided 
that they meet the criteria to start subsequent cycles of therapy and all vorinostat-related 
toxicities have resolved to baseline.  
 
6.2 
Dose Modification During Maintenance Phase (Parts A and B) 
For non-hematologic DLTs during maintenance therapy, vorinostat will be withheld until 
the toxicity resolves to meet on study parameters, and then vorinostat may be restarted 
per section 6.2.3.  
 
For hematologic DLTs during maintenance therapy, vorinostat will be withheld until 
criteria in 6.2.1 and 6.2.2 are met, and then vorinostat will be restarted per 6.2.3. Counts 
should be checked twice weekly until recovery of ANC ≥ 1,000/µL and platelet ≥ 
100,000/µL.  
 
6.2.1 
Platelet transfusion is permissible and strongly encouraged for patients with 
dose-limiting thrombocytopenia (platelet count < 50,000/µL). Vorinostat should 
not be restarted until platelet count has recovered to ≥ 100,000/µL. (transfusion 
independent). These patients should receive vorinostat at the next lower dose 
level for subsequent cycles; however, if the patient is already at Dose Level –1, 
then vorinostat will be discontinued. See Section 5.4 
 
6.2.2 
For dose-limiting neutropenia, filgrastim (G-CSF) is permitted as clinically 
indicated. Vorinostat should not be started until ANC recovers to ≥ 1,000/µL for 
at least 48 hours without G-CSF support. Patients should start the subsequent 
cycle at the next lower dose level, without G-CSF support; however, if a patient 
experiences dose-limiting neutropenia at Dose Level –1, then vorinostat will be 
discontinued. See Section 5.4 
  
6.2.3 
Once study parameters are met as described above for vorinostat-related DLTs, 
vorinostat will be restarted at one dose level lower, if not already at Dose Level -


 
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1. If the same DLT is experienced at the lower dose level, then vorinostat should 
be discontinued. If a different DLT is encountered, then the patient may restart 
vorinostat at the next lower dose level, if not already at Dose Level -1. Patients 
experiencing a DLT at Dose Level -1 will discontinue vorinostat. See Section 5.4 
 
6.3 
DSMB Monitoring of Toxicities During Maintenance 
 
Toxicities during the maintenance component of this study will be monitored at regular 
intervals by the DSMB, and the maintenance dose of vorinostat will be reduced if the 
monitoring rule is met. (See section 11.3.6 for toxicity monitoring rules). 
 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, immunotherapy, or biologic therapy 
may NOT be administered to patients receiving study drug. If these treatments are 
administered the patient will be removed from protocol therapy. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, steroid, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered in accordance with sections 6.1 and 6.2 or for culture proven bacteremia or 
invasive fungal infection. The Study Chair should be notified when growth factors are 
initiated. 
 
7.5 
Concomitant Medications 
Anticonvulsants: Patients must not receive enzyme inducing anticonvulsants while on 
protocol therapy. (Please see Appendix II for a list of enzyme inducing and non-enzyme 
inducing anticonvulsants.) 
 
Anti-coagulant: Patients must not receive coumadin, heparin, low-molecular weight 
heparin, or any other anti-coagulant while on protocol therapy. 
 
Anti-platelet agent: Patients must not receive ASA (> 81 mg/day), non-steroidal anti-
inflammatory drugs, clopidogrel (Plavix), dipyridamole (Persantine), or any other drug 
that inhibits platelet functions while on protocol therapy. 
 
7.6 
Management of Diarrhea 
Previous trials have shown that the frequency and severity of diarrhea rarely hindered 
administration of vorinostat and could be managed with loperamide. Patients with 
diarrhea must be monitored and treated for signs and symptoms of dehydration promptly. 
Should diarrhea develop, patients should be treated with loperamide every 2-3 hours 
while awake and every 4 hours while asleep, until the patient has a 12-hour diarrhea-free 
interval. The table below gives the recommend weight-based doses:   


 
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 Weight-Specific Guidelines for Therapeutic Use of Loperamide*  
 
Weight 
Initial (loading) 
loperamide dose 
Subsequent daytime 
loperamide dose 
Subsequent nighttime 
loperamide dose 
8-10 kg 
1 mg 
0.5 mg every 3 hours 
0.75 mg every 4 hours 
10-20 kg 
1 mg 
1 mg every 3 hours 
1 mg every 4 hours 
20-30 kg 
2 mg 
1 mg every 3 hours 
2 mg every 4 hours 
30-43 kg 
2 mg 
1 mg every 2 hours 
2 mg every 4 hours 
> 43 kg 
4 mg 
2 mg every 2 hours  
4 mg every 4 hours 
* The total daily dose should not exceed 16 mg. 
 
 


 
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluations 
All enrollment/eligibility studies must be performed within 1 week prior to study 
enrollment (unless otherwise specified).  If more than 7 calendar days elapse between the 
date eligibility studies outlined in section 4.1.5 were obtained and the start date of 
treatment, then the following studies must be repeated prior to treatment: CBC with 
differential, bilirubin, ALT (SGPT) and serum creatinine.  If any of these repeat 
laboratory studies are outside the parameters required for eligibility (labs may again be 
repeated within 48-72 hours), then the patient is off protocol therapy.  Imaging studies 
are required within 2 weeks prior to start of protocol therapy. 
STUDIES TO BE OBTAINED 
Pre-Study 
During  
Radiotherapy 
Start of Each Cycle of 
Vorinostat Maintenance 
History 
X 
Weekly 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
 
CBC, differential, platelets 
X 
Weekly4 
Weekly4 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, SGPT, bilirubin 
X 
Weekly 
X 
Total protein/albumin 
X 
- 
X 
Tumor Disease Evaluation: 
- MRI of brain with gadolinium 
 
X 
 
Before Maintenance 
Therapy Cycle 2, then 
every 2 cycles x 2, then 
every 3 cycles5 
- MRI of spine with gadolinium 
 X6 
 
 
Pregnancy Test1 
X 
 
 
Patient Diary2 – Part A Only 
 
End of 
vorinostat and 
XRT 
End of each cycle 
Correlative Studies3 
X3 
X3 
 
1 
Patients of childbearing potential require a negative pregnancy test prior to starting treatment and must 
use an acceptable method of birth control.  Abstinence is an acceptable method of birth control. 
2 
Review patient diary weekly with the patient and family during radiation treatment and at the 
completion of each treatment cycle during maintenance therapy. Fax a copy with the corresponding 
shuttle sheet at the end of radiotherapy and at the end of each cycle of maintenance therapy to the COG 
Statistics and Data Center (626) 447-2204. 
3  
If patient consents; see section 8.3.2 for timing of correlative studies. The correlative biology samples 
should be obtained the day of weekly CBC collection, if possible. 
4 
Patients with hematologic DLT should have CBC repeated twice weekly until recovery as specified in 
Sections 6.1 and 6.2. 
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 per COG administrative Policy 5.14 (except where 
explicitly prohibited within the protocol).  


 
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5 
Scans should be obtained prior to cycles 2, 4, 6, 9, and 12 of Maintenance Therapy. See Section 12.0 
for Evaluation Criteria. Tumor Disease Evaluation should be obtained on the next consecutive cycle 
after initial documentation of either a PR or CR.  If the institutional investigator determines that the 
patient has progressed based on clinical or laboratory evidence, he/she may opt not to confirm this 
finding radiographically. 
6 
Patients with suspected disseminated disease must have MRI of spine performed. Patients with 
disseminated disease are not eligible. 
 
This table only includes evaluations necessary to answer the primary and secondary aims. 
Obtain other studies as indicated for good clinical care. 


 
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8.2 
Required Observations Following Completion of Protocol Therapy 
The following studies are required until the patient is off study as defined in section 10.2. 
These observations are not applicable to patients enrolled on Part A who are NOT treated 
at the MTD. 
 
 
STUDIES TO BE 
OBTAINED 
3 
Month
s 
6 
Month
s 
9 
Months 
Every 6 
Months up to 
24 Months 
(Months 12, 
18, 24) 
Annually up to 
60 Months 
(Months  36, 
48, 60) 
History 
  x 
x 
x 
x 
x 
Physical Exam  with 
vital signs 
x 
x 
x 
x 
x 
Height, weight, BSA 
x 
x 
x 
x 
x 
CBC, differential, 
platelets1 
x 
x 
  
  
  
Creatinine, SGPT, 
bilirubin1 
x 
x 
  
  
  
Electrolytes 
including Ca++, PO4, 
Mg++2 
x 
x 
  
  
  
Disease evaluation2 
x 
x 
x 
x 
x 
1 Repeated as clinically indicated 
2 Repeat sooner if suspected disease recurrence/progression 
 
This table only includes evaluations necessary to answer the primary and secondary aims. 
Obtain other studies as indicated for good clinical care. 
 
8.3 
Correlative Studies 
These optional studies are to be obtained for all patients on Part A or Part B of the study 
who have provided consent for correlative studies. 
 
8.3.1 
NHEJ activity, HDAC2 level, and histone acetylation in PBMCs 
PBMCs will be isolated using Lymphoprep solution (Axis-Shield, Oslo, 
Norway), and protein lysates will be prepared by standard techniques. NHEJ 
activity will be analyzed via a published assay.92 HDAC2 level will be quantified 
using Western analysis. Histone acetylation will be quantified using either 
Western analysis or a PathScan® Acetylated Histone H3 and H4 Sandwich 
ELISA Kit (Cell Signaling, Danvers, MA). 
 
8.3.2 
Sampling Schedule (See Appendix V) 
Blood samples should be collected prior to the first dose of vorinostat and 
radiation, two weeks after starting vorinostat and radiation (any weekday, except 
Friday, during 3rd week of radiation), and at the end of radiation and vorinostat 
(any weekday, except Friday, during the last week of radiation). Blood samples 
should be collected 2-4 hours after the morning dose of vorinostat. Blood 
samples should be obtained the day of weekly CBC collection, if possible. For 
patients required to be NPO at night for sedation obtain blood samples in the 


 
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morning.  
 
8.3.3 
Sample Collection and Handling Instructions 
Whole blood samples (a minimum of 5-10 ml for children < 12 kg, and 10-20 ml 
for children ≥ 12 kg) should be collected in either heparinized (green tops, 
either sodium or lithium heparin is acceptable) or ACDA (yellow top) tubes.  
ACDA tubes are preferred if available. DO NOT collect blood samples on a 
Friday. Record the exact time that the sample is drawn along with the exact time 
that the drug is administered (see Appendix VI). 
 
8.3.4 
Sample Processing 
No processing is required. Keep the whole blood at room temperature until the 
time of shipping.  
 
 
 
8.3.5 
Sample Labeling 
Each tube must be labeled with the patient’s COG identification number, the 
study number (ACNS0927), and the date and time the sample was drawn.  Data 
should be recorded on the Correlative Study Form (Appendix VI), which must 
accompany the sample(s). 
 
8.3.6 
Sample Shipping Instructions 
Each sample should be shipped immediately on the day of collection.  Please 
follow packaging instructions on the Correlative Study Form (Appendix VI) 
Samples should be shipped at room temperature and by priority overnight via 
express carrier (Monday through Thursday only).  
 
Jack Su, MD; Attention: Elizabeth Hinojosa 
1102 Bates St., Room 1030 
Baylor College of Medicine 
Houston, TX  77030 
(832) 824-4688 or (832) 822-4306 
 
Prior to shipping, please contact Dr. Jack Su (832-822-4306, jmsu@txch.org), or 
Dr. Li (832-824-4580, xxli@txch.org) for notification of sample shipment. 
 
8.4 
Tumor Specimens  
 
8.4.1 
Description of Studies 
 
If formalin-fixed, paraffin-embedded (FFPE) tumors are available, 
immunohistochemical staining of HDAC2, Ku70, Ku80, DNA-PK, BRCA1 and 
2, Rad51, and ATM will be performed by standard techniques. 
 
8.4.2 
Sample Collection and Processing 
If FFPE tumors are available, fifteen to twenty unstained PLUS glass slides, 
containing 5-micron thick tumor sections, should be prepared. 
 
8.4.3 
Sample Labeling 
Each tube and slide must be labeled with the patient’s COG identification 
number, the study number (ACNS0927), and the date when tumor was biopsied. 
   


 
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8.4.4 
Sample Shipping Instructions 
 
Slides from FFPE tumors should be shipped at room temperature, with 
appropriate packing to prevent breakage of slides. Detailed instructions regarding 
sample labeling and shipping can be found in Appendix VIII. 
 
Shipments should be sent to the following address: 
 
Jack Su, MD; Attention: Elizabeth Hinojosa 
1102 Bates St., Room 1030 
Baylor College of Medicine 
Houston, TX  77030 
(832) 824-4688 or (832) 822-4306 
 
Prior to shipping, please contact Dr. Jack Su (832-822-4306, jmsu@txch.org) or 
Dr. Adekunle Adesina (832-824-5859, aadesina@bcm.edu or 
amadesin@texaschildrenshospital.org) for notification of sample shipment. 
 


 
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9.0 
AGENT INFORMATION 
 
9.1 
VORINOSTAT 
(Zolinza®, suberoylanilide hydroxamic acid, SAHA)     
(06/06/14) 
 NSC# 701852, IND#71976                                                 
 
Source and Pharmacology: Vorinostat also known as suberoylanilide hydroxamic acid 
(SAHA), is a histone deacetylase (HDAC) inhibitor.  Its chemical name is N-hydroxy-N’-
phenyl-octane-1, 8-diotic acid diamide, N-hydroxy-N’-phenyl (9CI) octanediamide.  The 
HDAC enzymes catalyze the removal of acetyl groups from the lysine residues of 
proteins, such as histones and transcription factors.  In some cancer cells, there is an 
overexpression of HDACs or an abnormal recruitment of HDACs to oncogenic 
transcription 
factors 
causing 
hypoacetylation 
of 
core 
nucleosomal 
histones.  
Hypoacetylation of histones is associated with a condensed chromatin structure and 
repression of gene transcription.  
 
Vorinostat inhibits HDAC by binding directly to the catalytic pocket of HDAC1, 
HDAC2, and HDAC3 (Class I) and HDAC6 (Class II) enzymes.  Inhibition of HDAC 
activity allows for the accumulation of acetylated histones.  This accumulation influences 
the regulation of gene expression.  In vitro, exposure of cultured transformed cell to 
vorinostat led to G1 or G2 phase cell-cycle arrest, apoptosis, or differentiation and 
demonstrated synergistic and additive activity in combination with other cancer therapies 
(including radiation, kinase inhibitors, cytotoxic agents, and differentiating agents). The 
mechanism of the antineoplastic effect of vorinostat has not been fully characterized. 
 
After oral administration, vorinostat is rapidly absorbed, however, administration with a 
high-fat meal resulted in a 33% increase in the extent of absorption and a 2.5-hour delay 
in the rate of absorption compared to the fasted state.  Vorinostat is approximately 71% 
bound to human plasma protein.  It is extensively metabolized to inactive metabolites, 
primarily by glucuronidation and hydrolysis followed by beta-oxidation. The two 
metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid are 
pharmacologically inactive. In vitro studies indicate that vorinostat is not metabolized by 
and does not inhibit the activity of cytochrome P-450 enzymes.  Less than 1% of an 
administered dose is excreted unchanged in the urine.  Approximately 35-52% of an oral 
dose of vorinostat is excreted in the urine as the two major metabolites.  The mean 
terminal half-life of vorinostat and the O-glucuronide metabolite is approximately 2 
hours, while that of the 4-anilino-4-oxobutanoic acid metabolite it is 11 hours.  
DDI 
 
Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were 
observed in patients receiving vorinostat with coumarin-derivative anticoagulants (eg, 
warfarin).  Therefore PT and INR should be monitored when coumarin-dervative 
anticoagulants are started or discontinued. 
 
When vorinostat was administered with other HDAC inhibitors (eg, valproic acid), severe 
thrombocytopenia and gastrointestinal bleeding have been reported.  


 
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Toxicity: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR)  
for  
Vorinostat (SAHA, Zolinza, NSC 701852) 
 
The Comprehensive Adverse Event 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 evehts that are protocol specific exceptions to expedited reporting to NCI (except as 
noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 1076 patients. Below is the 
CAEPR for Vorinostat (SAHA, Zolinza). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower 
of the grades to determine if expedited reporting is required. 
 
 
     Version 2.8, December 18, 20131 
 
 Adverse Events with Possible  
 Relationship to Vorinostat (SAHA, Zolinza) 
 (CTCAE 4.0 Term) 
[n= 1076] 
 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
  
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 2) 
 
Aspartate 
aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 2) 
 
Blood bilirubin increased 
 
  


 
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Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
Lymphocyte count decreased  
 Lymphocyte count decreased (Gr 4) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 3) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr 2) 
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle weakness3 
 
 Muscle weakness3 (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
 
Skin 
and 
subcutaneous 
tissue disorders - Other 
(skin necrosis) 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can 
be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the 
investigator, the protocol and the agent should be included in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC. 
 
3Muscle weakness includes Generalized muscle weakness, Muscle weakness left-sided, 
Muscle weakness lower limb, Muscle weakness right-sided, Muscle weakness trunk, and 
Muscle weakness upper limb under the MUSCULOSKELETAL AND CONNECTIVE 
TISSUE DISORDERS SOC. 
 
4Prolongation of prothrombin time and International Normalized Ratio have been 
observed in patients using vorinostat concomitantly with coumarin-derivative 
anticoagulants.  
 
Also reported on vorinostat (SAHA, Zolinza) trials but with the relationship to 
vorinostat (SAHA, Zolinza) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other 
(supraventricular arrhythmia); Chest pain - cardiac; Left ventricular systolic dysfunction; 
Myocardial infarction; Palpitations; Pericardial effusion; Sinus bradycardia; Sinus 


 
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tachycardia; Ventricular fibrillation 
EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
EYE DISORDERS - Blurred vision; Eye disorders - Other (retinal tear) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal hemorrhage; 
Bloating; Cheilitis; Colitis; Dysphagia; Esophageal hemorrhage; Esophagitis; Flatulence; 
Gastric hemorrhage; Gastritis; Gastroesophageal reflux disease; Gastrointestinal disorders 
- Other (duodenitis); Lower gastrointestinal hemorrhage; Mucositis oral; Oral 
hemorrhage; Oral pain; Small intestinal obstruction; Stomach pain; Upper gastrointestinal 
hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; 
Edema limbs; Gait disturbance; General disorders and administration site conditions - 
Other (failure to thrive); Malaise; Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (angioedema) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; 
Vascular access complication; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged4; Alkaline 
phosphatase increased; Cardiac troponin I increased; Electrocardiogram QT corrected 
interval prolonged; GGT increased; INR increased4; Investigations - Other (increased 
lactate dehydrogenase); Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; 
Hyperkalemia; Hypermagnesemia; Hyperuricemia; Hypoalbuminemia; Hyponatremia; 
Metabolism and nutrition disorders - Other (decreased total protein); Tumor lysis 
syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Chest wall pain; Musculoskeletal and connective tissue disorder - Other (muscle spasms); 
Musculoskeletal and connective tissue disorder - Other (myositis); Myalgia; Neck pain; 
Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(tumor hemorrhage); Tumor pain 
NERVOUS SYSTEM DISORDERS - Abducens nerve disorder; Ataxia; Cognitive 
disturbance; Depressed level of consciousness; Dysphasia; Encephalopathy; Facial 
muscle weakness; Facial nerve disorder; Headache; Intracranial hemorrhage; Ischemia 
cerebrovascular; Lethargy; Memory impairment; Nervous system disorders - Other 
(Guillain-Barre syndrome); Nervous system disorders - Other (head injury); Nervous 
system disorders - Other (polyneuropathy); Paresthesia; Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Seizure; Somnolence; Stroke; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Euphoria; 
Personality change; Psychosis 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria; 
Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; 
Pelvic pain; Uterine hemorrhage; Vaginal hemorrhage 
RESPIRATORY, 
THORACIC 
AND 
MEDIASTINAL 
DISORDERS 
- 
Bronchopulmonary hemorrhage; Epistaxis; Hypoxia; Pharyngeal mucositis; Pleural 
effusion; Pleuritic pain; Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail 
loss; Palmar-plantar erythrodysesthesia syndrome; Purpura; Rash maculo-papular; Skin 
and subcutaneous tissue disorders - Other (brittle nails) 


 
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VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypertension; 
Hypotension; Thromboembolic event; Visceral arterial ischemia 
 
Note: Vorinostat (SAHA, Zolinza) 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. 
 
 
PLEASE NOTE:  The potential risks listed in the CAEPR whose relationship to 
vorinostat is still undetermined are not required by CTEP to be described in the ICD; 
however, they may be communicated to patients according to local IRB 
requirements. 
 
 
Effect in pregnancy: Vorinostat is Pregnancy Category D.  It may cause fetal harm 
when administered to a pregnant woman.  Adequate contraception must be used by all 
patients (both male and female) and their partners during therapy with vorinostat and for 
30 days after the completion of study drug administration. 
 
Formulation and Stability: Vorinostat is supplied as a white, opaque gelatin, size 3 
capsule, containing 100 mg of vorinostat.  The inactive ingredients in each capsule include 
microcrystalline cellulose, sodium croscarmellose, and magnesium stearate.  Vorinostat 100 
mg capsules are supplied in bottles containing 120 capsules. 
 
Store vorinostat capsules at room temperature, 15 to 30ºC (59 to 86ºF). Do not store above 
30ºC and avoid exposure to excessive moisture.  
 
A formulation for compounding vorinostat suspension by the pharmacy is provided 
below: 
 
Ingredients: 
Vorinostat 100 mg capsules 
20 capsules 
OraPlus or Suspensol S  
20 mL 
OraSweet 
 
 
20 mL 
 
Instructions:  
Add 20 mL of Suspensol S or OraPlus into an amber or clear glass 4 ounce bottle.  Place 
the contents of 20 capsules of vorinostat 100 mg into the same bottle and shake to 
disperse.  Shaking may take up to 3 minutes.  Once dispersed, add 20 mL of OraSweet to 
achieve a total volume of 40 mL.  Shake again to disperse.  The final concentration is 50 
mg/mL.  Store at room temperature.  The suspension is stable for 4 weeks when stored at 
room temperature, away from excessive heat and humidity. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
Vorinostat should be taken with food.  The capsules should not be opened or 
crushed.  A suspension can be prepared by the pharmacy for patients that cannot 
swallow (see Formulation and Stability section above). 
 
If a patient needs less than 120 capsules for a treatment cycle, the exact number of 
capsules needed for treatment can be counted into a prescription bottle.   


 
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Page 41 
 
Direct contact of the powder in vorinostat capsules with the skin or mucous membranes 
should be avoided. If such contact occurs, wash thoroughly. Clean powder spills from 
broken or damaged vorinostat capsules carefully minimizing inhalation. Wash spill area at 
least 3 times with ethyl alcohol, followed by water. 
 
Supplier:  Supplied by Merck Research Laboratories and distributed by the NCI DTCD.  
Do not use commercially available drug 
 
Agent Ordering 
NCI supplied agent may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained.)  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), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), 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 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees must submit agent requests through the PMB Online Agent Order 
Processing 
(OAOP) 
application 
< 
https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  >.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account < https://eapps-
ctep.nci.nih.gov/iam/ > and the maintenance of an “active” account status and a “current” 
password. For questions about drug orders, transfers, returns, or accountability, call 
(240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See 
the CTEP home page at 
 http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs 
for 
the 
Procedures 
for 
Drug 
Accountability 
and 
Storage 
and 
http://ctep.cancer.gov/forms/default.htm to obtain a copy of the DARF and Clinical Drug 
Request form.) 
 
Agent Returns 
Investigators/Designees must return unused DCTD supplied investigational agent to the 
NCI clinical repository as soon as possible when: the agent is no longer required because 
the study is completed or discontinued and the agent cannot be transferred to another 
DCTD sponsored protocol; the agent is outdated or the agent is damaged or unfit for use. 
Regulations require that all agents received from the DCTD, NCI be returned to the 
DCTD, NCI for accountability and disposition. Return only unused vials/bottles. Do 


 
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NOT return opened or partially used vials/bottles unless specifically requested otherwise 
in the protocol. See the CTEP web site for Policy and Guidelines for Investigational 
agent Returns at: http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs. 
The 
appropriate 
forms 
may 
be 
obtained 
at: 
http://ctep.cancer.gov/forms/docs/return_form.pdf. 
 
 
 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
Criteria for Removal from Protocol Therapy  
 
a) 
Radiographic evidence of progressive disease (see section 12.0). 
b) 
Clinical evidence of disease progression that can not be clearly attributed to 
weaning of dexamethasone, side effects from anti-epileptics, electrolyte 
disturbance, infection/sepsis, or other clinical events not related to protocol 
therapy. 
c) 
Adverse Events requiring removal from protocol therapy (see section 6.0). 
d) 
Refusal of further protocol therapy by patient/parent/guardian. 
e) 
Non-compliance that, in the opinion of the investigator, does not allow for ongoing 
participation. 
f) 
Completion of 12 cycles of maintenance therapy. 
g) 
Physician determines it is not in the patient’s best interest. 
h) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
and serum creatinine) are outside the parameters required for eligibility prior to the 
start of vorinostat and radiation (see section 8.1). 
i) 
A patient becomes pregnant while receiving protocol therapy. 
j) 
Development of a second malignancy. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for 
Off Study (see below). Ongoing adverse events, or adverse events that emerge after the 
patient is removed from protocol therapy, but within 30 days of the last dose of 
investigational agent, must be followed and reported via RDE and CTEP-AERS (if 
applicable).  Follow-up data will be required unless consent is withdrawn. 
 
10.2 
Off Study Criteria 
 
a) 
Thirty days after the last dose of the investigational agent (patients on Part A NOT 
enrolled at the MTD) 
b) 
The fifth anniversary of the date the patient was enrolled on this study (patients on 
Part A enrolled at the MTD and all patients enrolled on Part B) 
c) 
Death. 
d) 
Lost to follow-up. 
e) 
Withdrawal of consent for any further data submission. 
f) 
Patient enrollment onto another COG study with tumor therapeutic intent (eg, at 
recurrence). 


 
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11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
There will be two parts in this study, for patients with newly diagnosed diffuse intrinsic 
pontine gliomas: 
 
PART A: Phase I dose-finding component 
PART B: Phase II component 
 
A minimum of 2 evaluable patients will be entered at each dose level for determination of 
MTD in Part A. Accrual to Part B of the study will only open once the MTD or 
recommended phase 2 dose has been determined in Part A. Review of patient accrual 
onto a recent COG study of DIPG, ACNS0126, enrolled 63 patients in 15 months; hence 
the expected annual accrual for this study is 50 patients (2-3 patients per month in phase 
1, and 4-5 patients per month in phase 2), which will permit completion of this study 
within 1.6 years. A maximum of 80 patients is anticipated. Twelve patients were enrolled 
on Part A and Phase II will enroll up to 68 patients to obtain 65 eligible patients for a 
maximum of 870 patients.  
 
11.2 
Part A of the Study 
 
11.2.1 Definitions 
 
Evaluable For Adverse Effects 
Any patient who receives the study drug will be evaluable for Adverse Effects. 
However, for the consideration of dose escalation, patients must be fully 
evaluable for toxicity. Any patient who experiences DLT at any time during 
protocol therapy is considered fully evaluable for Adverse Effects. Patients 
without DLT who receive at least 85% of the prescribed dose per protocol 
guidelines are also considered fully evaluable for Adverse Effects. Patients who 
are not fully evaluable for Adverse Effects at a given dose level will be replaced. 
 
 
Maximum Tolerated Dose  
The MTD will be the maximum dose at which fewer than one-third of patients 
experience DLT (See section 5.6) during the chemoradiotherapy component in 
part A of the study. In the event that two DLTs observed out of 6 evaluable 
patients are different classes of Adverse Effects (e.g. hepatotoxicity and 
myelosuppression), expansion of the cohort to 12 patients will be considered if 
all of the following conditions are met:  
 
•  One of the DLTs does not appear to be related to dose  
•  The Adverse Effects are readily reversible 
•  The study chair, DVL statistician, DVL committee chair or vice chair, 
and IND sponsor all agree that expansion of the cohort is acceptable 
 
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting 
toxicities, then dose escalation can proceed. 
 


 
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11.2.2 Dose Escalation and Determination of MTD  
 
The rolling six phase 1 trial design will be used for the conduct of this study92  
Two to six patients can be concurrently enrolled onto a dose level, dependent 
upon (1) the number of patients enrolled at the current dose level, (2) the number 
of patients who have experienced DLT at the current dose level, and (3) the 
number of patients entered but with tolerability data pending at the current dose 
level.  Accrual is suspended when a cohort of six has enrolled or when the study 
endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled 
in the cohort, the number of DLTs observed, and the number of participants at 
risk for developing a DLT (i.e., participants enrolled but who are not yet 
assessable for toxicity). For example, when three participants are enrolled onto a 
dose cohort, if toxicity data is available for all three when the fourth participant 
entered and there are no DLTs, the dose is escalated and the fourth participant is 
enrolled to the subsequent dose level. If data is not yet available for one or more 
of the first three participants and no DLT has been observed, or if one DLT has 
been observed, the new participant is entered at the same dose level. Lastly, if 
two or more DLTs have been observed, the dose level is de-escalated. This 
process is repeated for participants five and six. In place of suspending accrual 
after every three participants, accrual is only suspended when a cohort of six is 
filled. When participants are inevaluable for toxicity, they are replaced with the 
next available participant if escalation or de-escalation rules have not been 
fulfilled at the time the next available participant is enrolled onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the 
current dose level (ii) at an escalated dose level, (iii) at a de-escalated dose level, 
or whether the study is suspended to accrual: 


 
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# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
3 
0 
3 
0 
Escalate** 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
4 
0 
4 
0 
Escalate** 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
5 
0 
5 
0 
Escalate** 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
* If six patients already entered at next lower dose level, the MTD has been defined. 
**If final dose level has been reached, the recommended dose has been reached. 
 
If two or more of a cohort of up to six patients experience DLT at a given dose 
level, then the MTD has been exceeded and dose escalation will be stopped (see 
section 11.2.1 for exception to rule). 
 
Patients enrolled on Part A will continue on maintenance therapy as described in 
section 5.4. 
 
In addition to determination of the MTD, a descriptive summary of all toxicities 
will be reported. 
 
11.3 
Part B of the Study 
The second portion of the study will begin after selecting the treatment dose for 
vorinostat in the phase I portion (Part A) of the study.  The primary aim of this part of the 
study is to determine the effect on event-free survival and overall-survival, of 
administering vorinostat concurrently with radiation therapy, followed by maintenance 
vorinostat for twelve courses, in patients with diffuse intrinsic pontine gliomas.  This 
portion of the trial will be performed group wide once the recommended dose of 
vorinostat during radiation is defined.  Data collected from any patients enrolled at the 
MTD from the phase 1 component of the trial will be utilized in the Phase 2 study. 
 
11.3.1   Efficacy Endpoints  
The primary endpoint for the evaluation of treatment efficacy will be event-free 
survival (EFS), defined as the time to disease progression, disease relapse, 
occurrence of a second neoplasm, or death from any cause, or date of last follow-


 
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up measured from the time of study enrollment. 
 
Definitions of Evaluable 
 
Part B:  
Evaluable for Adverse Events and Efficacy 
Patients will be considered evaluable for adverse events and efficacy if they meet 
the following criteria: (1) the patient is eligible; (2) the patient receives one dose 
of vorinostat at the MTD determined in Phase 1 (230 mg/m2/day) per protocol 
guidelines, and (3) if central review is required, the patient is confirmed to have 
eligible diagnosis. 
 
The secondary efficacy endpoint is overall survival (OS), which is defined as the 
time to death from any cause. 
 
Primary Toxicity Endpoints: 
For purposes of analysis, toxicities are classified by whether they are attributed to 
initial therapy (XRT/vorinostat) or to maintenance therapy (vorinostat). 
XRT/vorinostat-specific toxicities are listed in sections 5.6.1 to 5.6.3. 
Maintenance vorinostat toxicities are the same as DLTs defined in 
XRT/vorinostat section above, excluding 5.6.1. Toxic death is death 
predominantly attributable to treatment-treated causes.  Toxic deaths occurring 
following the start of maintenance will be attributed to maintenance therapy, 
except when the death is clearly related to radiation necrosis or other XRT-
specific toxicities. 
 
11.3.2 Comparison with Baseline Established from Historical Control 
The most recent relevant historical data on the outcome for patients with DIPGs 
is derived from CCG-9941 and ACNS0126. Figure 1 presents an event-free 
survival plot for the 61 eligible DIPG patients on ACNS0126 and compares them 
to a similar cohort of 63 patients from CCG-9941. The one-year EFS was 15 ± 
5% for ACNS0126 and 21 ± 5% for CCG-9941.  For the planning of the current 
trial, the combined data of ACNS0126 and CCG-9941 will be used as the 
historical control data.  Figure 2 presents an approximation of the failure time 
distribution up to one year by an exponential failure time model.  Fitting an 
exponential model to the combined data yields =1.54/year, and that one-year 
EFS estimated from this model is 21%.   
 
The goal of this study is to compare outcome using historical control data 
described above as a baseline for comparison.  We wish to detect a one-third 
reduction in the risk of failure as a result of this therapy.  This corresponds to a 1-
year EFS of 36%.  Using the Woolson93,94 one-sample log-rank test, with a one-
sided 5% test of significance and 80% power, a total of 50 failures is obtained 
under the null hypothesis, which requires an enrollment of 65 patients in 15-18 
months.  


 
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0%
20%
40%
60%
80%
100%
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Years from study entry
Event-Free Survival Percent
'PL Estimate
Exponential
 
Figure 2:  Event Free Survival from Combined Data ACNS0126 and 
CCG 9941 Product Limit Estimate and Exponential Model 
 
11.3.3 Analysis of Toxicity 
 
The analysis of toxicity will focus on estimates of the rates of 
chemoradiotherapy-phase DLT and rates of maintenance phase toxicities.  
Estimates will be obtained using life-table methods, with an event defined as the 
first occurrence of a primary toxicity.  Patients who have progression or 
recurrence of disease will be censored in these analyses.  Appropriate adjustment 
will be made to the rates estimates to account for potential effects of the initial 
vorinostat dose selection. 
 
 
11.3.4 Interim Monitoring of event-free survival 
 
Interim monitoring will be based on the Lan-Demets criterion, with spending 
function αt2.  The time point for 100% information is defined as 1.5 years after 
the last patient has enrolled. Analysis year, percent information, and critical 
Figure 1: Event-Free Survival for DIPG 
0.00 
0.25 
0.50 
0.75 
1.00 
0 
1 
2 
3 
4
5 
6 
7 
8 
9 
10 
11 
Years from study entry 
                            
Probability 
CCG-9941 (n=63) 
ACNS0126 (n=61) 


 
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values for interim monitoring are listed in the table below. Let 
tZ be the Z-value 
of the one-sample one-sided log rank statistic computed at some interim look 
with 
corresponding 
percent 
information 
or 
information 
fraction 
t.  
Let
t
t
B
Z
t
=
.  For example, the first interim analysis will begin in analysis year 
1, which is at time that 37% information will be available.  According to the 
table, if B0.37 exceeds the critical Z-value, 2.47, then the study will be flagged for 
review. 
 
Analysis 
Year 
Number of Events 
under null 
hypothesis 
% 
Information 
One-Sided 
Z-Value 
Nominal one-
sided p-value 
1 
21 
37% 
2.47 
0.0068 
1.5 
39 
69% 
2.05 
0.02 
2 
51 
90% 
1.87 
0.024 
2.5 
55 
98% 
1.85 
0.03 
3.0 
56 
100% 
1.88 
0.03 
 
At each time of interim monitoring, we will also calculate the conditional 
probability that the test statistics will be less than the final monitoring boundary 
at the final projected analysis time, under the alternative hypothesis viz., 1-year 
EFS of 36% for patients.  If the conditional probability is less than 0.1, the study 
will be considered for termination because there will be little chance of 
concluding protocol therapy to be superior to historical outcome. 
 
11.3.5 Monitoring for Toxic Death 
 
No serious problems are expected with toxic death (TDR). We will nevertheless 
monitor rates of toxic death.  The maximum tolerable TDR is 5%. If TDR is truly 
5%, there is a 40% chance that there will be at least 1 toxic death among the first 
enrolled 10 patients, and a 72% chance that there will be at least 1 toxic death 
among the first 25 enrolled patients.  Statistical monitoring rules will not be used. 
Rather, a careful review of treatment and patient safety will be undertaken when 
the first toxic death occurs.  The 2nd toxic death on study will lead to accrual 
suspension.  
 
11.3.6 Monitoring for Toxicity 
 
Toxicities will be monitored separately in chemoradiotherapy and maintenance 
phase. The number of patients who discontinue vorinostat due to recurrent dose-
limiting toxicities as specified in the Study Endpoints section will be monitored 
using the following rule:  
 
If 3 or more of the first 16 patients or 7 or more of the first 48 patients 
discontinue vorinostat due to recurrent dose-limiting toxicities, then a careful 
review of treatment and patient safety will be undertaken. The operating 
characteristics of this stopping rule are summarized in the table. 


 
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True proportion of 
Toxicity 
Probability of 
Stopping 
0.05 
0.05 
0.07 
0.12 
0.1 
0.31 
0.15 
0.67 
0.2 
0.90 
0.25 
0.98 
0.3 
0.99 
 
Toxicities for the maintenance phase component of the trial will be monitored 
closely at regular intervals by the DSMB, and the vorinostat dose during 
maintenance therapy will be reduced if the monitoring rule is met. 
 
11.4 
Gender and Minority Accrual Estimates 
 
The gender and minority distribution of the study population is expected to be: 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
8 
1 
9 
Not Hispanic or Latino 
34 
37 
71 
Ethnic Category:  Total of All Participants* 
42 
38 
80 
Racial Categories 
  
  
  
American Indian/Alaska Native 
1 
0 
1 
Asian 
1 
0 
1 
Black or African American 
6 
10 
16 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
White  
34 
28 
62 
Racial Categories:  Total of All Subjects* 
42 
38 
80 
 
 
 
The distribution was derived from ACNS0222. 
 
11.5 
Correlative Studies 
 
The following measurements will be obtained for analysis of the secondary aims: 
 
(1) H3 and H4 acetylation in PBMC: Pre- and post-treatment levels of H3 and H4 
acetylation in PBMCs will be measured.  Degree of acetylation in peripheral blood 
monocytes will be divided into quartiles and coded as none, mild, moderation or 
marked.  
(2) NHEJ activity in PBMC: NEHJ activity is another possible inhibitory target for 
vorinostat. Whether there is a decreased NHEJ activity will be determined.  
(3) Quantifying 
DNA 
repair 
proteins 
from 
paraffin-embedded 
blocks: 
for 
immunohistochemistry from tumor blocks, the intensity will be graded from 1 to 3; 
for Western analysis, a percentage of the intensity relative to the tumor with the 
highest level will be measured. 


 
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With a total of 65 patients in Part B and unknown compliance rate in submitting samples, 
the analysis of above correlative studies will be exploratory in nature.  Descriptive 
statistics will be used to summarize the biological/laboratory measures and the changes in 
these measures across time-points. Mean and standard deviation will be used to 
summarize continuous measures; log transformation may be considered when 
appropriate. Categorical measures will be described by percentages with binary 
confidence intervals and frequency tables. Exploratory analyses to correlate the 
biological/laboratory measures with disease outcome will be performed. Log rank tests 
will be used to explore the prognostic significance of a categorical factor on EFS or OS. 
Cox proportional hazards models will be used to explore the effect of a continuous 
marker on EFS/OS, and will be used for exploratory multivariate analysis examining the 
effect of the predictor of interest with adjustments for other patient characteristics or risk 
factors. 
 
 
12.0  
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
12.2 
Methodology to Determine Tumor Measurement 
In order to completely document the assessment of response, the two-dimensional tumor 
measurements for all target lesions upon which the assessments of tumor response are 
based should be explicitly noted in the radiology report for the baseline and all 
subsequent follow-up exams. Reports for the follow-up exams should reiterate the 
measurements obtained at baseline for each target lesion. Newly occurring lesions should 
also be enumerated in these reports, and changes in lesions should be described. 
 
Tumor response criteria for this study are to be determined by changes in size using the 
maximal 2-dimensional cross-sectional tumor measurements, T x W (product of the 
longest diameter of the tumor [width (W)] and its longest perpendicular diameter 
[transverse (T)], using either T1 or T2 weighted images (which ever gives the best 
estimate of tumor size).  This will allow comparison with historical studies as outlined in 
the statistical design section, such as CCG-9941 and ACNS0126, which used cross-
sectional measurements in their determination of response status. 
  
Tumor length (L), perpendicular to the T x W plane should also be measured and 
recorded, since this will provide historical data for future studies that will rely 
exclusively on volumetric response determinations.  However, for the current study, 
3-dimensional tumor volume change will not be used to determine response status. 
  
The following section describes the methodology. 
  
(See drawing below for illustration) 


 
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1.   Longest diameter of target lesion(s) should be selected in the axial plane only for CT. 
For MRI imaging, the longest diameter can be measured from the axial plane or the 
plane in which the tumor is best seen or measured, provided the same plane is used in 
follow ups. 
2.   The longest measurement of the tumor (or width, W) should be determined.  
3.   The 2 perpendicular measurements should be determined (transverse (T) 
measurement-perpendicular to the width in the selected plane, and the length (L) 
tumor extent in the plane perpendicular to the selected plane). 
4.   Leptomeningeal tumor spread is not a target lesion, as its presence at diagnosis would 
make the patient ineligible for this brainstem glioma study.  The presence and 
location of leptomeningeal tumor spread at relapse should be noted. 
 
 
 
 


 
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12.3 
Selection of Target and Non-Target Lesions 
For intrinsic pontine brainstem gliomas, only one lesion/mass is present at diagnosis, and 
therefore is considered a “target” for measurement/follow up to assess for tumor 
progression/response. (Patients with multiple target lesions at diagnosis are considered to 
have disseminated disease and would be ineligible for this study). 
  
If other non-target lesions develop at relapse (including CSF positive for tumor cells), 
their location should be noted, although they do not need to be measured. 
 
12.4 
Response Criteria for Target Lesions 
For this study, comparison of maximal 2-dimensional measurements, T x W (product of 
the longest diameter [width (W)] and its longest perpendicular diameter [transverse (T)] 
will be used for Response Criteria for Target Lesions. 
  
Complete Response (CR): The disappearance of all abnormal signal within the 
brainstem and return to normal size of the brainstem. 
  
Partial response (PR): ≥50% decrease in the sum of the products of the two 
perpendicular diameters of the target lesion, taking as reference the initial baseline 
measurements 
  
Stable Disease (SD): Neither sufficient decrease in the products of the two perpendicular 
diameters of the target lesion to qualify for PR (taking as reference the initial baseline 
measurements), nor sufficient increase in the target lesion to qualify for PD, (taking as 
reference the smallest disease measurement since the treatment started). 
 
Progressive Disease (PD):  Progressive disease is defined as 25% or more increase in the 
sum of the product of the perpendicular diameters of the target lesions, taking as 
reference the smallest sum of products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
12.5 
Overall Response Assessment 
The overall response assessment takes into account response in the 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. 
 
 


 
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12.6 
Best Response 
Two objective status determinations of disease status, by MRI, obtained on two 
consecutive determinations, separated by at least a 4 week time period, are required to 
determine the patient’s overall best response.  Two objective status determinations of CR 
before progression are required for best response of CR.  Two determinations of PR or 
better before progression, but not qualifying for a CR, are required for a best response of 
PR. Two determinations of stable/no response or better before progression, but not 
qualifying as CR or PR, are required for a best response of stable/no response; if the first 
objective status is unknown, only one such determination is required.  Patients with an 
objective status of progression on or before the second evaluations (the first evaluation is 
the first radiographic evaluation after treatment has been administered) will have a best 
response of progressive disease.  Best response is unknown if the patient does not qualify 
for a best response of progressive disease and if all objective statuses after the first 
determination and before progression are unknown. 
 
1st Status 
2nd Status 
3rd Status 
Best Response 
Progression 
 
 
Progressive 
disease 
Stable, PR, CR 
Progression 
 
Progressive 
disease 
Unknown 
Progression 
 
Progressive 
disease 
Stable 
Stable 
Progression 
Stable 
Stable, Unknown 
PR, CR 
Progression 
Stable 
Stable, Unknown 
Unknown 
Progression 
Unknown 
PR 
PR 
Progression 
PR 
PR 
CR 
Progression 
PR 
PR, CR 
Unknown 
Progression 
Unknown 
CR 
CR 
Progression 
CR 
Unknown 
Stable 
Progression 
Stable 
 
 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
13.1 
Purpose 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  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. 
 
13.2 
Determination of reporting requirements 
 
Reporting requirements may include the following considerations: 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; and 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. 
 


 
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An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
 
13.3 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1:  Identify the type of event using the NCI Common Terminology Criteria  
The descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting and are located on 
the CTEP website at: 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE.   
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
 
 
Step 3:   Determine the attribution of adverse event in relation to the protocol therapy.   
Attribution categories are: Unrelated, Unlikely, Possible, Probable, and Definite. 
 
Step 4:  Determine the prior experience of the adverse event.   
 
Expected events for a CTEP IND agent are defined as those listed in the ASAEL 
(Agent Specific Adverse Event List), a subset of the CAEPR (Comprehensive Adverse 
Event and Potential Risks). For investigational agents that are not commercially available 
and are being studied under a company’s IND or an investigator held IND, expected AEs 
are usually based on the Investigator’s Brochure.   
 
Unexpected events for a CTEP IND agent are defined as those NOT listed in the 
ASAEL. 
 
Guidance on expectedness of the agent is provided in the Drug Information Section 
of this protocol. 
 
Step 5:  Review Table A or Table B in this section to determine if: 
• there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• there are any protocol-specific exceptions to the reporting requirements. 
 
13.4 
Reporting methods 
 
• 
Use the NCI’s Adverse Event Reporting System (CTEP-AERS). The NCI’s guidelines for 
CTEP-AERS can be found at http://ctep.cancer.gov. 
 
 
An CTEP-AERS report must be submitted by the following method: 
 
Electronically submit the report via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/CTEP-AERS.htm   
 
• 
Fax supporting documentation for AEs related to investigational agents to: 
o The NCI for agents supplied under a CTEP IND only (fax # 301-230-0159).  
o and to COG for all IND studies (fax # 626-241-1795; email: 


 
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COGQA@childrensoncologygroup.org attention: COG CTEP-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. 
 
13.5 
When to report an event in an expedited manner 
 
• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via the 
web based application. 
 
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.   
 
• 
Submit the report within 5 calendar days of learning of the event. 
 
13.6 
Other recipients of adverse event reports 
COG will forward reports and supporting documentation to the Study Chair. 
 
Adverse events determined to be reportable must also be reported according to the local policy and 
procedures to the Institutional Review Board responsible for oversight of the patient. 
 
13.7 
Reporting of Adverse Events for investigational agents  
Reporting requirements are provided in Table A and Table B.  The investigational agent used in this study 
is vorinostat. 


 
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Table A: For Part A of the Study Only  
Phase 1 Trials Utilizing an Agent under a CTEP IND or Non-CTEP IND:  CTEP-AERS Expedited 
Reporting Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of the 
Investigational Agent 
 
 
 
Grade 1 
 
Grade 23 
 
Grade 2 
 
Grade 33 
 
Grade 33 
Grades 
4 & 52, 3 
Unexpected  
and Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  
and 
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
5 Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
24-Hour; 
5 Calendar 
Days 
5 Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the 
last dose of treatment with an agent under a CTEP IND or non-CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification (via CTEP-AERS for CTEP IND agents; via e-mail to COG AE Coordinator for 
agents in non-CTEP IND studies) followed by complete report within 5 calendar days for: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 4 unexpected events  
• Grade 5 expected events and unexpected events 
 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
 
3    Please see exceptions below under section entitled “Additional Instructions or Exceptions.” 
March 2005 
 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
 
• 
Expedited AE reporting timelines defined: 
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-AERS 
within 24 hours of learning of the event followed by a complete CTEP-AERS report within 5 
calendar days of the initial 24-hour report. 
➢ “5 calendar days” - A complete CTEP-AERS report on the AE must be submitted within 5 
calendar days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via CTEP-AERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 


 
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Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 1 
Trials Utilizing an Agent under a CTEP-IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not due to 
cancer recurrence/progression must be reported via CTEP-AERS for an agent under a CTEP or 
non-CTEP IND agent per the timelines outlined in the table above. 
 
• Myelosuppression, including Grade 4, does not require expedited reporting unless unexpected. 
 
• Lymphopenia, including Grade 4, does not require expedited reporting unless unexpected. 
 
• 
Grade 2 adverse events listed in the table below do not require expedited reporting via CTEP-
AERS: 
 
Category 
Adverse Events 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
GENERAL DISORDERS AND 
ADMINISTRATION SITE CONDITIONS 
Chills 
GENERAL DISORDERS AND 
ADMINISTRATION SITE CONDITIONS 
Fever 
INFECTIONS AND INFESTATIONS 
Infection 
INVESTIGATIONS 
Activated partial thromboplastin time prolonged 
INVESTIGATIONS 
Alkaline phosphatase increased 
INVESTIGATIONS 
Blood bilirubin increased 
METABOLISM AND NUTRITION DISORDERS 
Hypoalbuminemia 
METABOLISM AND NUTRITION DISORDERS 
Hypocalcemia 
METABOLISM AND NUTRITION DISORDERS 
Hypokalemia 
METABOLISM AND NUTRITION DISORDERS 
Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE 
TISSUE DISORDERS 
Musculoskeletal and connective tissue disorder -  
Other (muscle spasms) 
RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS 
Dyspnea 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
Alopecia 
 
As referenced in the CTEP Adverse Event Reporting Requirements, an AE that resolves and then recurs 
during a subsequent cycle does not require CTEP-AERS reporting unless (1) the Grade increases; or (2) 
hospitalization is associated with the recurring AE. 


 
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Table B: For Part B of the Study Only 
Phase 2 and 3 Trials and COG Group-wide Pilot Studies utilizing an Agent under a CTEP IND or a 
Non-CTEP IND:  CTEP-AERS Expedited Reporting Requirements for Adverse Events That Occur 
Within 30 Days1 of the Last Dose of the Investigational Agent 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
43 & 52 
Unexpected  
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
5 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
5 
Calendar 
Days 
5 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
5 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after 
the last dose of treatment with an agent under a CTEP IND or non-CTEP IND require reporting as 
follows: 
CTEP-AERS 24-hour notification (via CTEP-AERS for CTEP IND agents; via e-mail to COG AE Coordinator 
for agents in Non-CTEP IND studies) followed by complete report within 5 calendar days for: 
• Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 5 calendar day report: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization (see exceptions 
below 
• Grade 5 expected events 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, 
a full report is required as outlined in the table. 
3 Please see exceptions below under section entitled “Additional Instructions or Exceptions.” 
March 2005 
 
 
Note: All deaths on study require timely reporting to COG via RDE regardless of causality.  
Attribution to treatment or other cause must be provided.   
 
 
• 
Expedited AE reporting timelines defined: 
➢ 
“24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS for CTEP IND agents within 24 hours of learning of the event 
followed by a complete CTEP-AERS report within 5 calendar days of the initial 
24-hour report. 
➢ 
“5 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
within 5 calendar days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions. 
 


 
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• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
• 
Protocol specific reporting of AEs, in addition to the CTEP-AERS requirements, are to 
be entered in the COG remote data entry system.   
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an 
investigational agent which can be attributed (possibly, probably, or definitely) to the agent 
and is not due to cancer recurrence/progression must be reported via CTEP-AERS per the 
timelines outlined in the table above. 
 
• Grades 1- 4 myelosuppression do not require expedited reporting unless unexpected. 
 
• As of August 25, 2010 all secondary malignancies should be reported via CTEP-AERS.   
 
 
13.8 
Routine Adverse Event Reporting 
Note: The guidelines below are for routine reporting of study specific adverse events on the COG case 
report forms and do not affect the requirements for CTEP-AERS reporting. 
 
 
 
 
 
The NCI defines both routine and expedited AE reporting. Routine reporting is accomplished via the 
Adverse Event (AE) Case Report Form (CRF) within the study database. For this study, routine reporting 
will include all CTEP-AERS reportable events, Grade 3 and higher Adverse Events and any events which 
constitute a dose limiting toxicity (DLT) per the protocol.  
 


 
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14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories: 
 
1. 
Non-computerized Information:  Roadmaps (Part A only), Pathology Reports, 
Surgical Reports. These forms are faxed, with the corresponding shuttle sheet, to 
the Statistics & Data Center at (626) 447-2204. 
 
2. 
Reference Labs, Biopathology Reviews, and QARC data:  These data accompany 
submissions to these centers, which forward their data electronically to the COG 
Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
entered in the COG Remote Data Entry System with the aid of schedules and 
worksheets (essentially paper copies of the RDE screens) provided in the data 
form packet. 
 
See separate Data Form Packet, which includes submission schedule. 
 
14.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports 
are due January 31, April 30, July 31 and October 31.  This is not a responsibility of 
institutions participating in this trial. 
 
14.3 
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. 
 
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 


 
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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 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 


 
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presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
14.4 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.4.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role 
of the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the developmental therapy 
scientific committee; and a member from the NCI. The DSMC meets at least 
every 6 months to review current study results, as well as data available to the 
DSMC from other related studies. Approximately 6 weeks before each meeting 
of the Phase 1 and 2 DSMC, study chairs will be responsible for working with 
the study statistician to prepare study reports for review by the DSMC. The 
DSMC will provide recommendations to the COG Developmental Therapeutics 
Chair and the Group Chair for each study reviewed to change the study or to 
continue the study unchanged. Data and Safety Committee reports for 
institutional review boards can be prepared using the public data monitoring 
report as posted on the COG Web site. 
 
14.4.2 Monitoring by the Study Chair and Developmental Therapeutics Leadership  
The study chair will monitor the study regularly and enter evaluations of 
patients’ eligibility into the study database.  
 
In addition, during Part A study data and the study chair’s evaluations of 
patients’ eligibility, evaluability and dose limiting toxicities will be reviewed by 
the Developmental Therapeutics Chair, Vice Chair and Statistician on a weekly 
conference call. 
 
 


 
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15.0 
RADIATION THERAPY GUIDELINES 
 
Radiation Therapy for patients on COG protocols can only be delivered at approved COG RT facilities.  
 
 
 
 
 
 
 
 
 
 
15.0.1 General Guidelines 
This is a phase 1/2 study to determine the maximum tolerated dose (MTD) of suberoylanilide 
hydroxamic acid (SAHA; vorinostat) in combination with radiation therapy, followed by 
maintenance therapy with vorinostat, in patients with newly diagnosed diffuse intrinsic pontine 
glioma (DIPG). All patients will receive radiation therapy on this protocol with the targeted 
volume based on the extent of disease defined by neuroimaging prior to radiation therapy. This 
study specifies a 1 cm clinical target volume margin and mandates the use of CT-MR registration 
to define the target volume. The allowed treatment methods are restricted to conformal or 
intensity-modulated radiation therapy using photons and electronic data submission is required. 
Proton therapy is not allowed. 
 
15.0.2 Treatment Planning Specifics 
The guidelines for this study were developed based on the performance of COG investigators 
when executing the guidelines in prior COG trials. The goal of the treatment planning process is 
to develop a plan to deliver a uniform dose to the planning target volume which includes all 
known tumor plus the specified clinical target volume margin. The protocol specified total dose is 
54 Gy using conventional fractionation. Because the total dose does not exceed the recommended 
dose limits for the spinal cord and optic chiasm, volume reductions are not required nor 
recommended.  
 
15.0.3 Required Benchmark and Questionnaires 
Radiation therapy will be administered using photons. Required photon methods include 3D-
conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT). Centers 
participating in this protocol using 3D-CRT are required to complete the 3D benchmark; those 
using IMRT must complete the IMRT questionnaire and benchmark or irradiate the RPC head 
and neck phantom. All centers participating in this protocol must complete the QARC CT/MR 
image fusion benchmark. Benchmark materials and questionnaires may be obtained from the 
Quality Assurance Review Center (www.qarc.org) and must be submitted before patients on this 
protocol can be evaluated. For information regarding the IMRT phantoms, please contact the 
RPC (http://rpc.mdanderson.org/rpc). 
 
15.0.4 Guidelines and Requirements for the Use of IMRT 
Investigators using IMRT will be required to comply with the guidelines developed for the use of 
IMRT in National Cancer Institute sponsored cooperative group trials. These guidelines are 
available through www.qarc.org. These guidelines require that the protocol explicitly state their 
requirements and methods for localization and immobilization; the use of volumetric imaging; 
target and organ motion management; nomenclature, definitions and rationale for targets and 
organs at risk; target volume coverage and normal tissue dose constraints; effects of heterogeneity 
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 per COG administrative Policy 5.14 (except where 
explicitly prohibited within the protocol).  


 
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in tissues; and quality assurance. 
 
15.1 
Indications for Radiation Therapy  
 
All patients enrolled on this protocol will receive concurrent chemotherapy and radiation 
therapy. 
 
15.2 
Timing 
 
15.2.1 All patients should be seen in consultation by a radiation oncologist at the time of 
study enrollment. The purpose of the consultation is to participate in the initial 
evaluation and to review the adequacy of the initial diagnostic imaging studies 
that will be used for subsequent RT planning. If additional imaging studies are 
pursued, thin section MR (T2-weighted and FLAIR) sequences should be 
obtained for registration to the CT data set to assist in treatment planning. 
 
15.2.2 There are no contraindications to radiation therapy.  There are, however, some 
restrictions with regard to concomitant medications and eligibility as detailed in 
section 4.2.2.  Patients receiving corticosteroids must be on a stable or decreasing 
dose for the prior 7 days to be eligible.  Patients taking valproic acid must 
discontinue this 2 weeks prior to protocol therapy.  In addition, patients must not 
be receiving enzyme-inducing anticonvulsants (see appendix II for a list of 
enzyme inducing and non-inducing anticonvulsants).  Within these constraints, 
corticosteroids and anticonvulsants should be used as clinically indicated and 
tapered as soon as possible. Prophylactic anticonvulsants are strongly 
discouraged.  
 
15.2.3 Please see section 5.1.1 for details of timing of vorinostat administration. 
Vorinostat should be administered between 1-2 hours prior to each radiation 
therapy fraction when feasible, beginning with the first fraction.  Younger 
patients with NPO requirements due to sedation during RT will be allowed to 
take vorinostat 6 hours prior to each fraction, or the night before each fraction. 
 
15.3 
Emergency Irradiation 
 
Patients are not allowed to have received radiation therapy prior to enrollment on this 
protocol and urgent irradiation is not envisioned under any circumstance.  
 
15.4 
Equipment and Methods of Delivery and Verification  
 
Equipment 
Photons 
(any energy) 
IMRT 
(4-10MV) 
Linear Accelerator 
X 
X 
 
15.4.1 Treatment planning 
CT (volumetric) based planning is required to optimize dose to the PTV while 
protecting normal tissues. Organs at risk within the irradiated volume should be 
contoured. A DVH is necessary to determine target coverage and evaluate dose to 
normal tissues. CT section thickness should be < 5mm although 2-3mm is 
preferred. 


 
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15.4.2 In-room verification of spatial positioning  
15.4.2.1 Portal imaging is the most common system used to verify patient 
position, in particular when the target volume is believed to 
possess a fixed spatial relationship with visualized bony 
anatomy. Orthogonal paired (AP and lateral) portal images (MV 
or kV) are required for IMRT and 3-D CRT to verify that the 
isocenter is in correct alignment relative to the patient position. 
 
15.4.2.2 Volumetric imaging is allowed in this study. This includes in-room kV or 
MV cone beam or conventional CT imaging. Please submit 
representative axial images showing the isocenter and the correct 
alignment in relationship to the patients’ position. For CT 
tomography where isocenters are not used, a printout of the 
isodoses overlaid on the fused CT images can be printed to 
demonstrate in room verification. 
 
15.5 
Target Volumes 
 
15.5.1 General comments 
International Commission on Radiation Units and Measurements (ICRU) Reports 
50 and 62 (www.icru.org) define prescription methods and nomenclature that 
will be utilized for this study where applicable. Although the MRI obtained 
immediately prior to radiation therapy should be used for treatment planning, the 
target volumes for this study will be determined by the collective information 
that delineates the extent of disease before and after surgical resection or CSF 
shunting procedure. The investigators recognize that resection and shunting are 
unlikely for these patients. The sequence that best defines the extent of disease 
and post-operative tumor bed (when applicable), should be used to determine the 
GTV and registered to the treatment planning CT. Most patients with DIPG 
require a combination of MR sequences to delineate the extent of disease.  MR 
T2 and FLAIR sequences are most likely to be those chosen for registration to 
the treatment planning CT data set. The GTV, CTV and PTV and normal tissues 
must be outlined on all axial imaging slices on which the structures exist.  
 
15.5.2 Definitions for GTV, CTV and PTV 
• 
Gross tumor volume (GTV) is based on the most recent MRI and/or post-
operative MRI examination (if resection was done) and includes gross 
residual tumor and the tumor bed at the primary site. In defining the GTV, 
the investigator should consider all imaging studies that have defined the 
extent of tumor and the tissues involved anatomically. The GTV in most 
cases will be the T2 or FLAIR abnormality on the appropriate MR sequence. 
Tissue defects resulting from surgical approaches, when undertaken, will not 
be included as part of the GTV when not previously involved by tumor. 
Investigators should register the immediate pre-irradiation MR imaging 
sequences that demonstrated tumor and contour the GTV. 
 
• 
Clinical target volume (CTV) includes the GTV with an added margin of 1 
cm.  This is meant to treat subclinical microscopic disease and is 
anatomically confined (i.e., the CTV is limited to the confines of the bony 


 
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calvarium, falx and tentorium where applicable or extends up to but not 
beyond neuroanatomic structures through which tumor extension or invasion 
is certain not to have occurred). The CTV may be manually moved inward to 
the inner table of the bony calvarium. When the GTV approaches the 
boundary of an anatomic compartment, the CTV will extend up to and 
include the boundary. The CTV margin chosen for this study requires 
treatment planning MR and/or diagnostic MR imaging data with image 
section thickness ≤ 5mm. 
 
• 
Planning target volume (PTV) includes a margin which is added to the CTV 
in 3-dimensions. It is geometric and not anatomically defined. The PTV has 
two components, the internal margin (IM) and the set-up margin (SM). The 
IM is meant to compensate for all movements and variations in size and 
shape of the tissues contained within the CTV. The SM is meant to account 
for set-up, mechanical and dosimetric uncertainties related to daily patient 
positioning, treatment equipment and software. For this study, the PTV 
margin should be 3 or 5mm. The use of a PTV margin of 3mm requires 
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. For this 
study, IGRT is defined as 2- or 3-dimensional digital imaging positioning. 
Given that the CTV is generally confined to the intracranial space, the PTV 
may extend into or beyond bone but is unlikely to extend beyond the surface 
of the patient. The PTV margin chosen by the treating investigator requires 
treatment planning MR and/or diagnostic MR imaging data with imaging 
section thickness ≤ the chosen PTV margin. 
 
15.6 
Target Dose 
 
15.6.1 Dose Definition  
Photon dose is to be specified in centigray (cGy)-to-muscle. 
 
15.6.2 Prescribed dose and fractionation 
The total dose to the isodose surface encompasses the PTV will be 5400cGy 
administered in 30 fractions of 180cGy.  The patient should be treated with one 
fraction per day.  All fields should be treated each day. 
 
Table 15.6.2 
Prescribed Doses and Fractionation 
 
Nominal Dose by Site 
Target Volume 
Dose/fraction 
Number of Fractions 
Primary Site 5400cGy 
PTV1 
180cGy 
30 
 
15.6.3 Dose uniformity 
At least 95% of the protocol-specified dose should encompass 100% of the PTV 
and no more than 10% of the PTV should receive greater than 110% of the 
protocol dose as evaluated by DVH. The 100% isodose should be equal to the 
protocol specified dose. Wedges, compensators and other methods of generating 
more uniform dose distributions are encouraged. 
 


 
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15.6.4 Tissue heterogeneity 
 
Calculations must take into account tissue heterogeneity and should be performed 
with CT-based treatment planning to generate dose distributions and treatment 
calculations from CT densities. For questions about heterogeneity corrections or 
approved algorithms, please contact QARC (www.QARC.org). 
 
15.6.5 Interruptions, Delays and Dose Modifications 
 
There will be no planned rests or breaks from treatment, and once radiation 
therapy has been initiated, treatment will not be interrupted except for life 
threatening infection or severe hematological toxicity defined as ANC < 300/L 
or platelets less than 40,000/L during the course of treatment. Blood product 
support should be instituted according to institutional/protocol guidelines.  The 
reason for any interruptions greater than 3 treatment days should be recorded in 
the patient treatment chart and submitted with the QA documentation. There 
should be no modifications in dose fractionation due to age or field size. 
 
 
15.7 
Treatment Technique 
 
15.7.1 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 required to minimize dose to 
normal tissues.  
 
15.7.2 Field Shaping  
 
Field shaping will be done with either customized cerrobend blocking or 
multileaf collimation. 
 
15.7.3 Simulation including patient positioning and immobilization 
 
15.7.3.1   
Patient positioning  
 
Reproducible setups are critical.  The patient may be treated in 
any appropriate, stable position. Consideration should be given 
to implications for inter and intrafraction motion when using 
non-standard position approaches. 
 
 
15.7.3.2 Immobilization devices 
 
Standard immobilization devices for the brain or head and neck 
are to be used.  For IMRT delivery approaches, the methods used 
for localization and immobilization of both patient and tumor are 
critical. The imaging studies should provide a clear assessment 
of the target volume with the patient in the treatment position.  
 
15.7.4 Special considerations  
 
Anesthesia or sedation may be required in certain patients, such as very young 
patients, to prevent movement during simulation and daily treatments.  
 
15.7.5 Motion Management and Margins to Account for Target Volume Changes 
During Treatment 
 
Considering motion of target volumes is important. Brain tumors susceptible to 


 
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cyst expansion should be monitored closely.  Any change in clinical condition or 
anatomy related to hydrocephalus, VP shunt placement, subdural fluid, 
pseudomeningocele, or steroid use should be monitored carefully with repeat 
imaging when indicated.  
 
A description of the method used and evidence of the remaining tumor motion 
(i.e., observed motion during fluoroscopy, motion of surrogate markers using 
camera systems, or analysis of 4D CT) should be submitted on the Motion 
Management Reporting Form with the Quality Assurance Documentation 
materials as noted in Section 15.10.  
 
15.8 
Organs at Risk 
The organ 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. In some cases, photon IMRT may be the preferred treatment method to 
meet these recommendations and the required target volume coverage guidelines. 
 
Dose Constraints 
 
15.8.1 Cochleae  
• 
D50% <  3500cGy – Goal (each cochlea) 
• 
D50% < 2000cGy – Preferred (each cochlea) 
• 
Comment – There is no dose limit for the cochleae. 
• 
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. 
 
15.8.2 Optic Globes  
• 
D90% <   500cGy, D50% < 1000cGy and D10% < 3500cGy – Goal 
• 
D90% < 1000cGy, D50% < 2000cGy and D10% < 5400cGy – Maximum 
• 
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. In the event that the recommended maximum dose 
constraints provided in this section would be exceeded, the treating radiation 
oncologist may use their discretion to reduce target volume coverage. 
• 
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. 
 
15.8.3 Right and Left Optic Nerves and Chiasm  
• 
D90% < 1000cGy, D50% < 5400cGy and D10% < 5600cGy – Goal 
• 
D90% < 5400cGy, D50% < 5600cGy and D10% < 5800cGy – Maximum 
• 
Comment – Effort should be made to avoid direct treatment of the optic nerves 
and chiasm without compromising target volume coverage. In the event that the 
recommended maximum dose constraints provided in this section would be 
exceeded, the treating radiation oncologist may use their discretion to reduce 
target volume coverage. 
• 
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. 


 
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15.8.4 Spinal Cord  
• 
D90% < 300cGy, D50% < 2600cGy and D10% < 5700cGy - Goal 
• 
D90% < 900cGy, D50% < 5000cGy and D10% < 5900cGy – Maximum 
• 
Comment – Effort should be made to minimize dose to the spinal cord without 
compromising target volume coverage. 
• 
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; 2mm, n=30; 2.5 mm, n=24; 3 mm, n=20). Using 
these guidelines, only the superior-most 6cm of anatomic spinal cord is 
contoured. 
 
15.9 
Dose Calculations and Reporting 
 
15.9.1 Prescribed Dose 
The dose prescription and fractionation shall be reported on the RT-1/IMRT 
Dosimetry Summary Form. The total dose delivered shall be reported on the RT-
2 Radiotherapy Total Dose Record. If IMRT is used, the monitor units generated 
by the IMRT planning system must be independently checked prior to the 
patient’s first treatment. Measurements in a QA phantom can suffice for a check 
as long as the patient’s plan can be directly applied to a phantom geometry.  
 
15.9.2 Normal Tissue Dosimetry 
The dose to the critical organs indicated should be calculated whenever they are 
directly included in a radiation field. The total dose shall be calculated and 
reported on the RT-2 Radiotherapy Total Dose Record form. The appropriate 
dose-volume histograms should be submitted. If IMRT is used for the primary 
tumor, a DVH must be submitted for a category of tissue called “unspecified 
tissue,” which is defined as tissue contained within the skin, but which is not 
otherwise identified by containment within any other structure.  
 
Table 15.9a Required DVH data:   
 
Required DVH 
Total Brain 
Optic Nerves (L+R) 
Optic Chiasm 
Brainstem 
Spinal Cord 
Cochleae (L+R) 
Unspecified Tissue 
 
15.10 Quality Assurance Documentation 
On-treatment review is NOT required for this study.  Within one week of the completion 
of radiation therapy, detailed treatment data shall be submitted. 


 
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External beam Treatment Planning System  
• 
Digitally reconstructed radiographs (DRR) or simulator films for each treatment field 
and orthogonal (anterior/posterior and lateral) images for isocenter localization for 
each group of concurrently treated beams.  When using IMRT, orthogonal isocenter 
images are sufficient.  
• 
Isodose distributions for the treatment plan in the axial, sagittal and coronal planes at 
the center of the treatment or planning target volume.  The planning target volume, 
isocenter and the normalization method must be clearly indicated. 
• 
Dose volume histograms (DVH) for all target volumes and required organs at risk.  A 
DVH shall be submitted for the organs at risk specified in Section 15.8.  When using 
IMRT, a DVH shall be submitted for a category of tissue called “unspecified tissue.”  
This is defined as tissue contained within the skin, but which is not otherwise 
identified by containment within any other structure. 
• 
Treatment planning system summary report that includes the monitor unit 
calculations, beam parameters, calculation algorithm, and volume of interest dose 
statistics. 
• 
Beams-eye-view (BEV) of portals showing collimator, beam aperture, target volume 
and critical structures are required when not using IMRT. 
 
 
 
 Digital Data 
• 
Submission of the treatment plan in digital format is required. Please refer to 
www.QARC.org and click on "Digital Data" for guidelines regarding digital submission.  
All submissions, including those that are digital, require hard copy submission of the 
other items included in this list.  If there are any problems with digital data submission, 
please contact QARC. 
 
Supportive Data 
• 
All diagnostic imaging used to plan the target volume. This includes CT or MRI 
PRIOR to attempted surgical resection of the primary tumor. Digital format is 
preferred. Radiotherapy record (treatment chart) including prescription and daily and 
cumulative doses to all required areas and organs at risk. 
• 
Documentation of an independent check of the calculated dose when IMRT is used. 
• 
If the recommended doses to the organs at risk are exceeded, an explanation should 
be included for review by the QARC 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.  See 
section 15.5.2 
• 
Motion Management Reporting Form (if applicable, see Section 15.10). 
 
 
Forms 
• 
RT-1/IMRT Dosimetry Summary Form. 
• 
RT-2 Radiotherapy Total Dose Record form. 


 
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These data should be forwarded to: 
Quality Assurance Review Center 
640 George Washington Highway Suite 201 
Lincoln, Rhode Island 02865-4207 
Phone: 
(401) 753-7600 
Fax: 
(401) 753-7601 
 
Questions regarding the dose calculations or documentation should be directed to: 
COG Protocol Dosimetrist 
Quality Assurance Review Center 
640 George Washington Highway Suite 201 
Lincoln, Rhode Island 02865-4207 
 
 
15.11 Definitions of Deviations in Protocol Performance 
 
 
DEVIATION 
 
Minor 
Major 
Prescription Dose 
 
Difference in prescribed or computed 
dose is 6-10% of protocol specified 
dose 
Difference in prescribed or computed 
dose is > 10% of protocol specified 
dose 
Dose Uniformity and Coverage 
 
>10% PTV received > 110% 
of the protocol dose or 
95% isodose covers < 100% of CTV 
> 20% of PTV received >110% of the 
protocol dose or 
90% isodose covers < 100% of CTV 
Volume 
 
CTV or PTV margins are less than the 
protocol specified margins in the 
absence of anatomic barriers to tumor 
invasion (CTV) or without written 
justification (PTV) 
GTV does not encompass MR-visible 
residual tumor 
Organs at Risk 
 
Dose to any OAR exceeds the goal dose 
stated in 15.8 
Dose 
to 
any 
OAR 
exceeds 
the 
maximum dose stated in 15.8 
 
 


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


 
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APPENDIX II:  ENZYME INDUCING AND NON-ENZYME INDUCING ANTICONVULSANTS  
 
 
 
 
 
Non-enzyme inducing anticonvulsants 
 
Generic Name 
Trade Name 
Gabapentin 
Neurontin 
Lamotrigine 
Lamictal 
Levetiracetam  
Keppra 
Tigabine 
Gabitril 
Topiramate 
Topamax 
Valproic Acid 
Depakote, Depakene 
Zonisamide 
Zonegran 
 
Enzyme inducing anticonvulsants 
 
Generic Name 
Trade Name 
Carbamazepine 
Tegretol 
Felbamate 
Felbatol 
Phenobarbital 
Phenobarbital 
Phenytoin 
Dilantin 
Primidone 
Mysoline 
Oxycarbazepine 
Trileptal 
 


 
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 APPENDIX III: VORINOSTAT DOSING NOMOGRAM FOR CAPSULE FORMULATION 
 
Vorinostat (SAHA) Dose Based on BSA (m2) and Assigned Dose Level* 
Dose Level 
200 mg 
300 mg 
400 mg 
500 mg 
180 mg/m2 
1.25-1.42 
1.43– 1.95 
1.96 – 2.49 
≥ 2.5 
230 mg/m2 
 
1.25 – 1.42 
1.43 – 1.95 
≥ 1.96 
*Patients with BSA < 1.25 m2 or unable to swallow capsules will receive the vorinostat 
suspension rounded to the nearest 5 mg (See section 9.1.5 for preparation guidelines.) 


 
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APPENDIX IV-A:  
PATIENT DIARY FOR VORINOSTAT CAPSULE 
ADMINISTRATION DURING CHEMORADIOTHERAPY  
 
(Part A only) 
 
COG Patient ID:___________   ACC # : _____     Institution :________________________________  
Please do not write patient name on this form. 
 
Please write the date, time and dose of vorinostat given. NOTE: Vorinostat capsules should be 
swallowed whole. If you vomit within 30 minutes after taking the medication, that dose should be 
repeated. If you vomit after 30 minutes, the dose will not be repeated. Make note of other drugs and 
supplements taken.  Return the completed diary to your institution after each treatment cycle.  Your 
institution will fax this document with the corresponding shuttle sheet, to the COG Statistics & Data 
Center at (626) 447-2204 after each treatment cycle.  
 
EXAMPLE 
 
 
 
 
WEEK 1 
Date 
Time 
(Circle AM or PM) 
Dose Given 
Comments 
Day 1 
1/15/09 
8:30 
 
am/pm 
Vorinostat  XX mg 
He felt nauseated an hour after 
taking the drug but did not vomit. 
 
 
Cycle #: _____        Dose Level: ____     Start Date: |__/__|__/__|__/__|   End Date: 
|__/__|__/__|__/__| 
 
Number of Days per Week to be Taken: 3 or 5 (circle one). If 3, then for days vorinostat is not to 
be taken, put an “X” in the Date Column. 
 
WEEK 1 
Date 
Time 
(Circle AM or PM) 
Dose Given 
Comments 
Day 1 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 2 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 3 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 4 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 5 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
 
WEEK 2 
Date 
Time 
(Circle AM or PM) 
 
Comments 
Day 8 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 9 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 10 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 11 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 12 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
 
 
WEEK 3 
Date 
Time 
(Circle AM or PM) 
Dose Given 
Comments 


 
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Day 15 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 16 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 17 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 18 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 19 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
 
WEEK 4 
Date 
Time 
(Circle AM or PM) 
 
Comments 
Day 22 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 23 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 24 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 25 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 26 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
WEEK 5 
Date 
Time 
(Circle AM or PM) 
Dose Given 
Comments 
Day 29 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 30 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 31 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 32 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 33 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
 
WEEK 6 
Date 
Time 
(Circle AM or PM) 
 
Comments 
Day 36 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 37 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 38 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 39 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 40 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
WEEK 7 
(if 
applicable) 
Date 
Time 
(Circle AM or PM) 
 
Comments 
Day 43 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 


 
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Day 44 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 45 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 46 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
Day 47 
 
 
am/pm 
Vorinostat:  _______  mg 
 
 
 
ADDITIONAL COMMENTS:   
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 
 
Signature: __________________________________________________                    Date::__________________________ 


 
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APPENDIX IV-B: PATIENT DIARY FOR VORINOSTAT PEDIATRIC SUSPENSION 
DURING CHEMORADIOTHERAPY (Part A only) 
 
COG Patient ID:___________   ACC # : _____     Institution :________________________________  
Please do not write patient name on this form. 
 
Please write the date, time and dose of vorinostat given. If you vomit within 30 minutes after taking the 
medication, that dose should be repeated. If you vomit after 30 minutes, the dose will not be repeated. 
Make note of other drugs and supplements taken.  Return the completed diary to your institution after 
each treatment cycle.  Your institution will fax this document with the corresponding shuttle sheet, to the 
COG Statistics & Data Center at (626) 447-2204 after each treatment cycle.  
 
EXAMPLE 
 
 
 
 
WEEK 1 
Date 
Time 
(Circle AM or PM) 
Suspension Taken 
Amount (mL) 
Comments 
Day 1 
1/15/09 
8:30 
 
am/pm 
Vorinostat  XX mL 
He felt nauseated an hour after 
taking the drug but did not vomit. 
 
 
Cycle #: _____        Dose Level: ____     Start Date: |__/__|__/__|__/__|   End Date: 
|__/__|__/__|__/__| 
 
Number of Days per Week to be Taken: 3 or 5  (circle one). If 3, then for days vorinostat is not to 
be taken, put an “X” in the Date Column. 
 
WEEK 1 
Date 
Time 
(Circle AM or PM) 
Suspension Taken 
Amount (mL) 
Comments 
Day 1 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 2 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 3 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 4 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 5 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
 
WEEK 2 
Date 
Time 
(Circle AM or PM) 
 
Comments 
Day 8 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 9 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 10 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 11 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 12 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
 
 
 
WEEK 3 
Date 
Time 
(Circle AM or PM) 
Suspension Taken 
Amount (mL) 
Comments 
Day 15 
 
 
am/pm 
Vorinostat:  _______  mL 
 


 
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Day 16 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 17 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 18 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 19 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
 
WEEK 4 
Date 
Time 
(Circle AM or PM) 
 
Comments 
Day 22 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 23 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 24 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 25 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 26 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
WEEK 5 
Date 
Time 
(Circle AM or PM) 
Suspension Taken 
Amount (mL) 
Comments 
Day 29 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 30 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 31 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 32 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 33 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
 
WEEK 6 
Date 
Time 
(Circle AM or PM) 
 
Comments 
Day 36 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 37 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 38 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 39 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 40 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
WEEK 7 
(if 
applicable) 
Date 
Time 
(Circle AM or PM) 
 
Comments 
Day 43 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 44 
 
 
am/pm 
Vorinostat:  _______  mL 
 


 
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ACNS0927  
 
 
Page 80 
 
Day 45 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 46 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
Day 47 
 
 
am/pm 
Vorinostat:  _______  mL 
 
 
 
ADDITIONAL COMMENTS:   
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 
 
Signature: __________________________________________________                    Date::__________________________ 
  


 
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ACNS0927  
 
 
Page 81 
APPENDIX IV-C: PATIENT DIARY FOR VORINOSTAT (CAPSULE OR PEDIATRIC 
SUSPENSION) DURING MAINTENANCE THERAPY (PART A ONLY) 
 
COG Patient ID:___________   ACC # : _____     Institution :________________________________  
Please do not write patient name on this form. 
 
Please write the date, time and dose of vorinostat given. NOTE: Vorinostat capsules should be 
swallowed whole. If you vomit within 30 minutes after taking the medication, that dose should be 
repeated. If you vomit after 30 minutes, the dose will not be repeated. Make note of other drugs and 
supplements taken.  Return the completed diary to your institution after each treatment cycle.  Your 
institution will fax this document with the corresponding shuttle sheet, to the COG Statistics & Data 
Center at (626) 447-2204 after each treatment cycle. Use a new form for each cycle of maintenance 
therapy. 
 
EXAMPLE 
 
 
 
 
WEEK 1 
Date 
Time 
(Circle AM or PM) 
Capsule (mg) or 
Suspension (mL) 
Amount Taken 
Comments 
Day 1 
1/15/09 
8:30 
 
am/pm 
______mg   or  ____  mL 
He felt nauseated an hour after 
taking the drug but did not vomit. 
 
 
Cycle #: _____        Dose Level: ____     Start Date: |__/__|__/__|__/__|   End Date: 
|__/__|__/__|__/__| 
 
Number of Days per Week to be Taken: 3 or 5 or 7 (circle one). If 3 or 5, then for days vorinostat 
is not to be taken, put an “X” in the Date Column. 
 
DAY 
Date 
Time 
(Circle AM or PM) 
Capsule (mg) or 
Suspension (mL) 
Amount Taken 
Comments 
Day 1 
 
 
am/pm 
______mg   or  ____  mL  
 
 
Day 2 
 
 
am/pm 
______mg   or  ____  mL   
 
Day 3 
 
 
am/pm 
______mg   or  ____  mL   
Day 4 
 
 
am/pm 
______mg   or  ____  mL   
Day 5 
 
 
am/pm 
______mg   or  ____  mL   
Day 6 
 
 
am/pm 
______mg   or  ____  mL   
Day 7 
 
 
am/pm 
______mg   or  ____  mL   
Day 8 
 
 
am/pm 
______mg   or  ____  mL   
Day 9 
 
 
am/pm 
______mg   or  ____  mL   
Day 10 
 
 
am/pm 
______mg   or  ____  mL   
Day 11 
 
 
am/pm 
______mg   or  ____  mL   


 
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Page 82 
Day 12 
 
 
am/pm 
______mg   or  ____  mL   
Day 13 
 
 
am/pm 
______mg   or  ____  mL   
Day 14 
 
 
am/pm 
______mg   or  ____  mL   
Day 15 
 
 
am/pm 
______mg   or  ____  mL   
Day 16 
 
 
am/pm 
______mg   or  ____  mL   
Day 17 
 
 
am/pm 
______mg   or  ____  mL   
Day 18 
 
 
am/pm 
______mg   or  ____  mL   
Day 19 
 
 
am/pm 
______mg   or  ____  mL   
Day 20 
 
 
am/pm 
______mg   or  ____  mL   
Day 21 
 
 
am/pm 
______mg   or  ____  mL   
Day 22 
 
 
am/pm 
______mg   or  ____  mL   
Day 23 
 
 
am/pm 
______mg   or  ____  mL   
Day 24 
 
 
am/pm 
______mg   or  ____  mL   
Day 25 
 
 
am/pm 
______mg   or  ____  mL   
Day 26 
 
 
am/pm 
______mg   or  ____  mL   
Day 27 
 
 
am/pm 
______mg   or  ____  mL   
Day 28 
 
 
am/pm 
______mg   or  ____  mL   
 


 
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Page 83 
APPENDIX V: BLOOD SAMPLE COLLECTION GUIDE FOR CORRELATIVE BIOLOGY 
STUDIES  (PART A AND PART B OF STUDY) 
 
Peripheral blood samples to be collected during vorinostat and radiation treatment: 
Blood samples should be collected: 
• 
prior to the first day of vorinostat and radiation 
• 
two weeks after starting vorinostat and radiation (any weekday, except Friday, during 3rd week of 
radiation) 
• 
at the end of radiation and vorinostat (any weekday, except Friday, during the last week of 
radiation)  
 
The correlative biology samples should be obtained the day of weekly CBC collection, if possible. 
 
For the second and third samples, blood should be collected 2-4 hours after the morning dose of 
vorinostat. For patients required to be NPO overnight for sedation and must take vorinostat the night 
before, obtain blood samples in the morning. Blood samples can be obtained either by venipunctures or 
through central lines. 
 
Whole blood samples (a minimum of 5 ml for children < 12 kg, and 10 ml for children ≥ 12 kg) should be 
collected in either heparinized (green tops, either sodium or lithium heparin is acceptable) or ACDA 
(yellow top) tubes. DO NOT collect blood samples on a Friday.  
 


 
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ACNS0927  
 
 
Page 84 
APPENDIX VI: CORRELATIVE STUDY FORM (PART A AND PART B OF STUDY, DURING RADIATION THERAPY) 
 
This completed form should be sent with each shipment of samples for correlative studies. Prior to shipping, please contact Dr. Jack Su (832-
822-4306, jmsu@txch.org) or Dr. Xiao-Nan Li (832-822-4277, xxli@txch.org) for notification of sample shipment. Samples should be shipped 
immediately on the same day of collection. DO NOT SHIP SAMPLES ON A FRIDAY OR WEEKEND.  
 
• 
Seal the original tube(s) with paraffin and place the tube(s) inside an insulated container 
• 
Place the container in a Styrofoam box.   
• 
Between April-October: please ship with a single ice pack placed in the Styrofoam box (ice pack should not be placed directly next to the 
samples). An ice pack is not necessary when shipping between November-March.  
• 
Package sample as appropriate for biologic material 
 
 
COG No._______________ 
Acc. No:________________ 
Institution:____________________ 
 
Vorinostat Dose Level _____, _______mg/m2/day, a) M through F OR b) M, W, F (circle one) 
 
 
List the scheduled time and actual times that blood was obtained. 
PBMC Collection 
Administration of 
Vorinostat 
Date Sample 
Collected 
Time Sample Collected 
WBC Count*  
 
Date 
Time 
Scheduled 
Actual 
Prior to Day 1 radiation therapy 
and first dose of vorinostat. 
Date:______ 
Time:_____ 
Date:_______ 
Time:__________ 
Time:__________ 
WBC 
Count:_____ 
Date  
Drawn:_____ 
2-4 hours after am vorinostat, on a 
weekday except Friday, during the 
3rd week of vorinostat and 
radiation 
Date:______ 
Time:_____ 
Date:_______ 
Time:__________ 
Time:__________ 
WBC 
Count:_____ 
Date  
Drawn:_____ 
2-4 hours after am vorinostat, on a 
weekday except Friday, during the 
last week of vorinostat and 
radiation 
Date:______ 
Time:_____ 
Date:_______ 
Time:__________ 
Time:__________ 
WBC 
Count:_____ 
Date  
Drawn:_____ 
* Provide the most recently taken white blood cell count. The correlative biology samples should be obtained the day of weekly CBC collection, if possible. 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature:__________________________________ 
Date:______________________________ 
(site personnel who collected sample)


 
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ACNS0927  
 
 
Page 85 
APPENDIX VII: YOUTH INFORMATION SHEETS (PART B ONLY) 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ACNS0927 (Part B only) 
(for children from 7 through 12 years of age) 
 
A Study of Adding Vorinostat to Treatment for Newly Diagnosed DIPG Brain Tumors 
 
1. We have been talking with you about your brain tumor, called a DIPG. Your brain tumor is a type of 
cancer that grows in the area of the brain that controls things like your breathing and your heart beat. 
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 were just diagnosed with a type of 
brain tumor that is hard to treat. 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 new treatment will work better to get rid of DIPG 
than the normal treatment.  
 
The normal treatment is the use of high-energy x-rays to get rid of the cancer cells. But this x-ray 
treatment may only work for a short time. Sometimes it does not work at all. Study doctors want to 
see if giving a drug during the x-ray treatment will help get rid of more cancer cells. Study doctors 
also want to see if giving the drug after x-ray treatments will help get rid of any cancer cells that may 
still be in the brain. Study doctors hope this new treatment will work better than the normal treatment 
to get rid of cancer cells. 
 
3. Children who are part of this study will be treated with an anti-cancer medicine called vorinostat. 
Vorinostat is a medicine that you will swallow. You will take it during the time you are having the x-
ray treatments. At the end of the x-ray treatment you will take more vorinostat as long as you do not 
have bad effects from it and your cancer does not get any worse. Treatment with the vorinostat may 
last up to about a year. Doctors will check you often to see how the treatment is working.  
 
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 the new 
treatment will work better than the normal treatment to get rid of the tumor. But we do not know for 
sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study are that you may have bad health problems from the 
vorinostat. If this happens you may need treatment for the health problems. Other things may happen 
to you that we do not 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 you have. 
 
7. We are asking your “okay” to collect some extra blood three times during your treatment.  One of the 
blood samples would be taken when other standard blood tests are being performed. The second 
sample would be taken during the third week of vorinostat and radiation. The third sample would be 
taken during the last week of vorinostat and radiation. So, there would be two extra blood draws. 
Sometimes doctors do an operation to find out if you have cancer. If you had an operation, we are 
also asking your “okay” to study any tissue the doctors took out during this operation. We want to see 
if there are ways to tell how the cancer will react to treatment. You can still take part in this study 
even if you do not allow us to collect the extra blood samples or the tissue for research.  
 


 
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ACNS0927  
 
 
Page 86 
INFORMATION SHEET REGARDING RESEARCH STUDY ACNS0927 (Part B only) 
(for teens from 13 through 17 years of age) 
 
A Study of Adding Vorinostat to Treatment for Newly Diagnosed DIPG Brain Tumors 
  
1. We have been talking with you about your brain tumor, called a diffuse intrinsic pontine glioma or 
DIPG, for short. DIPG brain tumors are a type of cancer that grows in the lowest part of your brain 
called the brain stem. The brain stem is the area of the brain that controls your breathing, blood 
pressure, and heart rate. DIPG tumors are hard to treat. 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 been newly diagnosed with 
DIPG and it is hard to treat. 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 new treatment will work better to get rid of DIPG 
than the standard treatment for this disease.  
 
The standard treatment for this kind of tumor is radiation therapy (the use of high-energy x-rays) to 
get rid of the cancer cells. But radiation therapy may only work for a short time. Sometimes it does 
not work at all. Study doctors want to see if giving a drug during the radiation therapy will help get 
rid of more cancer cells. Study doctors also want to see if giving the drug after radiation therapy will 
help get rid of any cancer cells that may still be in the brain. Study doctors hope this new treatment 
will work better than the standard treatment to get rid of cancer cells. 
 
3. Children and teens who are part of this study will be treated with radiation therapy once a day for 30 
days. During this time you will also take a drug called vorinostat. Vorinostat is a medicine that you 
will swallow. At the end of radiation therapy, you will then take more vorinostat as long as you do 
not have side effects from it and your cancer does not get any worse. Treatment with the vorinostat 
may continue for up to a year. You will have tests and scans done regularly to check how you are 
doing and how the treatment is working.  
 
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 the new 
treatment will work better to get rid of the tumor than the standard treatment. However, we do not 
know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study are that you may have side effects from the 
combination of radiation therapy with vorinostat, or the vorinostat alone. Some possible side effects 
include things like being very tired, an upset stomach, and not being able to keep food down. Other 
things may happen to you that we do not 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 you have.  
 
7. We are asking your permission to collect additional blood three times during your treatment. One of 
these blood samples would be taken when other standard blood tests are being performed, on the first 
day you have radiation therapy. The second blood sample would be taken during the third week of 
radiation therapy. The last blood sample would be taken during the last week of radiation therapy. So, 
there would be two extra blood draws. We are also asking your permission to study tumor tissue that 
may have been removed during surgery to diagnose your cancer. We want to see if there are ways to 
tell how the cancer will respond to treatment. You can still be treated on this study even if you do not 
allow us to collect the extra blood samples and/or tumor tissue for research.  


 
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ACNS0927  
 
 
Page 87 
 
APPENDIX VIII: TUMOR SPECIMEN (PART A AND PART B OF STUDY) 
 
Patient ID #: 
 
 
Study ID:   ACNS0927 
Accession #:   
Date:  
Please do not write patient names on this form or on samples. 
 
Sample Labeling: 
Samples should be labeled with the following information: 
Protocol number:    ACNS0927  
Institution:        _________________ 
Patient ID #:     _________________ 
Accession #:     _________________ 
Sample Date:    _________________ 
 
Shipment of Tumor Tissue: 
Slides from FFPE tumors should be shipped at room temperature, with appropriate packing to prevent 
breakage of slides. 
 
Jack Su, MD; Attention: Elizabeth Hinojosa 
1102 Bates St., Room 1030 
Baylor College of Medicine 
Houston, TX  77030 
(832) 824-4688 or (832) 822-4306 
 
Prior to shipping, please contact Dr. Jack Su (832-822-4306 or jmsu@txch.org), Dr. Li (832-822-4277 or 
xxli@txch.org), or Dr. Adekunle Adesina (832-824-5859, aadesina@bcm.edu or 
amadesin@texaschildrenshospital.org) for notification of sample shipment. 
 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
 
Signature: __________________________________________________ 
 
(site personnel who collected samples) 
 
Date:__________________________ 


 
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ACNS0927  
 
 
Page 88 
 
APPENDIX IX: ACNS0927 CHEMORADIOTHERAPY ROADMAP (PART B) 
(page 1 of 2) 
 
Acc # ________ 
COG Pt # _____________________ 
Ht ________ cm 
Wt ________ kg 
BSA ________ m2 
 
 
Dose of Vorinostat 
_____________ mg/m2/day 
Record Nomogram Dose ____________g (see Appendix III of the protocol) 
 
 
 
Radiation therapy (RT) will be administered in single daily fractions of 1.8 Gy for 30 treatments over 6-7 weeks.  The total dose of radiation will be 54 Gy 
(see section 15.0). During radiation, patients will receive vorinostat  230 mg/m2/day  Monday through Friday weekly during the duration of radiation 
therapy (on Days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40). If radiation continues into Days 43-47 then vorinostat should continue at the same dose 
and schedule until RT is completed. Vorinostat dosing during and throughout the radiation component of therapy should be based on BSA determined 
from height and weight at the start of radiation therapy. The absolute daily dose of vorinostat should not exceed 500 mg. Vorinostat should be given 60-
120 minutes prior to radiation therapy, whenever feasible. If a patient vomits within 30 minutes after the dose of vorinostat is administered, that dose 
should be repeated. If a patient vomits after 30 minutes, the dose will not be repeated. 
 
 
Therapy 
Required Observations for 
Radiation Therapy 
(see Section 8.0 for details) 
Comments 
Week 
 
Day 
Date 
Due 
Date 
Given 
vorinostat ______mg 
(Record calculated dose) 
RT 
 
Pre  
_______ 
_______ 
(Record Actual Dose) 
 
1, 2, 3, 4, 5, 6&, 7, 8, 9, 10 
 
1 
1 
_______ 
_______ 
vorinostat ______mg 
RT 
 
 
 
2 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
3 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
4 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
5 
_______ 
_______ 
vorinostat ______mg 
 
 
 
2 
8 
_______ 
_______ 
vorinostat ______mg 
RT 
1, 2, 5+ 
 
 
9 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
10 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
11 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
12 
_______ 
_______ 
vorinostat ______mg 
 
 
 
3 
15 
_______ 
_______ 
vorinostat ______mg 
RT 
1, 2, 5+, 10 
 
 
16 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
17 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
18 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
19 
_______ 
_______ 
vorinostat ______mg 
 
 
 
4 
22 
_______ 
_______ 
vorinostat ______mg 
RT 
1, 2, 5+ 
 
 
23 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
24 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
25 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
26 
_______ 
_______ 
vorinostat ______mg 
 
 
 
5 
29 
_______ 
_______ 
vorinostat ______mg 
RT 
1, 2, 5+ 
 
 
30 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
31 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
32 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
33 
_______ 
_______ 
vorinostat ______mg 
 
 
 
6 
36 
_______ 
_______ 
vorinostat ______mg 
RT 
10 
 
 
37 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
38 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
39 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
40 
_______ 
_______ 
vorinostat ______mg 
 
1$, 2$, 3$, 5$, 7$@ 
 
The section below is to be completed only if radiation continues into Days 43-47. Then vorinostat should continue at the same dose and schedule until RT is completed. 
7 
43 
_______ 
_______ 
vorinostat ______mg 
RT 
 
 
 
44 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
45 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
46 
_______ 
_______ 
vorinostat ______mg 
 
 
 
 
47 
_______ 
_______ 
vorinostat ______mg 
 
1$, 2$, 5$, 7$ 
 


 
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ACNS0927  
 
 
Page 89 
 
(page 2 of 2) 
 
+Patients with hematologic DLT should have CBC repeated twice weekly until recovery as specified in Sections 6.1 and 6.2. 
&Patients of childbearing potential require a negative pregnancy test prior to starting treatment and must use an acceptable method of birth control.  Abstinence is an 
acceptable method of birth control. 
$ These studies to be performed prior to Maintenance Therapy 
 
 
@ Not required if continuing radiation therapy into days 43-47  
1. 
History, Creatinine, Bilirubin, SGPT, Electrolytes including Ca++, PO4, Mg++ 
2. 
Physical exam with vital signs 
3. 
Height, weight, BSA 
4. 
Performance Status  
5. 
CBC, differential, platelets.  
6. 
Pregnancy test 
7. 
Total protein/albumin  
8. 
Tumor Disease Evaluation (MRI of brain with gadolinium)    
 
 
9. 
Tumor Disease Evaluation (MRI of spine with 
gadolinium). Patients with suspected disseminated disease must 
have MRI of spine performed. Patients with disseminated disease 
are not eligible. 
10. 
Correlative Studies (If patient consents; see Section 8.3.2 
for timing of correlative biology studies. Blood samples should be 
collected 2-4 hours after the morning dose of vorinostat. The 
blood samples should be obtained the day of weekly CBC 
collection, if possible.)   


 
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ACNS0927  
 
 
Page 90 
APPENDIX X: ACNS0927 MAINTENANCE ROADMAP (PART A AND B) 
(page 1 of 1) 
   Acc # ________ COG Pt # _____________________ 
Ht ________ cm 
Wt ________ kg 
BSA ________ m2 
_____Cycle # ________ 
 
   Dose of Vorinostat 
_____________ mg/m2/day 
Record Nomogram Dose _____________g (see Appendix III of the protocol) 
 
At the conclusion of chemoradiotherapy, all patients will continue vorinostat maintenance therapy daily without interruption at Dose 
Level 1 (230 mg/m2/day, continuously; Section 5.4, Table 2), including those patients who had discontinued vorinostat during 
chemoradiotherapy because of DLTs.  Vorinostat doses during the maintenance phase of therapy should be adjusted based on the BSA 
determined from height and weight obtained within one week prior to the beginning of each cycle. The absolute daily dose of 
vorinostat should not exceed 500 mg. If a patient vomits within 30 minutes after the dose of vorinostat is administered, that dose should 
be repeated. If a patient vomits after 30 minutes, the dose will not be repeated. A cycle of maintenance therapy is defined as 28 days. 
Maintenance therapy may be continued for a maximum of 12 cycles in the absence of disease progression and/or excessive toxicities.  
 
Therapy 
Required Observations for 
Maintenance Therapy 
(see Section 8.0 for details) 
Comments 
 
Day 
Date 
Due 
Date Given 
vorinostat ______mg 
(Record calculated dose) 
 
1 
_______ 
_______ 
vorinostat ______mg 
 
1, 2, 3, 4+, 5, 6* 
 
2 
_______ 
_______ 
vorinostat ______mg 
 
 
 
3 
_______ 
_______ 
vorinostat ______mg 
 
 
 
4 
_______ 
_______ 
vorinostat ______mg 
 
 
 
5 
_______ 
_______ 
vorinostat ______mg 
 
 
 
6 
_______ 
_______ 
vorinostat ______mg 
 
 
 
7 
_______ 
_______ 
vorinostat ______mg 
 
 
 
8 
_______ 
_______ 
vorinostat ______mg 
 
4+ 
 
9 
_______ 
_______ 
vorinostat ______mg 
 
 
 
10 
_______ 
_______ 
vorinostat ______mg 
 
 
 
11 
_______ 
_______ 
vorinostat ______mg 
 
 
 
12 
_______ 
_______ 
vorinostat ______mg 
 
 
 
13 
_______ 
_______ 
vorinostat ______mg 
 
 
 
14 
_______ 
_______ 
vorinostat ______mg 
 
 
 
15 
_______ 
_______ 
vorinostat ______mg 
 
4+ 
 
16 
_______ 
_______ 
vorinostat ______mg 
 
 
 
17 
_______ 
_______ 
vorinostat ______mg 
 
 
 
18 
_______ 
_______ 
vorinostat ______mg 
 
 
 
19 
_______ 
_______ 
vorinostat ______mg 
 
 
 
20 
_______ 
_______ 
vorinostat ______mg 
 
 
 
21 
_______ 
_______ 
vorinostat ______mg 
 
 
 
22 
_______ 
_______ 
vorinostat ______mg 
 
4+ 
 
23 
_______ 
_______ 
vorinostat ______mg 
 
 
 
24 
_______ 
_______ 
vorinostat ______mg 
 
 
 
25 
_______ 
_______ 
vorinostat ______mg 
 
 
 
26 
_______ 
_______ 
vorinostat ______mg 
 
 
 
27 
_______ 
_______ 
vorinostat ______mg 
 
 
 
28/1 
_______ 
_______ 
vorinostat ______mg 
 
4+,  6* 
 
*Before Cycle 2, then every 2 cycles x 2, then q 3 cycles 
+Patients with hematologic DLT should have CBC repeated twice weekly until recovery as specified in Sections 6.1 and 6.2. 
 
1. 
History, Creatinine, Bilirubin, SGPT, 
Electrolytes including Ca++, PO4, Mg++ 
2. 
Physical exam with vital signs  
3. 
Height, weight, BSA 
4. 
CBC, differential, platelets. 
5. 
Total protein/albumin 
6. Tumor Disease Evaluation (MRI of brain with gadolinium).Scans should be 
obtained prior to cycles 2, 4, 6, 9, and 12. See Section 12.0 for Evaluation 
Criteria. Tumor Disease Evaluation should be obtained on the next consecutive 
cycle after initial documentation of either a PR or CR.  If the institutional 
investigator determines that the patient has progressed based on clinical or 
laboratory evidence, he/she may opt not to confirm this finding radiographically. 


 
 
 
ACNS0927 
 
 
Page 91 
REFERENCES 
1. 
Hargrave D, Bartels U, Bouffet E: Diffuse brainstem glioma in children: critical review of clinical 
trials. Lancet Oncol 7:241-8, 2006 
2. 
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