Conditions: Solid Tumors Relapsed/Refractory Sarcomas
Keywords: ETOPOSIDE (VP-16) SAHA (SUBEROYLANILIDE HYDROXAMIC ACID) (Vorinostat) Pediatric 10-096 POETIC phase II component: the population will be restricted to relapsed/refractory sarcomas.
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out how safe and effective treatment with a new combination of drugs, vorinostat and etoposide, is in treating cancer. The medication etoposide is a standard medication used in the treatment of cancer in children. Vorinostat is an experimental drug which targets a protein(s) that control the way cancer cells grow and divide. Vorinostat is approved by the FDA in adults with certain cancers but not approved yet in children.

There are two parts to this study. In the first part of this study, the phase I portion, a safe dose of the combination, vorinostat and etoposide. The goal of second part of this study, the phase II portion, is to see how effective the combination of vorinostat and etoposide is in treating cancer.

Detailed description:

Arms:
arm 1: This is a multi-center, open label, phase I/II trial of escalating doses of vorinostat in combination with etoposide.

Interventions: intervention 1: Vorinostat and Etoposide
Intervention descriptions: intervention 1: Patients will be assessed in 3-week cycles. Escalating doses of vorinostat will be administered orally on a daily x 4 schedule in combination with a fixed dose of etoposide. Etoposide will be administered intravenously daily x 3 days. Cohorts of 3-6 patients will be treated with vorinostat and etoposide. In the phase II component, patients will be treated at the RP2D established in the Phase I component of the study, which was found to be 270 mg/m2/dose of Vorinostat and 100 mg/m2/dose of Etoposide.

Protocol document:
Prot_SAP_000.pdf: 
IRB: 10-096 A(8) 
Amended: 03/25/14 
 
 
 
THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
A Phase I/II Clinical Study of Vorinostat in Combination with Etoposide in 
Pediatric Patients < 21 Years at Diagnosis with Refractory Solid Tumors 
 
Vorinostat will be supplied by Merck & Co., Inc 
 
 
 
Principal 
Investigator: 
 
 
Tanya Trippett, MD 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021 
Telephone 
(212) 639-8267 
Fax 
(212) 717-3239 
E-mail 
Trippet1@mskcc.org 
Data Managers: 
 
Jennifer DiRenzo 
POETIC Data and Coordinating Center 
Memorial Sloan-Kettering Cancer Center 
405 Lexington Avenue, Room 3-512 
New York, NY 10174 
Telephone 
(646) 888-5714 
Fax 
(646) 888-5726 
E-mail 
direnzoj@mskcc.org 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, NY 10021 
 
 
 
 
 
 
 
Study Number:POE10-02 
 
Protocol Version: 
Version 8.0  Date: 03/03/14 


IRB: 10-096 A(8) 
Amended: 03/25/14 
 
 
 
Co-Principal 
Investigators: 
Lia Gore, MD 
Children's Hospital Colorado 
13123 East 16th Avenue, Box B115 
Aurora, CO 80045 
Telephone 
(720) 777-4159 
Fax 
(720) 777-7289 
E-mail 
lia.gore@ucdenver.edu 
Gregory Hale, MD 
All Children’s Hospital 
601 5th Street South, Suite 302 
Petersburg, FL 33701 
Telephone 
(727) 767-4176 
Fax 
(727) 767-8931 
E-mail 
Gregory.Hale@allkids.org 
Data Managers: 
Debra Schissel, RN 
Children's Hospital Colorado 
13123 East 16th Avenue, Box B115 
Aurora, CO 80045 
Telephone 
(720) 777-4159 
Fax 
(720) 777-7289 
Email 
Debra.Schissel@Childrenscolorado.org 
Frances Hamblin, RN, CCRP, CPHON, CCRP 
All Children’s Hospital 
601 5th Street South, Suite 302 
St. Petersburg, FL 33701 
Telephone 
(727) 767-2423 
Fax 
(727) 767-8931 
E-mail 
Frances.Hamblin@allkids.org 
Investigator(s): 
Patrick Brown, MD 
Johns Hopkins Medical Center 
Sidney Kimmel Comprehensive Cancer Center 
1650 Orleans Street, 2M51 
Baltimore, MD 21231-1000 
Telephone 
(410) 614-4915 
Fax 
(410) 955-8897 
E-mail 
pbrown2@jhmi.edu 
Tammy Scott, RN, BSN 
Johns Hopkins Medical Center 
Sidney Kimmel Comprehensive Cancer Center 
1650 Orleans Street, 2M51 
Baltimore, MD 21231-1000 
Telephone 
(410) 614-5990 
Fax 
(410) 955-0028 
E-mail 
scottta@jhmi.edu 
Jessica Boklan, MD 
Phoenix Children’s Hospital 
Center for Cancer and Blood Disorders 
1919 E. Thomas Road 
Phoenix, AZ 85016-7710 
Telephone 
(602) 546-0920 
Fax 
(602) 546-0276 
E-mail 
jboklan@phoenixchildrens.com 
Laureen Deublein, RN, BSN 
Phoenix Children’s Hospital 
Center for Cancer & Blood Disorders 
1919 E. Thomas Road 
Phoenix, AZ 85016-7710 
Telephone 
(602) 546-5004 
Fax 
(602) 546-0211 
E-mail 
ldeublein@phoenixchildrens.com 
Cynthia Herzog, MD 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Box 87 
Houston, TX 77030 
Telephone 
(713) 745-0157 
Fax 
(713) 792-0608 
E-mail 
cherzog@mdanderson.org 
Minerva Griffin, BS, MHA 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Box 87 
Houston, TX 77030 
Telephone 
(713) 794-1919 
Fax 
(713) 792-9808 
E-mail 
magriffin@mdanderson.org 


IRB: 10-096 A(8) 
Amended: 03/25/14 
 
 
 
Investigator(s): 
Suzanne Shusterman, MD 
Dana-Farber Cancer Institute 
450 Brookline Ave, DA3141F 
Boston, MA. 02215 
Telephone 
(617) 632-4901 
Fax 
(617) 632-5710 
E-mail 
suzanne_shusterman@dfci.harvard.edu 
Data Managers: 
Mei Yang 
Dana-Farber Cancer Institute 
450 Brookline Avenue, DA-155 
Boston, MA 02215 
Telephone 
(617) 532-7169 
Fax 
(617) 582-8604 
E-mail 
mei_yang@dfci.harvard.edu 
Lisa McGregor, MD 
Pennsylvania State University College of Medicine 
500 University Drive; MC H085 
Hershey, PA 17110 
Telephone 
(717) 531-6012 
Fax 
(717) 531-4789 
E-mail 
lmcgregor@hmc.psu.edu 
Kathryn Byrnes, BS, CCRP 
Penn State Children's Hospital 
500 University Drive, C7621 
Hershey, PA 17033 
Telephone 
(717) 531-3098 
Fax 
(717) 531-9808 
E-mail 
kbyrnes@hmc.psu.edu 
Tony Truong, MD 
Alberta Children's Hospital 
2888 Shaganappi Trail NW 
Calgary, Alberta T3B 6A8 
Telephone 
(403) 955-2946 
Fax 
(403) 955-7684 
E-mail 
Tony.Truong@albertahealthservices.ca 
Karen Mazil, RN, BN 
Alberta Children's Hospital 
2888 Shaganappi Trail NW, B2-115 
Calgary, Alberta T3B 6A8 
Telephone 
(403) 955-2242 
Fax 
(403) 955-7684 
E-mail karen.mazil@albertahealthservices.ca 
Kathleen Neville, MD 
Children’s Mercy Hospital & Clinics 
2401 Gillham Road 
Kansas City, MO, 64108 
Telephone 
(816) 234-3059 
Fax 
(816) 855-9158 
E-mail 
kaneville@cmh.edu 
Sara Soliman RN, BSN, CPN 
Children’s Mercy Hospital & Clinics 
2401 Gillham Road 
Kansas City, MO, 64108 
Telephone 
(816) 855-1977 
Fax 
(816) 855-1958 
E-mail 
sgsoliman@cmh.edu 
Amy Smith, MD 
Arnold Palmer Hospital for Children/ 
MD Anderson Cancer Center Orlando 
92 W Miller Street MP318 
Orlando, FL, 32806 
Telephone    (321) 841-8588 
Fax 
(321) 841-8560 
E-mail          Amy.Smith@orlandohealth.com 
Stephanie Garber, RN, BSN, CCRC 
Arnold Palmer Hospital for Children/ 
MD Anderson Cancer Center Orlando 
92 W Miller Street MP318 
Orlando, FL, 32806 
Telephone 
(321) 841-3837 
Fax 
(321) 843-6424 
E-mail 
Stephanie.Garber@orlandohealth.com 


Amended: 03/25/14 
IRB: 10-096 A(8) 
 
 
 
 
 
 
Pharmacist : 
 
 
 
 
 
 
 
 
 
Nurses: 
Michael Kellick, MS, Pharm.D. 
Clinical Coordinator, Pediatric Pharmacy Services 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021 
Telephone   (212) 639-8186 
Fax 
(646) 422-2180 
E-mail 
kellickm@mskcc.org 
 
 
 
Geraldine Wright, RN 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 
Telephone 
(212) 639-8267 
Fax 
(212) 717-3239 
E-mail 
wrightg@mskcc.org 
 
Nancy Kline, PhD, RN, CPNP, FAAN 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 
Telephone 
(646) 888-5651 
E-mail 
klinen@mskcc.org 
 
Statistician: 
 
 
 
 
 
 
 
 
 
Psychologist: 
Irina Ostrovnaya, PhD 
Memorial Sloan-Kettering Cancer Center 
Department of Epidemiology and Biostatistics 
307 East 63 Street 
New York, NY 10021 
Telephone 
(646) 735-8165 
Fax 
(646) 735-0010 
E-mail 
ostrovni@mskcc.org 
 
 
Jennifer S. Ford, PhD 
Memorial Sloan-Kettering Cancer Center 
641 Lexington Avenue, 7th Floor 
New York, NY 10022 
Telephone 
(646) 888-0042 
Fax 
(212) 888-2584 
E-mail 
fordj@mskcc.org 


IRB: 10-096 A(8) 
Amended: 03/25/14 
- 5 - 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
1.0 PROTOCOL SUMMARY AND/OR SCHEMA .......................................................................................8 
2.0 OBJECTIVES AND SCIENTIFIC AIMS .................................................................................................9 
3.0 BACKGROUND AND RATIONALE ......................................................................................................9 
4.0 OVERVIEW OF STUDY DESIGN/INTERVENTION ..........................................................................20 
5.0 THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................................23 
6.0 CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................................29 
7.0 RECRUITMENT PLAN .........................................................................................................................31 
8.0 PRETREATMENT/ENROLLMENT EVALUATIONS .........................................................................32 
9.0 TREATMENT/INTERVENTION PLAN ...............................................................................................33 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ...............................................................40 
11.0 TOXICITIES/SIDE EFFECTS ................................................................................................................47 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................................47 
13.0 CRITERIA FOR REMOVAL FROM STUDY .......................................................................................52 
14.0 BIOSTATISTICS ....................................................................................................................................52 
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ............55 
16.0 DATA MANAGEMENT ISSUES .........................................................................................................56 
17.0 PROTECTION OF HUMAN SUBJECTS ..............................................................................................61 
18.0 INFORMED CONSENT PROCEDURES ..............................................................................................68 
19.0 REFERENCE(S)......................................................................................................................................69 


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IRB: 10-096 A(8) 
 
 
APPENDICES (These are separate protocol documents) 
Appendix I 
Karnofsky/Lansky Performance Status Scales 
Appendix II 
Methods for Gene Expression Profiling and Histone Phosphorylation Profiling 
Appendix III 
Methodology for Histone Deacetylase Phosphorylation™ 
Appendix IV 
Customs Form 
Appendix V 
Medication Diary 
Appendix VI 
Drug Shipment Form 
Appendix VII 
DARF 
Appendix VIII 
Ficoll Hypaque Procedure for Whole Blood 


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IRB: 10-096 A(8) 
 
 
 
ABBREVIATIONS 
 
4A4OA 
4-anilino-4-oxobutanoic acid 
AUC 
Area under the curve 
BID 
Twice daily 
CIB 
Clinical Investigator Brochure 
Cmax 
Maximum concentration 
CTCAE 
Common Toxicity Criteria Adverse Event 
CTEP 
Cancer Therapy and Evaluation Program 
CTLC 
Cutaneous T-cell lymphoma 
CYP 
Cytochrome P450 
DCC 
Data and Coordinating Center 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
EFT 
Ewing family of tumors 
EKG 
Electrocardiogram 
FDA 
U.S. Food and Drug Administration 
[18F]FDG 
18F-Fluorodeoxyglucose 
HDAC 
Histone deacetylase 
MEL 
Murine erythroleukemia 
MSAS 
Memorial Symptom Assessment Scale 
MTD 
Maximum Tolerated Dose 
OG-V 
O-glucuronide of vorinostat 
POETIC 
Pediatric Oncology Experimental Therapeutics Investigators Consortium 
PPIs 
Proton Pump Inhibitors 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RMS 
Rhabdomyosarcoma 
RP2D 
Recommended Phase II Dose 
RSA 
Research Study Assistant 
SAHA 
Vorinostat 
SAMF 
Southern Alberta Microarray Facility 
SPSS 
Statistical Package for the Social Sciences 
t ½ 
Half-life 
TID 
Three times daily 
UGT 
Uridine diphosphate glucuronosyltransferase isoenzymes 
VEGF 
Vascular endothelial growth factor 


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IRB: 10-096 A(8) 
 
 
 
1.0      PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a multi-center, open label phase I/II trial evaluating the safety and efficacy of the novel regimen 
vorinostat and etoposide. In the Phase I portion, the primary objective will be to determine the dose 
limiting toxicity (DLT) and the maximum tolerated dose (MTD) for the combination vorinostat and 
etoposide in pediatric patients with relapsed/refractory solid tumors including tumors of the central 
nervous system. A standard dose escalation schema will be used with 3-6 subjects enrolled per dose 
level (cohort). Patients will be treated with vorinostat and etoposide primarily in the outpatient setting, 
although treatment as an inpatient will be permitted as long as eligibility criteria are met. The dose 
schedule will be comprised of escalation of the dose of vorinostat in increments of 30%. Vorinostat will 
be administered orally on Days 1-4 of every 21-day cycle and given 4 hours prior to the administration 
of etoposide on Days 3 and 4. The starting dose of vorinostat will be 50% of the single agent RP2D for 
the oral formulation. The etoposide will be administered intravenously at a fixed dose of 100 mg/m2/day 
on Days 3-5 of every 21-dose cycle. Inter-patient dose escalation will proceed as follows until the MTD 
and RP2D is established: 
 
DOSE ESCALATION SCHEDULE 
Dose Level 
Dose 
Etoposide 
( mg/m2 ) 
Vorinostat 
(mg/m2) 
-2 
75 
100 
-1 
100 
100 
1 
100 
125 
2 
100 
160 
3 
100 
210 
4 
100 
270 
 
Once the MTD level is determined, this level will be expanded to treat a total of 9 patients at the MTD 
to determine the safety of the RP2D. There will be no intra-patient dose escalation. An interim analysis 
for safety will be performed at the end of the phase I portion of this study. It is anticipated that the phase 
I component of the study will be completed within 1 year with an expected accrual of 18-25 patients. 
Once the MTD and RP2D have been established and an interim safety analysis performed, the phase II 
portion of the trial will begin. The primary objective of the phase II component will be to determine the 
efficacy (CR+PR rate) of the combination vorinostat and etoposide in patients with relapsed/refractory 
sarcoma. Tumor measurements by Revised RECIST guideline (version 1.1) will be obtained every 2 
cycles (every 6 weeks) according to section 12.0 to assess response. Subjects who achieve stable disease 
or better response to therapy will receive treatment until disease progression by RECIST, unacceptable 
toxicity or if the patient voluntarily withdraws from the study. It is anticipated that the phase II 
component of the study will be completed within 1 year with an expected accrual of 28 patients. 


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Secondary objectives of the study will include correlative studies evaluating the biologic effects of the 
novel combination of vorinostat and etoposide in pediatric patients enrolled on this study. Specifically, 
exploratory studies will be conducted to determine the changes in histone acetylation, gene expression 
profiling and histone phosphorylation in patients treated on this study. Functional imaging will be 
included as a secondary objective to evaluate alteration in the accumulation of [18F]- fluorodeoxyglucose 
([18F]FDG) with tumor response. 
An exploratory objective of this study will be the measurement of symptom distress in patients enrolled 
on this trial. It is hoped that these observations will provide unique insight into the changes children with 
relapsed/refractory solid tumors experience in symptom perception during treatment with investigational 
agents. In addition, these findings may help predict patterns of symptom distress and provide us with the 
opportunity to anticipate patients at risk for heightened symptom distress. 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.2 Primary Objectives 
 
2.2.1 Part I: To establish the Dose Limiting Toxicity (DLT), Maximum Tolerated Dose 
(MTD), and the recommended phase II dose (RP2D) of the novel combination 
vorinostat and etoposide in pediatric patients with relapsed/refractory solid tumors 
including tumors of the central nervous system. 
 
2.2.2 Part II: To establish the efficacy (CR+PR rate) of the novel combination vorinostat 
and etoposide in pediatric patients with relapsed/refractory sarcoma. 
2.3 Secondary Objectives 
2.3.1 To evaluate the efficacy (CR+PR rate) of the novel combination vorinostat and 
etoposide in pediatric patients enrolled in the phase I component of the study. 
 
2.3.2 To evaluate the biologic effects of the novel combination of vorinostat and etoposide 
in pediatric patients with relapsed/refractory solid tumors including central nervous 
system tumors using Histone Acetylation, Gene Expression Profiling, and Histone 
Phosphorylation Profiling. 
 
2.3.3 To correlate alterations in accumulation of [18F]FDG with tumor response in patients 
for whom this imaging modality is relevant. 
2.4 Exploratory Objectives 
2.4.1 To describe symptom distress over time in pediatric cancer patients treated with the 
novel combination of vorinostat and etoposide in both parts of the study. 
 
 
 
3.1 
BACKGROUND AND RATIONALE 
3.2 
Sarcomas 


IRB: 10-096 A(8) 
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Sarcomas comprise 15% of pediatric malignancies. In 2003, approximately 12,000 Americans were 
diagnosed with sarcoma and 5,200 died from the disease. These figures are probably underestimates as 
the number of Americans with each type of sarcoma subtype is unknown. 
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. It is a 
highly aggressive neoplasm typically composed of spindle cells producing osteoid. The development of 
recurrent and/or metastatic disease depends on the initial therapy, time to recurrence, and the site and 
number of recurrent tumors. With aggressive treatment, 40% of patients who develop metastatic disease 
survive > 5 years after relapse. However, patients who relapse following the use of modern treatment 
approaches, including chemotherapy and surgery, have a significantly lower probability of survival. 
These patients are candidates for participation in clinical trials with novel agents. 
The Ewing family of tumors (EFT) represents the second most common primary bone malignancy 
affecting children and adolescents. Patients who initially present with or develop metastatic disease have 
a significantly less favorable outcome than those with localized disease. Aggressive multimodality 
therapy can relieve pain, prolong the progression-free interval, and cure some patients of their disease; 
however, the 5- year overall survival rate averages 33%. 
Soft tissue sarcomas are highly malignant tumors that constitute 5-6% of all malignant childhood 
neoplasms. Of these, rhabdomyosarcoma (RMS) is the most common in children. Many children with 
RMS are cured with conventional chemotherapy and local therapy: surgery with or without 
radiotherapy. Children with metastatic disease at presentation, particularly those with bone marrow or 
bone involvement have a much poorer outcome. The 5-year overall survival for patients with metastatic 
disease is approximately 25%. 
Mortality rate remains disproportionately high when compared with other cancers common to these age 
groups such as testicular cancer and Hodgkin’s disease. Diagnosis was delayed in many patients by the 
lack of experience of primary physicians, who often attribute the initial mass to common benign lesions. 
Once diagnosed, patients cannot rely on a uniform standard of care, resulting in wide variations in 
outcomes. Treatment options for patients with advanced pediatric malignancies are limited. New 
therapies are needed, but the fragmentation of biologic, translational, and clinical research makes it 
difficult to initiate innovative and timely studies. 
This study will evaluate the role of a novel histone deacetylase inhibitor, vorinostat, in combination with 
the topoisomerase II inhibitor, etoposide in all pediatric tumors in the phase I component but will later 
focus on refractory sarcomas in the phase II component. 
3.3 
Vorinostat 
3.3.1 Histone deacetylase and HDAC Inhibitors 
Histone deacetylase (HDAC) are enzymes that catalyze the removal of acetyl groups from the lysine 
residues of proteins, including histones and transcription factors. HDAC inhibitors can induce tumor 
regression in animals. The transcription of genes is regulated at least in part by acetylation of 
nucleosomal histones. The core nucleosomal histones are the most widely studied of the proteins that 
become acetylated following inhibition of HDAC activity. In some tumor cells, there is an 
overexpression of HDACs or an aberrant recruitment of HDACs to oncogenic transcription factors 
causing hypoacetylation of core nucleosomal histones. Hypoacetylation of histones is associated with a 


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condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity allows 
for the accumulation of acetyl groups on the histone lysine residues resulting in an open chromatin 
structure and transcriptional activation. 
3.3.2 Mechanism of Action of Vorinostat 
Vorinostat is a potent inhibitor of HDAC activity that binds directly to the catalytic pocket of HDAC 
enzymes. Vorinostat, at low nanomolar concentrations (IC50 < 86 nM), inhibits the enzymatic activity of 
HDAC1, HDAC2, and HDAC3 (Class I) and HDAC6 (Class II). The concentration of vorinostat that 
causes the accumulation of acetylated histones also induces cell cycle arrest, differentiation or apoptosis 
of transformed cells. 
Vorinostat induces apoptosis in a wide variety of transformed cells in culture, including cutaneous T-cell 
lymphoma cell lines, circulating atypical T-cells derived from patients with CTCL, human lymphoma 
cell lines and murine erythroleukemia (MEL) cells. Vorinostat also inhibits proliferation of cultured 
transformed human cells derived from leukemias, non-small cell lung carcinomas, colon carcinomas, 
central nervous system tumors, melanomas, ovarian carcinomas, renal cell carcinoma, prostate and 
breast cancers. In cultured human transformed cell lines, vorinostat has synergistic or additive activity in 
combination with other cancer therapies, including radiation, kinase inhibitors, cytotoxic agents, and 
differentiating agents. In vivo, vorinostat demonstrates anti-neoplastic activity in a variety of rodent 
tumor models including xenograft models of human prostate, breast and colon carcinoma. 
3.3.3 Nonclinical Pharmacology of Vorinostat 
Vorinostat is approximately 71% bound to human plasma proteins over the range of concentrations of 
0.5 - 50 g/mL. 
Vorinostat has a low propensity to cause or be affected by drug-drug interactions. In animal models and 
in vitro human systems, the major pathways of metabolism of vorinostat are glucuronidation and 
hydrolysis followed by -oxidation. Additionally, the glucuronidation of vorinostat is mediated by 
multiple uridine diphosphate glucuronosyltransferase isoenzymes (UGTs), making it less susceptible to 
drug interactions through modulation of UGTs. Vorinostat is not recovered intact in urine to any 
appreciable extent. Therefore, compounds known to affect renal elimination are not expected to affect 
the pharmacokinetics of vorinostat. 
Vorinostat is not an inhibitor (IC50 of > 75 M) of CYP drug metabolizing enzymes in human liver 
microsomes. Gene expression studies in human hepatocytes detected some potential for suppression of 
CYP2C9 and CYP3A4 mRNA and enzyme activity levels were observed at ≥10 M vorinostat 
following a 48 hr treatment period. However, these changes were observed at concentrations of 
vorinostat higher than pharmacologically relevant serum concentrations of 2 M (Cmax). Thus, vorinostat 
is not expected to affect the pharmacokinetics of other agents. As vorinostat is not eliminated via the 
CYP pathways, it is anticipated that vorinostat will not be subject to drug-drug interactions when co- 
administered with drugs that are known CYP inhibitors or inducers. However, no formal clinical studies 
have been conducted to evaluate drug interactions with vorinostat. Please refer to vorinostat CIB for 
detailed information. 
3.3.4 Nonclinical Toxicology of Vorinostat 


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Vorinostat has been investigated in nonclinical acute and oral repeated-dose toxicity studies, 
reproductive, developmental toxicity studies, and genetic toxicity studies to support oral administration 
of this compound to humans. The main toxicities observed in animal models were weight loss and 
inappetence, apparent hemolytic anemia (rats only at 3.6 times the equivalent 400 mg human dose), 
leukopenia (rats only at 1.3 times the equivalent 400 mg human dose), thrombocytopenia (male rats 
only, statistically significant change at 0.5 times the equivalent 400 mg human dose but within normal 
range at all doses), and gastrointestinal tract irritation (dogs only, at 8.5 times the equivalent 400 mg 
human dose). Although statistically significant and dose- dependent, many of the clinical pathology 
findings were within normal historical ranges indicating that they should not have major toxicological 
consequences. The toxicities appeared to be rapidly reversible within 12 to 14 days. There has been no 
evidence of cardiac toxicity based on electrocardiogram (ECG, dogs only), blood pressure (dogs only), 
heart rate (dogs only), creatinine kinase, organ weight, gross pathology, or histopathology assessments 
in studies up to one month duration. No serious, irreversible damage to any vital organ has been 
observed. Importantly, toxicities in rats and dogs were predictive of adverse effects in humans (anorexia, 
weight loss, fatigue). Toxicities present in animals would be manageable in the clinic, and the onset of 
serious toxicity is readily forecast by prodromal symptoms. The nonclinical toxicity profile of vorinostat 
is acceptable for an oncology drug. Vorinostat rapidly crossed the placenta in both the rat and rabbit, 
following administration of a dose of 15 mg/kg/day and 150 mg/kg/day, respectively (<1 times the 
human exposure based on AUC0-24) and reached transplacental equilibrium within 30 minutes post-dose. 
Vorinostat was evaluated in a panel of genetic toxicity assays; in vivo and in vitro assays were found to 
be positive. Therefore, vorinostat should not be taken by pregnant women. Pregnancy should be avoided 
both in female subjects taking vorinostat, and in female partners of male subjects taking vorinostat for at 
least 30 days after last dose of vorinostat, as data are not yet available to establish the safety of 
vorinostat ingestion in male patients who impregnate their partners. No human safety data for the use of 
vorinostat during pregnancy are available. Please refer to the vorinostat CIB for detailed information 
3.3.5 Clinical Pharmacokinetics of Vorinostat 
The pharmacokinetics of vorinostat following 400 mg single-dose in a fasted state; and 400 mg single- 
and multiple-doses in a fed (high-fat meal) state were evaluated in 23 patients in a Phase I study with 
relapsed or refractory advanced cancer using a validated assay. {Rubin}. See Table 1. 


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-Value 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as 
unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of 
vorinostat. Recovery of two pharmacologically inactive metabolites, O-glucuronide of vorinostat (OG- 
V) and 4-anilino-4-oxobutanoic acid (4A4OA), in urine was more substantial. Please refer to the 
vorinostat CIB for detailed information. 
3.3.6 Summary of Clinical Experience with Vorinostat 
As of July 2, 2012, Vorinostat has been orally administered to more than 5,000 patients in Phase I, Phase 
II and Phase III clinical studies. These studies were sponsored by either Merck, Sharp & Dohme 
Corporation, a subsidiary of Merck & Co., Inc. (herein referred to as Merck), including MSD KK 
(Japan), in addition to the United States (U.S.) National Cancer Institute (NCI), the National 
Comprehensive Cancer Network (NCCN), or by Investigators participating in the Merck Investigator 
Studies Program (MISP). MISP clinical studies are small-scale clinical trials conducted and sponsored 
by an independent investigator for which Merck may provide support in the form of a supply of 
vorinostat or financial assistance. Vorinostat has been studied both alone and in combination with other 
chemotherapy agents. 
 
Merck & Co., Inc. sponsored 30 clinical trials and independent Investigators have sponsored 85 clinical 
Table 1 
PK Parameters of vorinostat following oral administration of single or multiple 
doses of 400 mg 
400-m
Dose 
g Single 
400-mg Single- 
400-mg Multiple 
Fasted 
Dose Fed 
Dose Fed 
GMR ¶
 
N 
23 
20 
14 
-- 
-- 
AUC 0-∞ , 𝛍𝐌·hr† 
3.87 
5.33 
-- 
1.38# 
< 0.001# 
 
3.82 
0-24 hr, 𝛍𝐌·hr†
 
5.33 
6.46 
1.21†† 1.23‡‡ 
0.019†† 
0.010‡‡ 
Cmax, 𝛍𝐌† 
1.12 
1.02 
1.13 
0.91# 
0.451# 
Tmax, hr ‡ 
1.50 
4.00 
4.21 
-- 
<0.001# 0.869§§ 
t1/2 , hr§ 
1.74 
1.44 
1.34 
-- 
0.036# 
fe ǁ 
0.0021 
0.0030 
0.0037 
-- 
-- 
fe = Fraction of dose excreted unchanged in urine 
†Geometric mean 
‡ Median 
§ Harmonic Mean 
" Arithmetic mean (single dose fasted N = 22, single dose fed N = 21, multiple dose fed N = 12). 
¶ Geometric mean ratio. 
# Single dose fed/single dose fasted. 
†† Accumulation ratio: AUC0-24 hr multiple dose fed/AUC0-24 hr single dose fed. 
‡‡ Linearity ratio: AUC0-24 hr multiple dose fed/AUC0-∞ single dose fed. 
§§ Multiple dose fed/Single dose fed. 


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trials with vorinostat. One thousand seven hundred and forty seven (1,740) patients have been treated 
with vorinostat alone or in combination with other chemotherapeutics in Merck & Co., Inc sponsored 
clinical trials. One thousand six hundred and seven (1,607) patients have been enrolled in investigator- 
initiated studies. In addition, 61 studies with vorinostat are ongoing, sponsored by the United States 
National Cancer Institute (NCI) under the Cancer Therapy Evaluation Program (CTEP) with one 
thousand seven hundred and eighteen (1,718) patients enrolled as of November 5, 2012. Therefore, over 
five thousand (5,000) patients have received at least one dose of vorinostat in studies sponsored by 
Merck the NCI, NCCN, or independent Investigators (MISP). Please refer to the vorinostat CIB for 
detailed information 
3.3.7 Safety of Vorinostat 
The total daily dose of vorinostat administered per patient ranged from 200 mg to 900 mg across all 
studies. The tolerability of vorinostat appears to be determined by total daily dose and the number of 
consecutive days of dosing. The administration frequency across all studies included once daily (QD) 
continuous dosing, twice daily (BID) continuous dosing, BID discontinuous dosing, and three times 
daily (TID) discontinuous dosing The maximum tolerated dose (MTD) for continuous daily dosing 
without a rest period is 400 mg daily or 200 mg twice daily (BID). The MTD for intermittent dosing has 
been established as 300 mg BID x 3 consecutive days per week, or 250 mg 3 times daily (TID) x 14 
consecutive days followed by a 7-day rest period {127}. 
Data are presented across all 30 Merck-sponsored protocols to examine the adverse experience profile in 
the overall population of study patients receiving vorinostat monotherapy and vorinostat in combination 
therapy. The clinical safety of vorinostat is supported by data from 1,740 patients and 1,744 patient 
exposures in CTCL monotherapy, CTCL combination therapy, hematologic malignancies monotherapy, 
hematologic malignancies combination therapy, solid tumor monotherapy, and solid tumor combination 
therapy populations. The additional patient-exposures occurred in the initial supportive CTCL study, 
where patients enrolled in one cohort were permitted to enroll in a subsequent cohort at a later time 
point. As a result, 4 patients participated in 2 dosing cohorts. While the total number of patients in the 
CTCL monotherapy population was 180, the total number of patient- exposures was 184. 
Among all 1,740 patients (1,744 patient-exposures), adverse experiences assessed by the investigator as 
Grade 3 or higher were mainly seen in the system organ classes (SOC) of: blood and lymphatic system 
disorders; gastrointestinal disorders; general disorders and administration site conditions; investigations; 
metabolism and nutrition disorders; nervous system disorders; respiratory, thoracic, & mediastinal 
disorders; and skin and subcutaneous tissue disorders. The vorinostat safety profile across the different 
populations is not significantly different. Most of the common AEs experienced by ≥10% of all patients 
across the different populations are generally comparable. Three hundred and five (17.5%) patients have 
had SAEs that were considered by the Investigators to be possibly related to vorinostat. 
Thrombocytopenia was the most common drug-related SAE reported across all 30 Merck-sponsored 
studies and occurred in 39 (2.2%) patients. Overall, treatment with oral vorinostat was well tolerated. 
Pulmonary embolism and deep vein thrombosis have been reported. Investigators should be alerted to 
the signs and symptoms of these events. QT prolongation has been observed as well. Monitoring of 
electrolytes and EKGs at baseline and periodically during treatment is clinically indicated. Please refer 
to the vorinostat CIB for detailed information. 


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Dose-limiting toxicities (DLTs) of single agent vorinostat were mainly non-hematologic (anorexia, 
dehydration, diarrhea, and fatigue); hematologic toxicities are primarily anemia and thrombocytopenia, 
most of which were mild to moderate. The majority of these DLTs occurred within the first month on 
vorinostat. The DLTs were manageable because these toxicities resolved quickly after drug 
administration was interrupted 
A phase I study of oral vorinostat was performed in children with recurrent or refractory solid tumors. 
Vorinostat was administered once daily at dose levels 180, 230, and 300 mg/m2/day. The toxicity profile 
was similar to adult trials. Of 24 patients evaluable for toxicity, DLTs included a deep vein thrombosis 
noted in 1/6 patients treated at a dose of 180 mg/m2/day and hypokalemia in 1/6 patients treated at 230 
mg/m2/day. DLTs at 300 mg/m2/day include reversible hypokalemia (1), neutropenia (1), and 
thrombocytopenia (2). The recommended phase II dose in children was established at 230 mg/m2/day. 
Additional Grade 3 or 4 non-dose limiting toxicities included elevation in ALT/AST, 
hyperbilirubinemia, leucopenia and lymphopenia.[7] A phase I study has been conducted with the oral 
vorinostat in combination with 13 cis-retinoic acid in children with refractory neuroblastoma, 
medulloblastoma, primitive neuroectodermal tumors and atypical rhabdoid tumor. Vorinostat was well 
tolerated at a dose of 180 mg/m2/day for 4 days a week when administered with cis-retinoic acid at a 
dose of 80 mg/m2/dose BID for 12 days of a 28 day course. [41] There have been no clinical trials 
conducted in children with vorinostat in combination with a cytotoxic agent to date. 
3.3.8 Efficacy of Vorinostat 
Vorinostat has recently been approved by the US FDA for the treatment of cutaneous manifestations in 
patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease 
on or following two systemic therapies. 
3.3.8.1 Efficacy in Patients with Solid Tumors 
In Protocol 002, a Phase II study of vorinostat in patients with head and neck cancer, no confirmed 
partial or complete responses were observed in the 12 patients enrolled in the study. An unconfirmed 
partial response was observed in one patient and stable disease was observed in three patients. In 
Protocol 006, a Phase I study of vorinostat in patients with advanced solid tumor and hematologic 
malignancies, 50 patients with solid tumors were enrolled. Tumor responses. and stable disease were 
noted in several patients with solid tumors, confirmed PR’s were observed in patients with thyroid 
papillary carcinoma and squamous cell carcinoma of the larynx and 2 unconfirmed partial responses for 
patients with – mesothelioma. The confirmed responses occurred at 400 mg twice daily x7d/wk. 
In a Phase I study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of 
vorinostat in patients with advanced cancers, no formal efficacy evaluations were performed. The study 
concluded that short-term administration of vorinostat to patients with advanced cancer was generally 
well tolerated. 
In a Phase II study of vorinostat in patients with relapsed or refractory breast, colorectal, and non-small 
cell lung cancer, the primary objectives of the protocol were to determine the response rate of anti-tumor 
efficacy using RECIST criteria and to evaluate positron emission tomography (PET) as an  early 
indicator of response to vorinostat at the initial starting dose of 400 mg po BID for 14 of 21 days. The 
efficacy evaluation included all patients who received 14 days of continuous study therapy and PET 
scans performed on Day 15. A total of 16 patients were enrolled. Seven (7) patients were reported to 


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have a best response of SD. Of the patients with SD, 1 patient had breast cancer and the remaining 6 
patients had lung cancer. No patients were observed to have a best response of partial or complete 
response. Please refer to the vorinostat CIB for detailed information. 
3.3.8.2 Efficacy in Patients who Received Combination Therapies 
Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as 
unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of 
vorinostat. Recovery of two pharmacologically inactive metabolites, O-glucuronide of vorinostat (OG- 
V) and 4-anilino-4-oxobutanoic acid (4A4OA), in urine was more substantial. Please refer to the 
vorinostat CIB for detailed information. 
In PN056, a phase II/III randomized double-blind study of paclitaxel and carboplatin in combination 
with vorinostat or placebo in patients with stage IIIB (with pleural effusion) or stage IV non-small cell 
lung cancer, 253 patients were enrolled. The study was stopped following a pre-planned interim analysis 
because the goal for this study to continue was not met, based on 100 events, a reduction in the hazard 
ratio for progression-free survival by >23% with a one-sided p-value <0.1. 
In PN058, a phase I clinical study of vorinostat in combination with gemcitabine and cisplatin in 
patients with advanced non-small cell lung cancer, 61 patients were enrolled. Of the 49 patients 
included in the efficacy analysis, across five dose cohorts, 13 had an objective overall response. 
In PN066, a phase I clinical study of vorinostat in combination with carboplatin and paclitaxel 
conducted in Japan (MSD KK) in patients with advanced non-small cell lung cancer, 3 patients 
were enrolled. All 3 patients experienced dose limiting toxicities during cycle 1 so no efficacy 
data was be available for this study 
 
3.4 
Etoposide 
Etoposide (VP16), a semisynthetic derivative of podophyllotoxin, acts as a topoisomerase II inhibitor. It 
is a cell-cycle, phase-specific drug which has demonstrated activity in the phase II setting in treating a 
broad spectrum of pediatric and adult malignancies. Single-agent activity for pediatric solid tumors of 
approximately 20% with variation in the disease specific response rates (ie., osteosarcoma 9%, soft 
tissue sarcoma 8%, rhabdomyosarcoma 19%, and Ewing’s sarcoma 40%). In most pediatric and adult 
salvage regimens, etoposide is usually administered intravenously at a dose of 100-200 mg/m2/day for 3- 
5 days every 3 weeks in association with other drugs, i.e., cyclophosphamide, ifosfamide and platinum 
derivatives. In this study, vorinostat will be added to etoposide to see if the anti-tumor activity will 
improve upon that seen with single agent etoposide alone. Data mainly in adults with small cell lung 
cancer suggested that low dose prolonged administration appears to be at least as effective as higher 
doses over a short period with better tolerance. 
 
 
3.5 
Rationale for Combination Therapy with Vorinostat and Etoposide 
Vorinostat has been shown to induce cell cycle arrest, differentiation, and apoptosis in a variety of adult 
and importantly in pediatric tumors including neuroblastoma and rhabdomyosarcoma. [13-17] Extensive 
preclinical studies have demonstrated evidence of anti-tumor activity of this agent in combination with a 
variety  of  agents  including  topoisomerase  II  inhibitors  (ie.  etoposide,  doxorubicin)  [18,  19],  DNA 


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hypomethylating agents (ie., 5-azacytidine or decitabine) [20] , Imatinib mesylate[21-23] , Bortezomib [24] , 
Ellipticine [19], Cisplatin [25] and Hsp 90 inhibitors [26] . Of interest, vorinostat has been shown to 
potentiate DNA damage induced by topoisomerase II inhibitors in a sequence-specific fashion. Pre- 
treatment with Vorinostat 48 H prior to exposure to a topoisomerase II inhibitor has been shown to be 
synergistic in breast cancer cell lines.[27] Enhanced cytotoxicity has also been demonstrated with other 
chemotherapeutic agents including ellipticine, doxorubicin, or cisplatin, but not of the topoisomerase I 
inhibitor camptothecin.[19] However, treating cells in the reverse order (anticancer drug followed by 
vorinostat) was no more cytotoxic than the anticancer drug alone. Additional unpublished data by Dr. 
Aru Narendran, an investigator in this trial demonstrated similar results with the combination of 
vorinostat and etoposide. First, drug sensitivity curves for etoposide were determined then leukemic 
cells were cultured with increasing concentrations of vorinostat alone or in combination with etoposide 
at its IC10 or IC25 values. In these experiments, etoposide was added at the same time, 48 hours after the 
addition of vorinostat. After four days in culture, cell growth inhibition was quantified by Alamar blue 
assay. The fraction affected (Fa) and the combination index (CI) were calculated with the CalcuSyn 
computer program (Biosoft) according to the method of Chou and Talalay.2 Results shown in Figure 1 
show the representative findings from the cell line C1 demonstrating synergistic effect when etoposide 
was added after 48 hours with a calculated CI of 0.64 compared to the final cytotoxicity when the two 
agents were added together (CI = 1.1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Cytotoxicity of Vorinostat and Etoposide in Leukemia 
 
Phase I has been completed and the combination Vorinostat and Etoposide has demonstrated a favorable 
toxicity profile in patients with relapsed/refractory solid tumors, including tumors of the central nervous 
system 
 
We will evaluate in a phase II trial the safety of vorinostat in combination with the topoisomerase II 
inhibitor etoposide in pediatric patients with relapsed/refractory sarcoma tumors. 
3.6 
Correlative Studies 
The study will incorporate biologic correlative analyses to evaluate the following: assessment of histone 
acetylation/gene expression profiling and assessment of cellular phosphorylation profiling. Incorporation 
of these correlative studies we hope will enhance our understanding of histone deacetylation and the 
SAHA-C1 
SAHA + Etoposide 
48h Time Interval 
100 
90 
80 
70 
60 
50 
40 
30 
20 
10 
0 
0.0781   0.15625   0.3125     0.625 
1.25 
2.5 
5 
10 
Concentration (uM) 
% Survival compare to control 


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ensuing anti-tumor activity in sarcoma patients treated with the proposed novel combination, vorinostat 
and etoposide. 
Histone Acetylation and Gene Expression Profiling 
Molecular studies of clinical samples obtained from patients with cancer can provide rich clinical and 
biological information. Gene expression profiling of diagnostic breast cancer samples has been used to 
identify expression profiles associated with risk of metastasis [28, 29] (van't Veer el al., 2002; van de 
Vijver, et al., 2002). In this protocol, pre- and post-treatment samples of tumor will be collected for 
correlative molecular studies. These samples will be used to search for (1) gene expression profiles that 
predict response to the combination vorinostat and etoposide; (2) expression changes that occur after 
exposure to Vorinostat and Etoposide. Results from these gene expression studies may provide 
important information regarding the mechanisms of response to vorinostat. Ultimately, these results 
could guide the selection of patients for treatment with vorinostat. 
Histone Phosphorylation Profiling 
Vorinostat and another HDAC inhibitor, depsipeptide, have shown efficacy in a wide range of cancers, 
in particular for cutaneous T-cell lymphoma (CTCL), and are progressing in phase II clinical studies. 
However, evidence is accumulating that specific HDAC enzymes are important with respect to clinical 
efficacy, calling the usefulness of the classical inhibitors into question. Class I enzymes are being 
heralded as the most clinically relevant; however, mechanisms involved in these processes are currently 
not clear. [30, 31] 
Class IIa histone deacetylases (HDACs) are found both in the cytoplasm and in the nucleus where they 
repress genes involved in several major developmental programs. [32] In response to specific signals, the 
repressive activity of class IIa HDACs is neutralized through their phosphorylation on multiple N- 
terminal serine residues and 14-3-3-mediated nuclear exclusion. It has been shown that class IIa HDACs 
are subjected to signal-independent nuclear export that relies on their constitutive phosphorylation. 
EMK and C-TAK1, two members of the microtubule affinity-regulating kinase (MARK)/Par-1 family 
have been identified as regulators of this process.[31] It has been shown that EMK and C-TAK1 
phosphorylate class IIa HDACs on one of their multiple 14-3-3 binding sites and alter their subcellular 
localization and repressive function. 
Using HDAC7 as a paradigm, it has been demonstrated that signal-independent phosphorylation of the 
most N-terminal serine residue by the MARK/Par-1 kinases, i.e., Ser155, is a prerequisite for the 
phosphorylation of the nearby 14-3-3 site, Ser181. This shows that multi-site hierarchical 
phosphorylation by a variety of kinases allows for sophisticated regulation of class IIa HDAC function. 
[31] 
We propose to investigate target modulation patterns in peripheral blood lymphocytes in response to 
specific anti-tumor activity of Vorinostat. This is based on the rationale that vorinostat inhibits its target 
enzyme (HDAC) in peripheral mononuclear cells while exerting its activity on tumor tissue.[13] The anti- 
tumor activity of HDAC inhibitors has been attributed to both their ability to inhibit deacetylases and 
their capacity to down-regulate phenotypic expression of oncoproteins as well as activation of the 
intrinsic apoptosis-inducing cascade. [32-35] It has been shown that cell cycle arrests or induction of 
apoptosis are dependent on treatment conditions such as drug concentrations and duration of drug 
exposure, as well as the intrinsic sensitivity of malignant cells to this class of anticancer agents.[36]  In 


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addition, HDAC inhibition has been shown to induce acetylation and inhibit the ATP binding and 
chaperone function of heat shock protein (HSP) 90. This promotes the polyubiquitylation and 
degradation of the pro-growth and pro-survival client proteins such as FLT-3, Raf and AKT.[37] 
In the mantle cell lymphoma model, HDAC inhibitors have been shown to reduce VEGF production and 
to induce growth suppression of the malignant cells. [38] Effects of HDAC inhibition also lead to 
decreased expression of angiogenesis-related genes such as angiopoietin-2, Tie-2, and survivin in 
endothelial cells and down-regulated hypoxia-inducible factor 1-alpha and VEGF expression in tumor 
cells. [39, 40] Based on these data, we hypothesize that the analysis of cell cycle regulators, apoptosis 
related proteins, clients of Hsp90 and angiogenesis related molecules in the peripheral mononuclear cells 
of patients undergoing therapy would provide effective target modulation analysis for this protocol. 
 
3.7 
Exploratory Objectives 
Symptom distress 
Symptoms are “perceived indicators of change in normal functioning as experienced by patients”.[42] 
Lenz et al suggest that each symptom can be conceptualized as a multidimensional experience which 
can be described and measured separately by individuals.[42] Symptoms possess common dimensions 
such as intensity (strength or severity), timing (duration and frequency of occurrence), level of perceived 
distress (degree of discomfort or bothersome) and quality. Symptom distress is defined as the amount of 
physical or mental upset, anguish, or suffering experienced by an individual in relation to specific 
symptoms [43, 44]. Lenz et al proposes that symptom distress is the degree to which a person is bothered 
by the symptom and asserts that it is the dimension that contributes most to quality of life and is the 
most influential dimension in treatment decisions. Lenz et al suggest that the degree of symptom distress 
felt by an individual in relation to one symptom may be different if it is experienced in the presence of 
other symptoms. Furthermore, Lenz et al suggest that the concurrence of multiple unpleasant symptoms 
is likely to result in an experience that is multiplicative rather than additive. This has significance for 
cancer patients who experience a variety of unpleasant symptoms related to their disease and associated 
treatments. 
Symptom clusters 
Depending on a particular disease or treatment type, patterns of symptoms emerge. It is this grouping of 
symptoms that define symptom clusters. While individuals are able to distinguish the unique qualities of 
each symptom, the concurrent experience of multiple symptoms appears to have an effect that is greater 
than, and different from, the effect of each individual symptom alone. This phenomenon has been 
demonstrated in studies examining the effect of symptoms on quality of life [45, 46, 47] 
 
Symptom Clusters and Symptom Distress in Children with Cancer 
Although pediatric cancer clinical trials traditionally have focused on survival or toxicity, there is an 
emerging interest in the measurement of outcomes that reflect the impact of treatment on patients and 
therefore, their quality of life. This interest is related both to the improved survival of children with 
cancer and to a consensus that quality of life outcomes are highly relevant. [48, 49] 
The distressing symptoms caused by childhood cancer and the associated treatments occur frequently 
due  to  aggressive  therapy  regimes  implemented  to  cure  the  disease.  The  measurement  of  these 


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symptoms is important to understanding the effect of treatment on a child’s quality of life. The intensity 
of these symptoms may ultimately influence the child and adolescent’s ability to meet important 
developmental challenges and milestones. Therefore, attention must be given to the symptom 
experiences that occur during childhood cancer treatment so that we may decrease their distress and 
promote the needed energy for engaging in normal activities of childhood and adolescence. [50] 
There is much still to be learned about the symptoms pediatric cancer patients experience and the effect 
of these symptoms on their quality of life. Few studies have attempted to describe the experience of 
symptoms in children with cancer. This is due, in part, to the lack of validated symptom assessment 
scales for this population. [51] Only recently have studies begun to address the distressing cancer events 
and symptoms from the perspective of the child and the family. Collins, et al in 2000 described the most 
common physical symptoms in a group of 160 children with cancer as lack of energy, pain, drowsiness, 
nausea, coughing, and lack of appetite.[48] In 2003, Hedstrom et al discovered that the most common 
causes of distress in a group of 121 children with cancer were treatment related pain, nausea and fatigue 
rather than the cancer itself. [52] Woodgate and Degner evaluated expectations and beliefs about 
childhood cancer symptoms in a group of 39 children and their families that showed that these 
individuals expected to experience suffering as part of the cancer treatment, even believing that 
unrelieved symptoms were necessary for the cure. [53] In a review of the research program at Texas 
Children’s Hospital, it was demonstrated that fatigue, sleep disturbances, and pain are significant 
symptoms experienced by children. They also found an association between these symptom clusters and 
physical performance changes as well as behavior problems. It was also at Texas Children’s Hospital 
that the Memorial Symptom Assessment Scale (MSAS) was reviewed and modified by experts in 
developmental pediatrics and pain management resulting in the development of tools specific  for 
children in two separate age groups: the MSAS (10-18) and the MSAS (7-12). [54] 
At present, there is no published data regarding multi - symptom assessment in a Phase I/II setting. In 
this study, we will use the MSAS (10-18) instrument to assess symptom complexes in relation to the 
novel chemotherapy regimen, vorinostat and etoposide. 
This exploratory study may potentially lead to more definitive studies to establish a correlation between 
the symptom complexes and quality of life in children and adolescents on early clinical trials. The 
primary focus of these exploratory studies will be to determine whether symptom distress differs over 
time in children with relapsed/refractory sarcoma receiving vorinostat and etoposide. 
This study will provide unique insight into the changes children with relapsed or refractory sarcoma 
experience in symptom perception during treatment with vorinostat and etoposide. In addition, findings 
may help us predict patterns of symptom distress and provide us with the opportunity to anticipate 
patients at risk for heightened symptom distress. Effective clinical practice should be based on accurate 
assessments and anticipation of needs. In order to do this, the first step is identifying symptoms and their 
pattern of manifestation. Findings from this study will accomplish this. Future strategies include 
applying interventions known to be effective in the management or prevention of symptoms or testing 
the efficacy of newly developed interventions that may prevent or minimize specific symptoms 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.2 
Design 


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Part 1: Dose Escalation Phase 
This is a multi-center, open label, phase I trial of escalating doses of vorinostat in combination with 
etoposide. This component of the study is designed to establish the MTD, DLT, and the RP2D of the 
combination vorinostat and etoposide in pediatric patients with relapsed/refractory solid tumors. Patients 
will be assessed in 3-week cycles. Escalating doses of vorinostat will be administered orally on a daily x 
4 schedule in combination with a fixed dose of etoposide. Etoposide will be administered intravenously 
daily x 3 days. Cohorts of 3-6 patients will be treated with vorinostat and etoposide. The dose escalation 
schema for vorinostat is summarized in Section 9.3. 
A minimum of 2 evaluable patients will be entered at each dose level. Dose escalation will not be 
considered until at least 3 patients at a given dose level have completed one course of therapy (e.g. 3 
weeks) without a DLT. For the purposes of this study, DLT will be defined during the first cycle of 
treatment. The individual parameters of DLTs are defined in Section 9.7. 
If a patient does not experience a DLT as defined in Section 9.7 but is taken off study due to 
unacceptable adverse events/toxicity, that patient will be considered to have had a DLT for the purposes 
of dose escalation. If therapy is discontinued during the first cycle for reasons other than toxicity, an 
additional patient may be enrolled at the dose level of the off-study patient to ensure adequate evaluation 
of toxicity. 
The MTD is defined as the highest dose level with an observed incidence of DLT in no more than one 
out of six patients treated at a particular dose level. The dose escalation scheme is as follows: 
The dose escalation scheme is as follows: 
 
1) If none of initial three patients at a given dose level experience DLT, the next dose level is 
studied in another cohort of three patients. 
 
2) If one of the initial three patients at a given dose level experience DLT, up to three additional 
patients will be treated at that same dose level. Escalation will continue if one of the six 
patients experience DLT. 
 
3) If two or three patients experience DLT in the first three patients, or two or more patients 
experience DLT in six patients at a given dose level, the MTD will be determined as the 
preceding dose level. 
 
4) If three or fewer patients are treated at a dose under consideration as the MTD, additional 
patients to total six will be treated at that level to confirm the MTD. 
Once the MTD level is determined, this level will be expanded to treat a total of 9 subjects to determine 
the safety of the RP2D. If two (or more) of the 3-6 subjects, or 3 of the 9 subjects treated at a particular 
dose level experience a DLT at any time during the first cycle, then the MTD will have been exceeded. 
NUMBER OF PATIENTS WITH DLT 
AT A GIVEN DOSE LEVEL 
ESCALATION DECISION RULE 
Table 2 


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0 of 3 
Enter 3 patients at the next dose level. 
> 2 of 3 
Dose escalation will be stopped. This dose level will be declared the 
maximally administered dose (highest dose administered). Three (3) 
additional patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
1 of 3 
Enter at least 3 more patients at this dose level. If 0 of these 3 
patients experience DLT, proceed to the next dose level. 
If  1  or  more  of  this  group  suffer  DLT,  then  dose  escalation  is 
stopped, and this dose is declared the maximally administered dose. 
< 1 of 6  at highest dose level below the 
maximally administered dose 
This is generally the MTD. At least 6 patients will be entered at the 
MTD. 
 
For those patients with measurable disease, response evaluation should be performed following every 
two cycles of treatment (> 4 and < 6 weeks from the start of the first cycle of treatment). The 
determination of antitumor efficacy in patients will be based on an objective tumor assessment made 
according to RECIST. An interim analysis will be performed by the Study Committee after Part 1 is 
completed and prior to initiation of the Part 2 (Phase II component) of the study. 
 
Part 2: Efficacy Phase 
This is a multi-center, open label phase II trial. The purpose of this component of the study is to establish 
the efficacy (CR+PR rate) of the novel combination vorinostat and etoposide in pediatric patients with 
relapsed/refractory sarcoma. Patients will be treated at the RP2D established for the combination 
vorinostat and etoposide in Part 1 of the study, which was found to be 270 mg/m2/dose of Vorinostat and 
100 mg/m2/dose of Etoposide. The determination of antitumor efficacy will be based on objective tumor 
assessment made according to RECIST defined in section 12.0. 
 
 
 
 
 
4.3 
Intervention 
Refer to Section 9.0 
4.4 
Number of Patients 
Phase I Component: Approximately 18-25 patients will participate in this component of the study. 
Phase II Component: Approximately 15-28 patients will participate in this component of the study. 
 
4.5 
Centers 
This multi-center study will be conducted in 11 participating centers of the Pediatric Oncology 
Experimental   Therapeutics   Investigators’   Consortium  (POETIC)  These  institutions  include  All 


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Children’s Hospital, MD Anderson Cancer Center, Memorial Sloan-Kettering Cancer Center, Phoenix 
Children’s Hospital, Sidney Kimmel Cancer Center (Johns Hopkins Medical Center), Alberta Children’s 
Hospital, Children’s Hospital Colorado, Pennsylvania State University College of Medicine, Dana- 
Farber Cancer Institute, Children's Mercy Hospital & Clinics and Arnold Palmer Hospital for 
Children/MD Anderson Cancer Center Orlando. 
 
4.6 
Exploratory Studies 
Symptom Distress 
A descriptive, longitudinal study design will be conducted to prospectively compare the effect of the 
novel combination of vorinostat and etoposide on symptom distress in children, ages 10 – 18, enrolled 
on study using the MSAS (10-18) during routine visits to the outpatient clinic. [48, 51] At the pre-study 
visit and at the time of each radiographic evaluation (every 5 weeks + 7 days), the instrument will be 
given to the patient to complete in a private area with assistance from the research nurse or trained RSA 
in completing it. The research nurse or trained RSA will assist the participant in completion of the 
instrument thereby ensuring consistency across administration as well as completeness of the data 
collected. Completion of the questionnaire will take approximately 10-15 minutes. The time points for 
assessment have been selected in accordance with key time periods during treatment. A copy of this 
assessment will be submitted to the POETIC DCC along with the CRF’s from the corresponding cycle 
as defined in section 16.0 of the protocol. 
Symptom distress will be measured with the MSAS (10-18) [48] self-report instruments that measure the 
presence, frequency, severity and level of distress in children with cancer. The MSAS (10-18) measures 
30 symptoms derived from a multidimensional symptom assessment instrument validated for use with 
adults. For each symptom, separate 4-or 5 point Likert scales were used to measure the dimensions of 
frequency, severity and distress. Twenty-two symptoms will be evaluated for each of the three 
dimensions; frequency was not relevant for eight symptoms and for these only severity and distress are 
assessed. Scoring of the MSAS yields several valid subscores, assessing psychological symptoms, 
physical symptoms and a global distress scale. Finally, the total MSAS score will be computed as an 
average of the symptom scores for all 30 symptoms across all applicable dimensions, whereby each 
symptom score is an average of the dimensions A high score will indicate a high level of symptom 
distress. 
 
 
Descriptive statistics will be used to examine the effect of treatment and time on symptom distress. 
 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.2 
Vorinostat 
5.2.1 Formulation 
Vorinostat (N-hydroxy-N’-phenyl-octane-1,8-diotic acid diamide, N hydroxy-N’-phenyl (9CI) 
octanediamide, suberoylanilide hydroxamic acid, also known as SAHA, or MK-0683), is an orally 
available HDAC inhibitor. The physical and chemical properties of vorinostat are listed in Table 3. 
 
Table 3 


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- 24 - 
 
 
 
MOLECULAR FORMULA 
C14H20N2O3 
Molecular Weight 
264.32 
Physical Appearance 
White to light orange powder 
Moisture (Karl Fischer) 
Maximum of 0.3% 
HPLC† 
Single peak in reference system, Rt = 12.0 min 
Melting Point 
159.5 to 160.5 oC 
PKa 
9.2 
Ultraviolet Absorption 
max= 242 nm (in methanol) 
Hygroscopicity 
Non-hygroscopic 
Hydrates 
None 
Chirality 
None 
†HPLC = high pressure liquid chromatography. 
Rt = retention time. 
 
The oral formulation of vorinostat is available as a 100-mg capsule. Each 100 mg vorinostat capsule for 
oral administration contains 100 mg vorinostat and the following inactive ingredients: microcrystalline 
cellulose, sodium croscarmellose and magnesium stearate. The capsule shell excipients are titanium 
dioxide, gelatin and may contain sodium lauryl sulfate. 
5.2.2 Labeling and Packaging 
 
5.1.2.1 Patient Information 
Vorinostat will be packaged in an open-label fashion. Clinical supplies will be packaged to 
support enrollment of approximately 50 patients. 
 
5.2.3 Product Descriptions 
Investigational material will be provided by Merck & Co., Inc.  as summarized in Table 4. 
 
 
 
 
Table 4 
Product Descriptions 
 
PRODUCT NAME & 
POTENCY 
DOSAGE FORM 
COMMENTS 
Vorinostat 100 mg 
Capsule 
 
5.2.4 Primary Packaging and Labeling Information 
Vorinostat clinical supplies will be packaged in HDPE (high-density polyethylene) bottles as described 
in Table 5. 
 
Table 5 
Packaging of Clinical Supplies 


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PRODUCT NAME & 
POTENCY 
FILL COUNT 
DOSING INSTRUCTIONS 
Vorinostat 100 mg 
120 capsules 
Take as directed by your study physician 
 
5.2.5 Clinical Supplies Disclosure 
This study is open-label; therefore, the patient, the Investigator, and site personnel are not blinded to 
treatment. Drug identity for vorinostat is included in the label text. Disclosure envelopes are  not 
provided. 
5.2.6 Investigational Agent Management 
FDA regulations require investigators to establish a record of the receipt, use, and disposition of all 
investigational agents. The investigators in this study have the responsibility to assure the FDA that 
systems for agent accountability are being maintained by investigators in the clinical trials network. 
Investigators may delegate responsibility for agent ordering, storage, accountability and preparation to a 
designee in their institutions.  However, the investigator is ultimately responsible for all agents shipped 
in his/her name.  The intent of agent accountability is to assure that supplied agents are only used for 
patients enrolled on this trial.  Investigational agents will not be shipped to a site unless all site and study 
specific regulatory documents have been received by the POETIC Data and Coordinating Center (DCC). 
The POETIC DCC will notify the site of their activation and provide clearance to order study drug from 
Fisher Clinical Sciences. 
Requests and Shipping 
Upon site activation by the POETIC DCC, the site will complete a Drug Shipment Authorization form 
(Appendix VI) and submit to the POETIC DCC. Sites may submit the authorization form for subsequent 
shipments to Fisher Clinical Sciences at the address listed below: 
 
 
 
 
 
Fisher Clinical Sciences 
Distribution Study Administration 
7554 Schantz Road 
Allentown, PA 18106 
Phone: 610-871-8300 
Fax: 
610-871-8590 
E-mail: distribution.allentown@Thermofisher.com 
The information needed for completion of the Drug Shipment Authorization form is the POETIC 
protocol number, address, product information and quantity. The POETIC protocol, POE10-02, is 
included on the form. Investigational agents will only be shipped to the investigator’s designated 
shipping address. All changes to the shipping address must be in writing and signed by the investigator 
or designee. The amount of drug requested will be in quantities of 3 bottles per order (each bottle 
contains 120 capsules), which will provide a supply for treatment of 3 patients for 2 cycles. 


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Requests for investigational agents for new subjects should be submitted the day of registration and no 
less than 3 business days prior to the start of treatment.  Requests for subsequent cycles should be made 
a minimum of 1 week prior to treatment.  Telephone requests will not be accepted. 
Investigational agents will only be shipped to the investigator’s designated shipping address.  All 
changes to the shipping address must be in writing and signed by the investigator or designee. 
 
Upon receipt of the drug supply, the site must verify and document that correct agent(s), lot numbers, 
and quantity were received in adequate shipping conditions. Once verified the Packing Slip (Appendix 
IV) must be completed, signed and returned to Fisher Clinical Sciences to the following contact and 
FAX: AOR Administrator, FAX# 610-871-0775. If there are problems with the shipment, the Site must 
notify the AOR Administrator immediately. 
If there are any additional problems contact: 
Gregg J. Rieker 
Distribution Project Manager 
Thermo Fisher Scientific (Fisher Clinical Sciences) 
700 Nestle Way 
Breinigsville, PA 18031 
Phone: 484-538-2139 
Fax: 
610-871-0711 
gregg.rieker@thermofisher.com 
 
Agent Transfer, Return, or Destruction 
Transfer of investigational agents between sites is prohibited unless approved by the DCC and the 
pharmaceutical management for drug distribution prior to the transfer. 
 
Investigational agents are not interchangeable with approved commercial agents. Correct stock must be 
used for all doses, if investigational agent is not available for a subject at the scheduled time the 
subject’s appointment must be changed. 
Every effort should be made to minimize the amount of agent ordered and returned unused. Unused 
agents will either be returned or destroyed on-site as directed by the study staff when the study is 
completed or discontinued; agent is outdated, damaged or unfit for use. Opened or partially used 
vials/bottles are not to be returned unless specifically requested otherwise in the protocol. Broken vials 
are to be destroyed at the site, not returned. 
If return of investigational agent is not required, the agent will be treated as chemotherapy or biological 
hazardous waste as appropriate and disposed of in accordance to the policies for hazardous waste 
management at the Site. 
For agents destroyed on-site, the DAR must be completed and faxed to the POETIC DCC. If the 
investigational agent is returned, the completed DAR must accompany the agent. 
Sites must maintain copies of all Requests for Drug Shipment, Packing Slips, and DARs on site, 


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available for monitoring and auditing until final closure of the study. After final closure of the study, 
forms may be stored off site as per the policy of the site. 
5.2.7 Storage and Accountability 
Documentation (receipt, transfer, dispensing, or return) will be maintained on the NCI Investigational 
Drug Accountability Record (DAR) (Appendix VII). Alternative accountability records may be provided 
to meet study specific requirements (example – oral medication involving return of meds by patient) 
beyond the DAR form’s capability. A copy of the appropriate accountability record will be sent with the 
investigational agent. 
A DAR must be maintained at each location an agent is stored (example – main pharmacy, satellite, etc). 
A separate DAR will be maintained for each protocol. Protocols using more than one supplied agent or 
more than one strength or formulation of the same agent, each agent, strength, and formulation will be 
stored separately and a separate DAR maintained. Proper completion of the DAR is mandatory, failure 
to complete all fields as required may prevent future shipments until it is determined appropriate 
accountability can be maintained. Audit of the DAR will be included in the monitoring visits of studies 
with investigational agents. All investigational agents will be stored as per manufacturer 
recommendations in a secure location away from commercial drug stock that is only accessible to 
authorized personnel.  Each agent is to be stored and accounted for separately by protocol. 
Investigational agents requiring storage in refrigerator or freezer must be stored within the temperature 
range required by the manufacturer upon receipt. The agents must be stored separately by protocol 
within the refrigerator/freezer. No food products may be stored within the refrigerator/freezer. A 
thermometer or monitoring device must be utilized to monitor and record temperatures on a log posted 
on the equipment at a minimum of once daily. Out of range temperatures must be documented with 
reason for situation and actions taken to correct. 
 
Investigational agents must not be prepared until the subject is present, required testing completed, and 
the treating physician’s orders are received. The investigator will administer the agent only to subjects 
registered to the study and under the investigator’s personal supervision or under the supervision of a 
sub-investigator responsible to the investigator. 
Procedures for proper handling and disposal of anticancer drugs should be considered. Several 
guidelines on this subject have been published. There is no general agreement that all of the procedures 
recommended in the guidelines are necessary or appropriate. Direct contact of the powder in vorinostat 
capsules with the skin or mucous membranes should be avoided. 
If such contact occurs, wash thoroughly as outlined in the references. Personnel should avoid exposure 
to crushed and/or broken capsules. Please refer to the published guidelines regarding the handling of 
anticancer agents (refer to Vorinostat CIB). 
 
5.3 
ETOPOSIDE (VePesid®, Etopophos®, VP-16) NSC #141540 
5.3.1 Formulation: 
Commercial supply will be used for this study. Etoposide for Injection is available in sterile multiple 
dose vials. The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL contains 20 mg 


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etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 80/Tween 80, 650 mg 
polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial headspace contains nitrogen. 
Etoposide phosphate for injection is available for intravenous infusion as a sterile lyophilized powder in 
single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 mg sodium 
citrate USP, and 300 mg dextran 40. 
5.3.2 Storage 
Unopened vials of Etoposide are stable until expiration date on package at room temperature (25°C). 
Etoposide phosphate must be stored under refrigeration 2°-8°C (36°- 46°F). Unopened vials of etoposide 
phosphate are stable until the expiration date on the package. 
5.3.3 Solution Preparation/Handling 
Dilute Etoposide to a final concentration <0.4 mg/mL in Dextrose or Normal Saline containing IV 
solutions. 
Etoposide Phosphate: 
Dilute the 100 mg vial with 5 or l0 mL of Sterile Water for Injection, USP; 5% Dextrose Injection, USP; 
0.9% Sodium Chloride Injection, USP; Bacteriostatic Water for Injection with Benzyl Alcohol; or 
Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol for a concentration equivalent to 20 
mg/mL or 10 mg/mL etoposide (22.7 mg/mL or 11.4 mg/mL etoposide phosphate) respectively. 
Following reconstitution, etoposide phosphate may be further diluted to concentrations as low as 0.1 
mg/mL etoposide with Dextrose or Saline infusion solutions. Etoposide Phosphate may be administered 
as a bolus or by IV infusion. 
 
 
5.3.4 Stability 
Etoposide infusions are stable at room temperature for 96 hours when diluted to concentrations of 0.2 
mg/mL; stability is 24 hours at room temperature with concentrations of 0.4 mg/mL. The time to 
precipitation is highly unpredictable at concentrations > 0.4 mg/mL. 
5.3.5 Administration 
Administer IV over 60 minutes (+ 10 minutes). Do not administer etoposide by rapid intravenous 
injection. 
To avoid leaching of DEHP from PVC bags and tubing, prepare the Etoposide solution as close as 
possible preferably within 4 hours to the time of administration or alternatively as per institutional 
policy, non-PVC containers and tubing may be used. 
When reconstituted with diluent containing a bacteriostat, etoposide phosphate solutions can be stored in 
glass or plastic containers under refrigeration at 2°-8°C (36°-46°F) for 7 days or at controlled room 
temperature 20°-25°C (68°-77°F) for 48 hours; following reconstitution with Sterile Water for Injection, 
USP, 5% Dextrose Injection, USP, or 0.9% Sodium Chloride USP store at controlled room temperature 
20°-25°C (68°-77°F) for 24 hours. 
5.3.6 Availability 


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Commercially available from various manufacturers. See package insert for further information. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.2 
Subject Inclusion Criteria 
6.2.1 Phase I Component: Histologic confirmation of relapsed/refractory solid tumors, including 
tumors of the central nervous system that have failed to respond to standard therapy, progressed 
despite standard therapy, or for which standard therapy does not exist. Patients with diffuse 
pontine glioma are not required to have histologic confirmation of disease, and are eligible with 
radiologic confirmation. 
Phase II Component: the population will be restricted to relapsed/refractory sarcomas. 
6.2.2 Patient must be between 4-21 years of age at the time of study enrollment. Efforts will be made 
to enroll patients <13 years of age so that adequate information about the biologic effects of this 
agent in younger patients can be obtained. 
6.2.3 Patient must have Karnofsky > 60% for patients >10 years of age; Lansky Play Scale > 60 for 
children < 10 years of age (see Appendix I). 
6.2.4 Patient must have a life expectancy of > 8 weeks. 
6.2.5 There is no limit to the number of prior treatment regimens provided that performance status and 
life expectancy meet the criteria above. 
 
 
 
6.2.6 
Normal organ and marrow function as defined below: 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥ 1000 / mcL 
Platelets 
≥100,000 / mcL (transfusion not permitted) 
Hemoglobin 
≥ 9 g/dL qualifications (transfusion permitted) 
Coagulation 
Prothrombin Time or INR 
≤ 1.5x upper limit of normal (ULN) 
Renal 
Serum creatinine 
≤ 1.5x upper limit of normal (ULN) OR calculated creatinine clearance ≥ 60 
mL/min for patients with creatinine levels > 1.5x institutional ULN. 
or calculated creatinine clearancea 
Hepatic 
Serum total bilirubin 
≤ 1.5 x ULN. Patient’s who don’t meet this criteria must have a Direct 
bilirubin ≤ 1.5 x ULN. 
AST (SGOT) and ALT (SGPT) Alkaline Phosphatase 
(liver fraction) 
≤  2.5 x ULN. If AST or ALT is > 2.5 x ULN, then the liver fraction of 
Alkaline Phosphatase should be ≤  2.5 x ULN 
a Creatinine clearance should be calculated per institutional standard. 


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6.2.7 Phase I component: Patients may have measurable or non-measurable disease. 
Phase II component: Patients may only have measurable disease. 
6.2.8 Patient must have no persistent toxicities from prior therapy > Grade 2 with the exception of 
hematologic indices (i.e. hemoglobin, WBC, ANC, ALC). 
6.2.9 For females of childbearing potential, a negative serum pregnancy test must be documented 
within 72 hours of receiving the first dose of vorinostat. 
6.2.10 Patient, or the patient’s legal representative, has voluntarily agreed to participate by giving 
written informed consent. 
6.2.11 Female patients of childbearing potential must be willing to use 2 adequate barrier methods of 
contraception to prevent pregnancy or agree to abstain from heterosexual activity throughout the 
study, starting with visit 1. 
6.2.12 Male patients must agree to use an adequate method of contraception for the duration of the 
study. 
6.2.13 Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to entering this study. 
Myelosuppressive chemotherapy: At least 2 weeks must have elapsed since the administration 
of previous therapy. Six weeks must have elapsed since administration of nitrosoureas or 
mitomycin C. Seven days must have elapsed since the administration of G-CSF and/or GM-CSF. 
 
Biologic agents: At least 14 days must have elapsed since the completion of therapy with a 
biologic agent such as a monoclonal antibody. Seven days must have elapsed since the last dose 
of retinoids. 
Radiation therapy (XRT): > 2 weeks must have elapsed for local XRT (small port); > 6 months 
must have elapsed if prior radiation to > 50% of the pelvis or if other substantial bone marrow 
irradiation, including total body irradiation. 
6.2.14 Patient must be able to swallow capsules. 
6.2.15 Patient must have an available archival/pre-treatment block, or fresh tumor biopsy for molecular 
profiling to be performed (See section 10.8.2 of the protocol for specific requirements). 
 
6.3 
Subject Exclusion Criteria 
A patient meeting any of the following criteria is not eligible to participate in this study: 
6.3.1 Patients currently participating or has participated in a study with an investigational compound 
or device within 4 weeks of initial dosing with study drugs. 
6.3.2 Patients with a prior history of treatment with HDAC inhibitors (e.g. SNDX-275/entinostat, 
LAQ-824, LBH589, PXD-101/belinostat, etc). Patients who have received Valproic acid will be 
excluded from this study. 
6.3.3 Patients with non CNS primary tumors who have known brain metastases or symptomatic CNS 
disease (e.g. cranial nerve abnormalities) without cytologic abnormality in the CSF should be 


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excluded from this clinical trial because of their poor prognosis and known propensity for the 
development of progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events. Patients with metastatic CNS tumors will not be excluded 
from enrollment on this study in the phase I component only. 
6.3.4 Patients who have undergone prior autologous stem cell transplantation or allogeneic 
transplantation. 
6.3.5 Uncontrolled intercurrent illness or circumstances that could limit compliance with the study 
requirements including, but not limited to: ongoing or active bacterial or fungal infection, acute 
or chronic graft versus host disease, symptomatic congestive heart failure, cardiac arrhythmia, or 
psychiatric illness/social situations. 
6.3.6 Patients who are pregnant or breastfeeding, or expecting to conceive within the  projected 
duration of the study. Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with vorinostat, lactating patients will be 
excluded from this study. 
6.3.7 Patients known to be Human Immunodeficiency Virus (HIV)-positive. 
6.3.8 Patients with known hypersensitivity to the components of the study drugs or their analogs. 
6.3.9 Patients with symptomatic ascites or pleural effusion. A patient who is clinically stable following 
treatment for these conditions is eligible. 
 
6.3.10 Patients who are at the time of signing informed consent, a regular user of any illicit  drugs, 
substance abuser or who have a recent history of drug or alcohol abuse. 
6.3.11 Patients with a known history of Hepatitis B or C. 
6.3.12 Patients who have a history of gastrointestinal surgery or other procedures that might in the 
opinion of the investigator, interfere with the absorption or swallowing of the study drug. 
6.3.13 Patients who are unable to take or tolerate oral medications on a continuous basis. 
6.3.14 Patients with a history of a prior malignancy who have undergone potentially curative therapy 
with no evidence of that disease for five years, or patients who are deemed low risk  for 
recurrence by his/her treating physician are permitted to enroll. 
 
7.0 
RECRUITMENT PLAN 
7.1 
Patients or their parent/legal guardian will be required to sign a statement of informed consent 
indicating the investigational nature of this study. 
7.2 
Qualified physicians who may seek consent for entry of patients on this study are listed in 
Section 15.1. 
7.3 
The informed consent will be signed and dated by the patient, parent or the patient's legally 
authorized representative and by the physician obtaining informed consent according to 
institutional guidelines. One copy will be given to the patient/parent/legal guardian to be retained 
for their personal records. One copy will be maintained on file at the POETIC DCC. The 
original document will be confidentially maintained by the participating institution. 


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7.4 
A note will be placed in the medical record documenting that informed consent was obtained for 
this study, and that the patient and/or his/her parents, to the degree of their understanding, 
acknowledge and accept the risk of participation in this study. 
7.5 
Written consent must be documented on the appropriate consent form approved by the local 
Institutional Review Board at each of the respective participating centers. Attainment of the 
written consent must be verified by the DCC prior to entry on study. A copy of the consent form, 
along with the eligibility checklist, and Health Insurance Portability and Accountability 
Agreement (HIPAA) must be submitted to the DCC prior to enrollment of any subject on this 
study. Verification of subject enrollment on this study is defined in section 15.0. 
Every effort will be made to include women, children of both sexes, and minorities in the study 
population for this trial. No patient will be excluded from participation in this trial on the basis of 
gender, ethnicity, or race. Review of accrual to past pediatric multicenter studies of new agents 
demonstrates the accrual of both genders and all NIH-identified ethnicities to such studies. The 
small number of patients entered into this trial will obviate any analysis of variation in toxicity 
profile or response rate with gender or ethnicity. 
Data from the institutions participating in this trial have been reviewed with respect to 
enrollment of patients of different races and genders. It is anticipated that enrollment of the 
current study will follow the same pattern. 
Table 6 
Institution 
Number of New 
Patients/ Year 
White 
Non-Hispanic (%) 
Black 
Non-Hispanic (%) 
Hispanic 
(%) 
Other 
(%) 
MSKCC 
147 
61.0 
19.0 
15.0 
5.0 
JHMC 
77 
73.0 
21.0 
1.0 
5.0 
UCD/TCH 
204 
62.0 
0.0 
34.0 
4.0 
MDACC 
146 
60.0 
5.0 
29.0 
6.0 
UF 
93 
81.5 
16.5 
0.8 
0.8 
PCH 
137 
65.7 
< 0.1 
27.7 
6.5 
All Children’s 
100 
63 
19 
15 
2 
CMH 
184 
71.0 
12.0 
13.0 
4.0 
DFCI 
250 
81.3 
4.7 
5 
9.2 
8.0       PRETREATMENT/ENROLLMENT EVALUATIONS 
Studies required for patients enrolled on this study are summarized in the table included in Section 10.1. 
The following studies will be performed for all patients. If the complete physical exam, laboratory 
evaluations and EKG are completed within 72 hours of receiving treatment in cycle 1, then cycle 1 week 
1 evaluations do not need to be repeated. 
8.1 
A complete physical examination to be completed < 7 days prior to start of protocol therapy and 
will include: vitals signs (HR, RR, BP, Temp, height, weight, and performance status), complete 
medical history, prior anti-cancer therapy, and medications given within 7 days prior to the start 
of protocol therapy. 
8.2 
Laboratory studies will be obtained ≤ 7 days prior to the start of protocol therapy and will 
include: complete blood count w/diff, PT/PTT (with INR), fibrinogen, LDH, albumin, alkaline 
phosphatase,   total   bilirubin,   bicarbonate,   BUN,   calcium,   chloride,   creatinine,   glucose, 


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phosphorus,  potassium,  total  protein,  SGOT(AST),  SGPT(ALT),  and  sodium.  A  serum 
pregnancy test will be obtained in all females of childbearing potential. 
8.3 
A serum pregnancy test will be obtained in all females of childbearing potential within 72 hours 
of receiving the first dose of vorinostat. 
8.4 
Pre-treatment samples for correlative studies conducted on peripheral blood and bone marrow 
specimens are described below in section 10.0 
8.5 
An EKG will be performed at baseline 
8.6 
An extent of disease evaluation should be performed to evaluate the primary tumor and sites of 
metastatic disease including radiologic studies appropriate for the disease (i.e. CT, MRI, PET, 
bone scan, chest x-ray, etc.) and must be done  4 weeks prior to the start of therapy. PET 
imaging will be obtained as a correlative study in all patients for whom this imaging study is 
standard of care and who have PET capability at their sites. For these patients, it is recommended 
that a baseline PET scan be performed as part of the pre-treatment extent of disease evaluation 
and that the PET scan be repeated after the second cycle of treatment for the analysis. While 
these scans are recommended, they are not required for study entry. 
8.7 
In the event that the patient's condition is deteriorating due to disease progression, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the first and all subsequent 
cycles of therapy 
9.1 
TREATMENT/INTERVENTION PLAN 
9.2 
Treatment Administration 
Treatment may be administered on an inpatient or outpatient basis. Reported adverse events and 
potential risks for vorinostat and etoposide are described in Section 17.2. Appropriate dose 
modifications for vorinostat and etoposide are described in Section 9.13. No investigational or 
commercial agents or therapies other than those described below may be administered with the intent to 
treat the patient's malignancy. 
9.3 
Treatment Schema 
The dosing schedule for this study will consist of a 21-day cycle. The study PI must be contacted in the 
event of scheduling conflicts due to holidays. Vorinostat will be administered orally on Days 1-4 of 
every cycle at a starting dose of 125 mg/m2/dose. The starting dose of vorinostat will be 50% of the 
pediatric single agent RP2D for the oral formulation. The starting dose of vorinostat is approximately 
70% of the dose that acceptable dose reported in combination with the biologic agent 13 cis-retinoic acid 
reported by Fouladi et al. The dose of Vorinostat will be escalated in increments of 30% as long as there 
is no evidence of dose limiting toxicity. 
If dose limiting toxicity is demonstrated at the Dose level 1, the dose of Vorinostat will be reduced de- 
escalated by 25% (Dose Level -1). If a patient experiences emesis within 30 minutes of receiving 
vorinostat the dose should then be repeated. 
Etoposide will be administered intravenously over 1 hour (+ 10 minutes) on Days 3-5 of every cycle at a 
fixed dose of 100 mg/m2/dose in both phase I and II components of the study. See Schema in Table 7 
below. 


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For initial onset of treatment, in both components of the study, the patient must meet the ANC criteria of 
≥ 1000/mcL and a platelet criteria of ≥ 100,000/mcL as defined in section 6.1.6. For the second or 
greater courses of treatment, the hematologic criteria for initiation will be ANC ≥ 750/mcL and platelet 
count of ≥ 75,000/mcL. 
Table 7 
REGIMEN DESCRIPTION 
Agent 
Route 
Schedule 
(per cycle) 
Cycle Length 
Vorinostat 
Po 
Days 1-4 
21 days 
Etoposide 
IV 
Days 3-5 
 
 
 
9.4 
Phase I Component: Dose Escalation 
Inter-patient dose escalation will proceed as follows: 
 
Table 8 
DOSE ESCALATION SCHEDULE 
Dose Level 
Dose 
Etoposide 
( mg/m2 ) 
Vorinostat 
(mg/m2) 
-2 
75 
100 
-1 
100 
100 
1 
100 
125 
2 
100 
160 
3 
100 
210 
4 
100 
270 
 
The following dose rounding table should be used as a reference for drug dosing dispensed based upon 
body surface area: 
 
Vorinostat 
Dose 
(mg/m2) 
BSA 
0.5 – 
0.75 – 
1 – 
1.25 – 
1.5 – 
1.75- 
2 - 
2.25- 
0.74 
0.99 
1.24 
1.49 
1.74 
1.99 
2.24 
2.49 
100 
100 
100 
100 
100 
200 
200 
200 
200 
125 
100 
100 
100 
200 
200 
200 
300 
300 
160 
100 
100 
200 
200 
200 
300 
300 
400 
210 
100 
200 
200 
300 
300 
400 
400 
500 
270 
200 
200 
300 
400 
400 
500 
500 
600 


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Intra-patient dose escalation is not permitted. At the highest dose level below the MTD, if the 
equivalent of 1 out of 6 patients experiences DLT, then this dose will be the recommended Phase II 
dose (RP2D). At least 9 patients must be entered at the RP2D. Prior to proceeding to the Phase II 
component, the Principal Investigators of the study will review all clinical data with the sponsor before 
establishing the RP2D. 
9.5 
Phase II Component 
In the phase II component, patients will be treated at the RP2D established in the Phase I component of 
the study, which was found to be 270 mg/m2/dose of Vorinostat and 100 mg/m2/dose of Etoposide. 
Evaluation for response will be determined by Revised RECIST guideline (version 1.1) [55] after every 2 
cycles of therapy (> 4 and < 6 weeks from the start of the first cycle of treatment) as defined in section 
12.0. 
 
9.6 
Vorinostat 
9.6.1 Route of Administration 
Vorinostat capsules will be administered on Days 1-4 of every cycle. Vorinostat must be administered 
exactly 4 hours prior to administration of Etoposide on Days 3 and 4 of therapy. All doses and 
administration times of vorinostat must be documented on the patient diary and/or the patient’s medical 
record. 
 
9.6.2 Diet 
Vorinostat should be taken within approximately 30 minutes of a meal whenever possible. Altered taste 
and decreased food and liquid intake are associated with vorinostat administration. These toxicities can 
be actively managed with fluid management and nutritional consult. 
During the period of vorinostat administration, patients should consume at least 2 liters or maintenance 
volume of fluids orally, each day, to prevent dehydration. Patient may require electrolyte replacement. If 
patients are experiencing dysgeusia, popsicles or Gatorade may be successful in maintaining oral intake. 
Early use of anti-emetics should be encouraged. 
9.6 
Etoposide 
9.6.1 Route of Administration 
Etoposide will be administered at a fixed dose of 100 mg/m2/day intravenously over 1 hour (+ 10 
minutes) for three consecutive days on Days 3-5 of therapy. Most pediatric patients with recurrent, 
refractory disease will have a central venous access device (CVAD) in place prior to entry onto this 
study and, when possible, the drug will be infused using the CVAD. In patients who do not have 
indwelling CVADs, etoposide will be administered via peripheral intravenous (IV) access. In the event 
of an anaphylactic reaction, the infusion of etoposide should be terminated. In the event of hypotension, 
the infusion of etoposide should be stopped and Normal Saline administered until the blood pressure 
normalizes. Once the blood pressure has normalized, the infusion may be re-instituted and the rate of 
administration decreased to double the interval of administration (2H). Source documentation for 
etoposide administration start and end times, and dose must be provided. 
9.6.2 Etopophos 


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In the event of an anaphylactic reaction to Etoposide, Etopophos may be used in place of Etoposide. The 
dose and schedule of administration will be identical to that previously indicated for Etoposide in 
Section 9.2. 
9.7 
Definition of Dose-Limiting Toxicity 
Toxicity will be evaluated according to NCI CTCAE Version 4.0. Any of the following events which are 
attributed to study therapy (i.e., considered possibly, probably, or certainly related to study therapy) will 
be considered DLTs. Only DLTs occurring in the first cycle will be considered in the determination of 
dose cohorts and the MTD. The period of observation for DLT will be 21 days from the first dose of 
study medications. 
 
9.7.1 Definition of Hematologic Dose-Limiting Toxicity 
9.7.1.1 Any  Grade  4  hematologic  toxicity  including  neutropenia  and  thrombocytopenia  as 
indicated below: 
 
• Febrile neutropenia defined as Grade 3 or 4 neutropenia with fever > 38.5ºC and/or 
infection requiring antibiotic or antifungal treatment 
• Any Grade 4 neutropenia lasting > 7 days 
• Grade 4 thrombocytopenia lasting > 7 days 
• Treatment delay for more than 21 days due to toxicity > Grade 2 
• Any drug-related adverse experience, regardless of grade, leading to a dose reduction of 
one or more study drugs. 
 
9.7.2 Definition of non-hematologic Dose-Limiting Toxicity 
9.7.2.1 Non-hematologic  dose-limiting  toxicity  will  be  defined  as  any  Grade  3,  4,  or  5 
nonhematologic toxicity, with the specific exception of: 
• Grade 3 nausea or Grade 3 vomiting that in the opinion of the Investigator occurs in the 
setting of inadequate compliance with supportive care measures specified in Section 
9.8.5 and lasts for less than 48 hours. 
• Grade 3 diarrhea that in the opinion of the Investigator occurs in the setting of 
inadequate compliance with supportive care measures specified in Section 9.8.5 and 
lasts for less than 48 hours. 
• Grade 3 dehydration that in the opinion of the Investigator occurs in the setting of 
inadequate compliance with supportive care measures specified in Section 9.8.5 and 
lasts for less than 48 hours. 
• Alopecia 
• Inadequately treated hypersensitivity reactions 
• Grade 3 elevated transaminases of < 1 week in duration 
 
9.7.3 In addition, the following will also be considered DLT: 
• Any drug-related adverse experience, regardless of (CTCAE) version 4.0  grade, leading 


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to a dose modification of vorinostat; 
• Unresolved drug-related toxicity, regardless of (CTCAE) version 4.0  grade, lasting for 
3 weeks or more from the date of the last scheduled treatment; 
• Requirement for dose reduction by two dose levels due to toxicity. 
Dose escalation will be determined based on the occurrence of DLTs. For the purposes of deciding 
whether to advance the Dose Level, DLTs will be counted by patient (i.e., a patient who experiences 
more than 1 DLT will be counted only once). 
Management and dose modifications associated with the above adverse events are outlined in Section 
9.13. 
 
Dose escalation will proceed within each cohort according to the following scheme. 
 
Number of Patients with 
DLT at Given Dose Level 
Escalation Decision Rule 
0 of 3 
Enter 3 patients at the next dose level. 
>2 of 3 
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose (highest dose 
administered). Up to 3 additional patients will be entered at 
the next lowest dose level if only 3 patients were treated 
previously at that dose. 
1 of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
• If 1 or more of this group suffer DLT, then dose escalation 
is stopped, and this dose is declared the maximally 
administered dose. 
<1 of 6 at highest dose 
level below the maximally 
administered dose 
This is generally the recommended phase 2 dose. At least 6 
patients must be entered at this dose. 
 
9.8 
General Concomitant Medications 
The major pathways for metabolism of vorinostat involve glucuronidation and hydrolysis followed by ß- 
oxidation. Therefore, it is anticipated that vorinostat will not be subject to drug-drug interactions when 
co-administered with drugs that are known to be CYP enzyme inhibitors. Formal drug-drug interaction 
studies have not been performed with vorinostat. All concomitant medications received within 7 days 
before the first dose of study medication and 30 days after the last dose of study medication must be 
recorded in the source document and on the case report form. 
9.8.1 The  Principal  Investigator  should  be  alerted  if  the  patient  is  taking  any  over  the  counter 
medication or herbal supplements. 


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9.8.2 The concomitant use of other medications/therapies is allowed unless specifically prohibited in 
the protocol. Patients should be stabilized prior to study entry on all medications. 
• Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) have been 
observed in patients receiving vorinostat concomitantly with coumarin derivative 
anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently 
administered vorinostat and coumarin derivatives. 
 
• Patients may not receive chemotherapy, radiotherapy, biological therapy or investigational 
anticancer therapy during the study. Patients who require these therapies should be 
considered to have progressive disease and be withdrawn from the study. 
• Vorinostat should not be administered concomitantly with other HDAC inhibitors (e.g., 
valproic acid) as class-specific adverse reactions may be additive. 
9.9 
Supportive Care Guidelines 
9.9.1 Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes, and general supportive 
care are to be used as clinically indicated. Diagnostic studies needed for good supportive care 
should be performed as clinically indicated. Patients who experience indigestion or 
gastroesophageal reflux symptoms on vorinostat may be treated with Proton Pump Inhibitors 
(PPIs) as well as H2 blockers as clinically indicated. 
9.9.2 Growth factors are not to be used routinely in patients on this study. Administration of filgrastim 
in patients with serious neutropenic complications such as sepsis syndrome, fungal infection, etc. 
may be administered at the investigator’s discretion. Use of filgrastim should be discussed with 
the Study Principal Investigator prior to its use, but should only be administered if clinically 
warranted. 
9.9.3 Use of corticosteroids as anti-emetics is contraindicated. 
9.9.4 There is no contraindication to administration of anti-emetics for the subjects. 
9.9.5 Patients will be permitted to receive appropriate supportive care measures as deemed necessary 
by the treating physician including but not limited to the items outlined below: 
• Diarrhea: Diarrhea should be treated promptly with appropriate supportive care, including 
administration of an anti-diarrheal agent according to standard practice guidelines for 
loperamide. The anti-diarrheal agent loperamide should not be taken prophylactically. 
Patients should be instructed to begin taking the anti-diarrheal agent loperamide at the first 
sign of: 1) poorly formed or loose stool, 2) occurrence of more bowel movements than usual 
in one day or 3) unusually high volume of stool. Loperamide should be taken in  the 
following manner: 4 mg at first onset of diarrhea, then 2 mg after each unformed stool. The 
daily dose of Loperamide should not exceed 16 mg/day. Loperamide should be deferred if 
blood or mucus is present in the stool or if diarrhea is accompanied by fever. In this setting, 
appropriate diagnostic microbiologic specimens should be obtained to exclude an infectious 
etiology. Patients should also be advised to drink liberal quantities of clear fluids to help 
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• Nausea/vomiting: Nausea and vomiting should be treated aggressively, and strong 
consideration should be given to the administration of prophylactic antiemetic therapy 
according to standard institutional practice. In particular, the use of anti-emetics including 
5HT3 antagonists and/or aprepitant is encouraged. Patients should be strongly encouraged to 
maintain liberal oral fluid intake during therapy, especially during the initial 14 days of each 
treatment cycle. 
 
• Anemia: Transfusions may be used as clinically indicated for the treatment of anemia, but 
should be clearly noted as concurrent medications. 
• Neutropenia: Prophylactic use of colony-stimulating factors including G-CSF, pegylated G- 
CSF or GM-CSF should not be used during the first cycle of therapy. This must be discussed 
with the Study Principal Investigator prior to institution of this modality. 
Factors may be used if clinically indicated in subsequent cycles as outlined in the guidelines 
for dose modification. This must be discussed with the Study Principal Investigator. 
• Thrombocytopenia: Transfusion of platelets may be used if clinically indicated in a manner 
consistent with the guidelines for dose modification. 
• Hyperglycemia: Hyperglycemia has been observed in patients receiving vorinostat. Serum 
glucose should be monitored. Adjustment of diet and/or anti-hyperglycemic therapy may be 
necessary. 
• Electrolyte Disturbances: Hypokalemia or hypomagnesemia should be corrected prior to 
administration of vorinostat, and consideration should be given to monitoring potassium and 
magnesium in symptomatic patients (e.g. patients with nausea, vomiting, diarrhea, fluid 
imbalance or cardiac symptoms.) 
9.10 
Duration of Therapy 
In the absence of treatment delays due to adverse events and as long as the patient has optimal response 
(stable disease or greater), treatment may continue up to 1 year or until one of the following criteria 
applies: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• 
Pregnancy 
 
9.11 
Duration of Follow Up 
For patients removed from study due to disease progression or unacceptable toxicity, a follow-up period 
of 30 days from the last dose of protocol therapy will be required. Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse event. 


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Patients that achieve an objective response will be followed every 3 months or until another treatment is 
administered. 
 
 
 
 
 
9.12 
Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed in Section 9.7 and 13.0 apply. The 
reason for study removal and the date the patient was removed must be documented on the Case Report 
Form 
9.13 
Dosing Delays/Dose Modifications 
Therapy will be held for patients who experience ≥ grade 3 non-hematologic toxicities related to therapy 
until resolution or return to baseline. If dosing is delayed >3 weeks, the patient will be removed from 
study. 
9.13.1 Dose Modification Plan (Phase I Component only) 
Patients who experience a DLT may be retreated with doses of vorinostat reduced by one level for a 
maximum of 2 dose level reductions. There will be no dose re-escalations. All toxicity from the higher 
dose level must have resolved prior to re-treatment at a lower dose level. Patients who respond to 
therapy but experience a DLT may continue to receive vorinostat at a lower dose level until intolerable 
toxicity is encountered or until the patient experiences progressive disease regardless of the duration of 
treatment. 
9.13.2 Dose Modification for Toxicity Not Considered to be DLT (Phase I Component only) 
Following the occurrence of any Grade 3 toxicity with the exception of neutropenia, thrombocytopenia, 
leukopenia, lymphopenia and anemia that does not constitute a DLT, vorinostat will be held until there 
is resolution to < Grade 1 or return to baseline. Patients whose treatment is re-started after a dose delay 
for transient toxicity will continue at the original dose and frequency. In this manner, the whole schedule 
will be moved forward in time but the interval between subsequent doses will not change. Thus, in the 
absence of disease progression or DLT, the effect of schedule interruption will be to reduce the dose 
intensity without reducing the total dose. If dosing is delayed for > 3 weeks, the patient will be removed 
from the study. 
 
10.0     EVALUATION DURING TREATMENT/INTERVENTION 
 
Studies required for patients enrolled on this study are summarized in the table below. The following 
studies will be performed in all patients. Cycle 1, week 1 complete physical exam, laboratory 
evaluations and EKG evaluations do not need to be repeated if completed within 72 hours of treatment. 
10.1 
A complete physical examination to be completed weekly and as clinically indicated, to include: 
vitals (HR, RR, BP, Temp), and all current medications will be documented. 
10.2 
Height, weight, BSA, and performance status will be collected at the beginning of each cycle 


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prior to receiving treatment. 
10.3 
The following laboratory studies will be obtained weekly: complete blood count w/diff, PT/PTT 
(with INR), fibrinogen, LDH, chemistry panel including the following components: albumin, 
alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
phosphorus, potassium, total protein, SGOT(AST), SGPT(ALT), and sodium. 
10.4 
Post-treatment samples for correlative studies conducted on peripheral blood and bone marrow 
specimens are described below. 
10.5 
An EKG will be performed prior to every cycle of therapy. If the EKG is performed within 72 
hours of starting each cycle, then a repeat EKG does not need to be performed. 
10.6 
An extent of disease evaluation should be performed to assess the primary tumor and sites of 
metastatic disease including radiologic studies appropriate for the disease (i.e. CT, MRI, PET, 
bone scan, chest x-ray, etc.) as defined in section 12.0. 
Disease assessment must be completed at a POETIC institution. For collaborating non-POETIC 
institutions, the reviews may be done by an institutional radiologist. PET imaging will  be 
obtained as a correlative study in all patients for whom this imaging study is standard of care 
and who have PET capability at their site. For these patients, it is recommended that a baseline 
PET scan be performed as part of the pre-treatment extent of disease evaluation and that the PET 
scan be repeated after the second cycle of treatment for this analysis. While these scans are 
recommended, they are not required for study entry. 
10.7 
In the event that a patient's condition is deteriorating due to disease progression, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the first and all subsequent 
cycles of therapy. 


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REQUIRED OBSERVATIONS 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 10 
(Every 3 weeks) 
Final Visit 
 Vorinosta a 
t 
X 
X 
X 
X 
 Etoposide b 
X 
X 
X 
X 
 Informed consent 
X 
 Demographics 
X 
 Medical history 
X 
 Concurrent meds 
X 
X --------------------------------------------------------------------------------------------- X 
X 
 Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (weekly) 
X 
 Vital signs (HR, RR, BP, Temp) i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (weekly) 
X 
 Height,  Weight,  BSA,  Performance 
status i 
X 
X 
X 
X 
X 
X 
 CBC w/diff, Fibrinogen, 
PT/PTT/PT(INR) i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Serum/Plasma chemistryc, i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 EKGg 
X 
X 
X 
X 
X 
X 
 B-HC  d 
G 
X 
 Adverse event evaluation 
X 
X --------------------------------------------------------------------------------------------- X 
X 
 Radiologic evaluations/ 
Tumor measurements 
X 
Tumor measurements are repeated > 4 and < 6 from the start of the 
first cycle of Documentation (radiologic) must be provided for 
patients removed from study for progressive disease. 
e 
X 
 MSAS ( for ages 10-18) optional 
X 
MSAS is to be completed between > 4 and < 6 weeks from the start of 
the first cycle of treatment 
 PET scan (if applicable to disease) 
optionalh 
X 
Radiologic measurements should be performed > 4 and < 6 weeks 
after the 1st 2 cycles then every 6 weeks. 
e 
X 
 Archival tissue or fresh tissue biopsy 
for expression profiling (required) f 
X 
X 
 Blood and/or Bone marrow for 
expression profiling (optional) f 
X 
X 
 Histone Phosphorylation Profiling 
(optional) f 
X 
X 
 Blood and/or Bone marrow for 
Histone Acetylation (optional) f 
X 
X 


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Evaluations in patients who experience treatment delays 
In the event of a treatment delay, the timetable for the evaluations above will be modified so that studies 
are performed at the times appropriate relevant to drug administration. Height, weight, vital signs, and 
performance status will be checked and documented during weeks in which drug is administered. The 
body surface area will be re-calculated every cycle and the dose adjusted if there is a 10% change in 
body weight. Physical examinations will also be performed and documented during weeks in which drug 
is administered. Laboratory studies as shown in the table will be performed on a weekly basis during 
weeks in which drug is administered and during the following weeks. In the event of treatment delay, 
laboratory studies will be performed at additional time-points as needed for good patient care. 
Radiographic assessments will be performed after every 2 cycles of therapy. 
10.8     Correlative/Exploratory Studies 
The study will incorporate biologic correlative studies to evaluate the following: histone acetylation, 
gene expression profiling, and histone phosphorylation profiling. It is hoped that incorporation of these 
correlative studies will enhance our understanding of histone deacetylation in pediatric patients with 
refractory solid tumors treated with the proposed novel combination, vorinostat and etoposide. All 
correlative studies are optional, but are strongly encouraged to be collected. 
10.8.1  Histone Acetylation 
The processing of the peripheral blood and if possible bone marrow samples from patients with > 25% 
tumor involvement will be carried out in the laboratory of Dr. Robert Arceci at Ron Matricaria Institute 
of Molecular Medicine at Phoenix Children’s Hospital, an expert in the molecular pharmacology of 
histone acetylation. Dr. Arceci has an experienced laboratory for analysis of histone acetylation and was 
a critical collaborator in the development of vorinostat. Processing the samples at Dr. Arceci’s lab will 
ensure consistent sample handling and high quality data. Collection of blood and bone marrow is an 
important part of this study and whenever possible should be collected at the time points indicated 
below. 
Sample Collection Time Points 
Five mL of peripheral blood and five mL of bone marrow aspirate specimen if indicated (bone marrow 
with > 25% tumor involvement), will be obtained in a sodium heparin tube prior to treatment with 
Vorinostat and Etoposide and 24 H following the first dose of vorinostat if consent for this procedure is 
obtained. 
Sample Collection Procedure and Handling 
a: Vorinostat: Dose as assigned; Po Days 1-4 of every 21 day cycle ( Vorinostat to precede Etoposide exactly 4 H on the day of administration of Etoposide ) 
b: Etoposide:  Dose as assigned; IV Days 3-5 of every 21 day cycle 
c:  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium. 
d: Serum pregnancy test (women of childbearing potential) 
e:  Final visit evaluations 
f:  Collection procedures for the pre study and 24 hour collection for Histone expression profiling, Histone acetylation, Histone phosphorylation profiling are described in Section 10.8 
and in Appendices II; III; VII 
g: If baseline EKG is performed within 72 hours of starting treatment, then the Cycle 1 EKG does not need to be performed. This may apply for all subsequent cycles prior to treatment 
with vorinostat. 
h: The PET scans taken for regular radiologic disease evaluation at baseline and Cycle 2 will also be used for the correlative study component. 
i: If the baseline assessment is completed with 72 hours of starting treatment, then cycle 1, week 1 assessment does not need to be performed. 


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Phase I Component: For the first six patients enrolled on trial, the blood will be collected and handled 
in the following manner. One sample of peripheral blood will be collected, submitted, and shipped 
immediately without processing to the laboratory listed below. The second sample with be processed 
Ficoll Hypaque and flash frozen then shipped to the lab listed below (See Appendix VIII for Ficoll 
Hypaque process for whole blood). 
Phase II Component: All patients in the phase II component of the trial, blood will be collected and 
handled in the following manner. One sample of peripheral blood and bone marrow if indicated (bone 
marrow with > 25% tumor involvement) will be collected without processing and shipped immediately 
to the laboratory listed below. These samples are to be collected prior to receiving treatment and 24 
hours following the first dose of vorinostat. 
Samples should be obtained and shipped Monday through Thursday via overnight delivery to: 
Robert J. Arceci, M.D, PhD 
C/O David Lee 
Department of Child Health 
University of Arizona, College of Medicine-Phoenix 
Ron Matricaria Institute of Molecular Medicine 
At Phoenix Children’s Hospital 
445 N. 5th Street 
TGen Building, 3rd Fl, Room 322 
Phoenix, AZ 85004 
Phone: 602-933-0920 
Fax: 
602-933-0276 
E-mail: rarceci@phoenixchildrens.com 
 
10.7.1  Gene Expression Profiling 
The processing of archival tumor or fresh tissue biopsy (if available), and peripheral blood samples 
(including bone marrow if > 25% tumor involvement) for gene expression profiling of will be carried 
according to established procedures. These samples will be shipped to Dr. Aru Narendran at the address 
listed below, but the processing will be carried out by Dr. Olga Kovalchuk at the University of 
Lethbridge to ensure consistent sample handling and high quality gene expression data. Collection of 
peripheral blood (including bone marrow if > 25% tumor involvement), and archival tumor or fresh 
tissue biopsy (if available) samples for expression profiling is an important part of this study and will be 
collected at the time points indicated below. 
To ensure that these samples are obtained at the correct time, the vorinostat dose will be administered in 
the clinic on Cycle 1only. The time of the vorinostat dose and sample collection must be recorded. Refer 
to Appendix II for detailed methodology. Refer to Appendix II for the detailed sample collection 
procedure for peripheral blood. 
 
Sample Collection Time Points 
Formalin-Fixed Paraffin-Embedded Tissue and RNAlater™ Preserved Tumor Biopsy (Required) 


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It is required that patients have archival tumor samples available. Archival tumor samples may be from 
original diagnosis and/or any subsequent biopsy material. Whole formalin-fixed paraffin embedded 
tissue from patient’s original diagnosis and/or any subsequent biopsy material tissue must contain a 
tumor specimen measuring at least 0.5cm x 0.5cm x 100 microns. If the blocks cannot be sent to for 
sectioning, then sections from the blocks will be accepted. At least six sections measuring 10 microns 
and ten sections measuring 4 – 5 microns should be provided. 
 
 
Fresh Tissue Biopsy 
For patients that do not have an archival tissue or prior biopsy available, a fresh tissue biopsy may be 
obtained in patients who have an accessible site for biopsy and for whom informed consent is obtained 
for this procedure. These samples will be obtained prior to treatment with vorinostat and 24 hours 
following the first dose of Vorinostat. These samples must be immediately placed in a 5 mL cryovial 
containing RNAlater™ after collection 
Peripheral Blood and Bone Marrow (If > 25% tumor involvement) 
The pre-treatment and on-treatment blood samples (2.5 mL each) will be collected in a PAXgeneTM 
RNA collection tube (2 tubes per patient) in all patients. The on-treatment samples will be collected 24 
hours following the first dose of vorinostat. 
Samples should be obtained and shipped Monday through Wednesday via overnight delivery to: 
Dr. Aru Narendran 
Alberta Cancer Research Institute 
HRIC Lab 2a34 
3280 Hospital Drive NW 
Calgary, Alberta 
T2N 4Z6 
CANADA 
Tel: (403) 210-6402 
E-mail: anarendr@ucalgary.ca 
 
10.7.3 Histone Phosphorylation Profiling 
Previous studies have shown that the effects of HDAC inhibitors can be detected in peripheral 
mononuclear cells. In this study, we plan to evaluate phosphorylation profiling using antibody arrays to 
provide target identification and target validation data to monitor the effectiveness of vorinostat. The 
rationale for this approach and the methodology to be used are described in Appendix III. The analysis 
will be conducted in peripheral blood mononuclear cells in Cycle 1 only prior to vorinostat and 24 H 
following the first dose of vorinostat. These studies will be conducted in the laboratory of Aru 
Narendran MD, PhD at Alberta Cancer Research Institute. The address is listed below: 
If patients/guardians give appropriate consent, peripheral blood (2.5 mL) will be collected as described 
in Appendix II. Samples should be obtained and shipped Monday through Wednesday via overnight 
delivery to: 
Dr. Aru Narendran 


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Alberta Cancer Research Institute 
HRIC Lab 2a34 
3280 Hospital Drive NW 
Calgary, Alberta 
T2N 4Z6 
CANADA 
Tel: (403) 210-6402 
E-mail: anarendr@ucalgary.ca 
 
Refer to Appendix III for detailed methodology. 
10.7.4 Positron Emission Tomography (PET) 
Positron emission tomography (PET) will be incorporated into this trial as a correlative study in patients 
with solid tumors to obtain exploratory data about response assessment using this imaging modality in 
pediatric patients. PET is a diagnostic imaging tool that evaluates in vivo biologic changes using 
radiopharmaceuticals that mimic endogenous molecules. Accuracy of tumor assessment has been 
enhanced significantly by using 
18F-fluorodeoxyglucose ([18F]FDG) PET for dynamic imaging of 
response to a variety of regimens used for treatment of adult tumors. There is a paucity of data regarding 
functional imaging in pediatric patients. A secondary objective of this study will be to evaluate 
accumulation prior to and during treatment with vorinostat and etoposide in pediatric patient with solid 
malignancies. 
PET/CT scans will be done at institutions with the capability to perform this imaging study. The 
PET/CT component of this study is not required for enrollment of patients with solid tumors. Solid 
tumors will be imaged with PET/CT at baseline and following completion of the second cycle of 
therapy. 
The results will be compared to baseline PET/CT results. The probability of disease progression over 
time among patients with reduction in the [18F]FDG standardized uptake value (SUV) of 60% or greater 
will be estimated using the method of Kaplan-Meier. PET results will not be used for assessment of 
response according to RECIST criteria but will be used to achieve the secondary study objective to 
correlate alterations in accumulation of [18F]FDG with tumor response. 
The protocol for PET/CT imaging is summarized as follows: Prior to PET/CT scanning, patients will 
fast for 6 hours (except for water). A whole body PET/CT scan will be carried out per institutional 
protocol for whole body evaluation of extent of disease after 15 mCi/1.73 m2 [18F]FDG. Patients will be 
scanned 60 minutes after FDG injection. Imaging will commence immediately after the patient has 
voided. Whole body attenuation corrected images will be obtained per protocol. 
A diagnostic CT scan will be carried out prior to acquisition of the emission PET images. There is no 
breath hold for the CT component. Emission scans are typically carried out from the base of the skull to 
the mid-thigh. About 3 minute acquisition is carried out per field of view (~15 cm). 
Studies are reconstructed using iterative reconstruction and using the non-contrast CT for attenuation 
correction. Attenuation-corrected PET images are visualized concurrently with the CT component. For 
the purpose of this trial, interpreters will not be blinded as to clinical or disease state parameters. Studies 
carried out at baseline (before treatment) and after 2 cycles of treatment with Vorinostat and Etoposide 


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will be comparable especially with respect to time after injection, camera used, and emission and CT 
acquisition parameters. A standardized uptake value (SUV), a semi-quantitative measure of tumor 
uptake of the [18F]FDG adjusted for injected dose and body weight, will be calculated for each lesion. 
The method for calculating tumor uptake is by a differential uptake ratio of FDG in the tumor. It is 
defined as the ratio of the activity per gram within the lesion to the activity per gram if the activity were 
uniformly distributed through the whole patient. See equation below. 
 
SUV = activity/gram ( lesion ) 
activity injected/body weight 
The SUV is obtained from the PET scanner directly for any region drawn on a PET scan image. In more 
depth, the numerator in the above equation is obtained from a region drawn around the lesion on one of 
the PET slices. The PET scanner is calibrated in units of activity per unit volume, and therefore this 
number is obtained automatically. This calibration is performed by medical physics, using a cylinder of 
water into which an exactly known amount of FDG has been added. A PET scan of this cylinder is used 
to determine a calibration factor which converts the counts from the PET scanner directly into activity 
per unit volume. The denominator is the activity injected into the patient divided by the patient weight. 
These numbers are entered into the PET scanner computer by the technologist. Hence the scanner is 
already calibrated to provide SUVs. SUV is a semi-quantitative measure of selective tracer uptake 
within lesions that is independent of the PET scanner upon which it is performed and therefore does not 
vary from center to center. 
Interpretation of changes will follow visual scores (0: no uptake; 1: uptake equal to soft tissue; 2: uptake 
greater than soft tissue, equal to liver; 3: uptake greater than liver) and standardized uptake value (SUV), 
which will be normalized both to overall patient weight and to body surface area. 
 
10.8.5  Exploratory Studies (MSAS) 
 
Please refer to section(s) 3.6 and 4.5 of the protocol. 
 
11.0     TOXICITIES/SIDE EFFECTS 
 
Refer to Section 17.2 
 
12.1 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Response in patients with measurable disease will be assessed by standard criteria. For the purposes of 
this study, patients with solid tumors should be reevaluated every 2 cycles ( > 4 and < 6 weeks from the 
start of the first cycle of treatment). In addition to a baseline scan, confirmatory scans will also be 
obtained 3 weeks following initial documentation of an objective response. If a durable response is 
documented, response will be re-assessed every 6 weeks. 
 
12.2 
Definitions of Response in Patients with Solid Tumors 
Response and progression will be evaluated in this study using the international criteria proposed by the 
Revised RECIST guideline  (version  1.1).[55]  Changes  in  only  the largest  diameter (unidimensional 


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measurement) of the tumor lesions are used in the RECIST guideline. Note: Lesions are either 
measurable or non-measurable using the criteria provided below. The term “evaluable” in reference to 
measurability will not be used because it does not provide additional meaning or accuracy. 
 
 
 
12.2.1 Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 
 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm.) 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must 
be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
 
12.2.2 Non-measurable Disease 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodes with > 
10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly non- 
measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/ abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
 
12.2.3 Target Lesions 
All measurable lesions up to a maximum 2 lesions per organ and 5 lesions in total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be representative 
of all involved organs, and should be those that are suitable for reproducible repeated measurement 
(either by imaging techniques or clinically). If the largest lesion does not lend to reproducible 
measurement, the next largest lesion which can be measured reproducibly should be used. A sum of 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, 
only the short axis is added to the sum. The baseline sum diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
12.2.4 Non-target Lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each 


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should be noted throughout follow-up, in rare instances unequivocal progression can be used. It is 
possible to record multiple non- target lesions involving the same organ as single item (e.g. multiple 
pelvic lesions). 
 
 
 
12.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 4 weeks before the beginning of the treatment. Tumors in a previously irradiated area will be 
considered measurable. 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable 
by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and > 10 
mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation 
by color photography including a ruler to estimate the size of the lesion is suggested. As noted above, 
when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, 
lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at 
a later date and, because they are operator dependent, it cannot be guaranteed that the same technique 
and measurements will be taken from one assessment to the next. If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about 
radiation exposure at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is  not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If markers are 


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initially above the upper normal limit, however, they must normalize for a patient to be considered in 
complete response. Because tumor markers are disease specific, instructions for their measurement 
should be incorporated into protocols on a disease specific basis. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases if 
required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). When effusions are known to be a potential adverse effect of 
treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of 
the neoplastic origin of any effusion that appears or worsens during treatment can be considered if the 
measurable tumor has met criteria for response or stable disease in order to  differentiate  between 
response (or stable disease) and progressive disease. 
 
12.4 
Response Criteria for Patients with Solid Tumors 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
 
Partial Response (PR): At least a  30%  decrease  in  the  sum  of  the  diameters  of  target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of  the  diameters  of  target 
lesions, taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression) 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study. 
 
12.4.2 Evaluation of Non-target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 
10 mm short axis) 
 
NonCR/NonPD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions. (Note: the 


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appearance  of  the  one  or  more  new  lesions  is  also  considered 
progression.) 
 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances the 
opinion of the treating physician should prevail, and the progression status should be confirmed at a later 
time by the Study Principal Investigator. 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
12.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until the end of 
treatment taking into account any requirement for confirmation. The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria (Section 12.3 and 
Section 12.4) 
 
Target Lesions 
Non-target 
Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration.” Every effort should be made to document the objective progression, even after 
discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the 


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evaluation of complete response depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before confirming the complete response status. 
 
12.5 
Confirmatory Measurement/Duration of Response for Patients with Solid Tumors 
12.5.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments obtained 3 weeks after the criteria for response are first met. In the case of SD, follow-up 
measurements must meet the SD criteria at least once after study entry at a minimum interval of 6 
weeks. 
12.5.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (utilizing as reference for progressive disease the smallest measurements recorded since the 
treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR until the 
first date that recurrent disease is objectively documented. 
12.5.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
utilizing as reference the smallest measurements recorded since the treatment started. 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition that render the patient unacceptable 
for further treatment in the judgment of the investigator 
• 
Pregnancy 
 
The Study Principal Investigator must be notified if a patient is taken off study. The specific reason for 
discontinuation of therapy will be noted on case report forms (CRFs). 
 
14.1 
BIOSTATISTICS 
14.2 
Study Design/Endpoints 
14.2.1 Phase I Component 
This trial is a Phase I evaluation of vorinostat and etoposide with the starting dose and schedule as 
described in Section 9.3 The primary study endpoints will be assessment of toxicity based upon the 
determination of toxicity profile of the combination and determination of the MTD, DLT, and RP2D. A 


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minimum of 2 evaluable patients will be entered at each dose level. Patients will be evaluated for 
toxicity within the first cycle (3 weeks) of therapy. Dose escalation will not be considered until at least 3 
patients at a given dose level have completed one course of therapy (e.g. 3 weeks) without a DLT. If a 
patient does not experience a DLT as defined in Section 9.7 but is taken off study due to unacceptable 
adverse events/toxicity, that patient will be considered to have had a DLT for the purposes of dose 
escalation. If therapy is discontinued during the first cycle for reasons other than toxicity, an additional 
patient may be enrolled at the dose level of the off-study patient to ensure adequate evaluation of 
toxicity. 
The following design will be used to determine the MTD. Patients will be treated in cohorts of size 3 
and 6 and the dosage will be escalated if the clinical toxicity is acceptable. The design is constructed to 
reduce the chance of escalating the dose when the probability of DLT is high, an increase the chance of 
escalating the dose when the probability of DLT is low. The MTD is defined as the highest dose level 
with an observed incidence of DLT in no more than 1 out of 6 patients treated at a particular dose level. 
The dose escalation scheme is as follows: 
 
1) If none of initial 3 patients at a given dose level experience DLT, the next dose level is studied 
in another cohort of 3 patients. 
 
2) If 1 of the initial 3 patients at a given dose level experience DLT, up to 3 additional patients 
will be treated at that same dose level. Escalation will continue if one of the six patients 
experience DLT. 
 
3) If two or three patients experience DLT in the first three patients, or two or more patients 
experience DLT in six patients at a given dose level, the MTD will be determined as the 
preceding dose level. 
 
4) If three or fewer patients are treated at a dose under consideration as the MTD, additional 
patients to total six will be treated at that level to confirm the MTD. 
 
The dose escalation scheme provides the following probabilities of escalation based on the true chances 
of DLT at a specific dose level. One can see that the probability of escalation is high if the toxicity risks 
are low. 
 
True Probability of Toxicity: 
.10 .20 .30 .40 .50 .60 
Probability of Escalation: 
.91 .71 .49 .31   .17 
.08 
 
When the MTD is reached, the additional cohort of 3 patients will be recruited at this dose to allow for 
greater confidence in estimating the toxicity rate in this patient population (RP2D). If none of the 9 
patients treated at the MTD experience a DLT, then we are 90% confident that the probability of a toxic 
event in this patient population is less than 0.23. However, if 3 or more DLTs are observed, the 
approximate 95% lower confidence bound on the probability of a DLT is 0.12, indicating unacceptable 
toxicity. If 3 or more DLTs occur in 9 patients, we will recommend the next lower dose level for further 
evaluation of this therapy, which would then be the recommended Phase II dose. This trial will require a 


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minimum of 2 patients. The maximum number of patients needed depends on the dose level reached. An 
interim safety analysis of the data in the Phase I component will be completed prior to starting the Phase 
II component. Although not a primary objective of this portion of the study, proportion of patients with 
response will be calculated. 
 
14.2.2 Phase II Component 
The primary endpoint of this component will be to evaluate the efficacy of the novel combination, 
vorinostat and etoposide, in the treatment of recurrent or refractory childhood malignancies with 
recurrent or refractory sarcoma. Efficacy is defined as a binary endpoint (CR+PR versus neither) after 2 
cycles of treatment. We will use a minimax Simon two-stage design. Treatment of pediatric solid tumors 
with etoposide only results in approximately 20% response rate, however the disease type specific 
response rates are variable (osteosarcoma 9%, soft tissue sarcoma 8%, rhabdomyosarcoma 19%, and 
Ewing’s sarcoma 40%). These 4 disease groups account for 20-30%, 10-20%, 30% and 30% of pediatric 
sarcomas respectively. Due to highly variable response rates and possible variability in number of 
recruited patients with specific sarcoma type, we have chosen an unpromising overall response rate to be 
15%. The promising response rate is 35%. Initially we will recruit 15 patients. If there are 2 or fewer 
responses, the trial will terminate and the combination therapy will be deemed unpromising. If there are 
3 or more responses among 15, enrollment will be extended to 28 patients. If 8 or more responses are 
observed among 28 patients, the trial will be considered to have a positive result. If there are 7 or fewer 
responses, the combination therapy will be considered unpromising for further study. The design allows 
early termination of the study due to inefficacy. The probability of early termination is 60% if the true 
treatment response is 15%. This design will effectively discriminate between true response rates of 
<15% and >35% with a type I error of 5% and power of 80%. Upon the completion of the study, the true 
response rate will be estimated as an observed rate, and the exact confidence interval will be 
constructed. Response rate within different sarcoma types will also be calculated. 
 
14.3 
Sample Size/Accrual Rate 
14.3.1 Phase I Component 
Review of data from the participating institutions regarding numbers of relapsed patients as well as 
accrual to Phase I studies indicates that 2-3 patients per month may be accrued. It is anticipated that 18- 
25 patients will be accrued. This will permit completion of the study within 1 year. Upon completion of 
the phase I component, an interim safety analysis will be performed before determination of the 
recommended Phase II dose of the combination. 
 
14.3.2 Phase II Component 
Review of data from the participating institutions regarding numbers of relapsed patients as well as 
accrual to Phase I studies indicates that 2-3 patients per month may be accrued. It is anticipated 
approximately 28 patients will be accrued. This will permit completion of the study within 1 year 
 
 
 
14.4 
Correlative Analysis 


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This study will incorporate biologic correlative analyses conducted in the phase I and II setting to 
evaluate the following: histone acetylation, gene expression profiling and cellular phosphorylation 
profiling. These markers will be correlated with tumor response and clinical characteristics using 
Wilcoxon rank sum test for continuous variables and Fisher exact test for binary variables. Descriptive 
statistics will be used to summarize the data at different time points. 
A standardized uptake value (SUV), a semi-quantitative measure of tumor uptake of the [18F]FDG 
adjusted for injected dose and body weight, will be calculated for each lesion using PET scan. The 
association of SUV with tumor response will be tested using Wilcoxon rank sum test. 
 
14.5 
Exploratory Analysis of symptom distress survey 
It is expected that ¾ of all patients will be of the age 10-18 and will participate in the MSAS exploratory 
studies. The Statistical Package for the Social Sciences (SPSS, Version 17 for Windows) will be used to 
analyze the data regarding symptom distress. To test the research question in this study, the total MSAS 
scores and their subscales will be used. Descriptive statistics like mean, median and inter-quartile range 
will be calculated and compared across time. All variables will be examined for outliers through 
frequency distributions, measures of central tendency and skewness. Although comparisons will be 
made at each time point, the primary time points for evaluation are at baseline and at the time of the first 
three radiographic evaluations. Intraclass correlation (ICC) of the MSAS will be used to calculate the 
test. 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.2 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain written informed consent, by following procedures defined in Section 18.0, Informed Consent 
Procedures. 
During the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. 
All patients must be centrally registered at the POETIC Data and Coordinating Center (DCC) located at 
Memorial Sloan-Kettering Cancer Center. Registrations will be handled by the Research Study Assistant 
(RSA) at the POETIC DCC. The contact telephone number is (646) 888-5714/5715 and the fax number 
is (646) 888-5726. Registrations will occur between 9:00 am and 5:00 pm Eastern Standard Time (EST), 
Monday through Friday and will include review of the signed consent form, HIPAA research 
authorization form, eligibility checklist, and eligibility source documentation. The RSA will also verify, 
via a FAX/email copy, that the written informed consent is obtained and dated prior to subject entry on 
the study. 
The participating site must contact the RSA at the POETIC DCC to reserve a slot on the protocol when a 
patient is being considered for a trial. To begin a registration, the participating site must fax/email the 
signed consent form and HIPAA research authorization to the RSA within 48 hours of the patient 
signing consent. To complete the registration, the completed eligibility checklist, and eligibility source 


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documentation must be sent to the RSA at the DCC via fax/email prior to protocol treatment or any 
research tests. 
All research participants are registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center by the DCC RSA. PPR is available Monday through Friday 
from 8:30 am - 5:30 pm. Registrations must be sent to the POETIC DCC and the RSA at MSKCC will 
verify eligibility and complete the registration with the PPR Office. Registration documents must be sent 
directly to the DCC prior to 4:00 PM to ensure timely processing, so that enough time is allowed for 
source verification. If a registration is sent to the DCC after 4:00PM, all efforts will be made to have the 
patient registered that day, but it cannot be guaranteed that a patient will be registered that day. 
Once eligibility has been established and the participant is registered, the participant will be assigned an 
MSKCC Clinical Research Database (CRDB) number (protocol participant number). This number is 
unique to the participant and must be written on all data and correspondence for the participant. This 
protocol participant number will be relayed back to study staff at the registering site via e-mail and will 
serve as the enrollment confirmation. 
Written consent must be documented on the appropriate consent form and Research Authorization 
designated and approved by the Institutional Review Board at the institution at which the patient is 
enrolled. The following Principal Investigators or their designated Co-Investigators may obtain informed 
consent: 
 
 
 
 
 
 
 
 
 
 
 
15.2Randomization 
Tanya Trippett, MD 
Patrick Brown, MD 
Jessica Boklan, MD 
Lia Gore, MD 
Cynthia Herzog, MD 
Suzanne Shusterman, MD 
Lisa McGregor, MD,PhD 
Tony Truong, MD 
Gregory Hale, MD 
Kathleen Neville, MD 
Amy Smith, MD 
This study does not include randomization. 
16.1 
DATA MANAGEMENT ISSUES 
16.2 
Data and Coordinating Center (DCC) 
The Research Study Assistant (RSA) at the POETIC DCC will be assigned to the study. The 
responsibilities of the RSA include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problems and prioritization. The Clinical Research Coordinator, (CRC) 
is responsible for coordination between the RSA and Research Staff at the following member 
institutions: All Children’s Hospital, MD Anderson Cancer Center, Phoenix Children’s Hospital, Sidney 
Kimmel Cancer Center (Johns Hopkins Medical Center), Alberta Children’s Hospital, Children’s 
Hospital Colorado, Pennsylvania State University College of Medicine, Dana-Farber Cancer Institute, 


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Children’s Mercy Hospital & Clinics and Arnold Palmer Hospital for Children/ MD Anderson Cancer 
Center Orlando. The CRC at the POETIC DCC will also serve as the liaison among all staff involved 
including the principal investigators, attending physicians, and nurses. 
Case report forms (CRFs) will be drafted in a standard format and will be provided to each participating 
institution by the DCC. Required study tools for each protocol including correlative studies, vital signs, 
drug administration and protocol evaluations will also be provided to each participating institution by 
the DCC. The participating Site PI is responsible for ensuring these forms are completed accurately and 
legibly. The Site PI is also responsible for ensuring that all CRFs, study tools, and corresponding source 
documentation are to the DCC one week after the completion of each cycle. 
The data collected for this study will be entered into a secure database by the RSA at the POETIC DCC. 
Data will be collected, stored, and monitored at an institutional level via the Clinical Research Database 
(CRDB) system. Data will be provided from CRDB to protocol-defined sponsors (CTEP, FDA, etc.) as 
required, through the Data Management Resource Division, a division of the Office of Clinical 
Research. 
Source documentation will be available to support the computerized patient record and must be 
submitted with the case report forms and required study tools. Case report forms will not be considered 
source documentation. 
 
• Variables that will be recorded include the patient's birth date, date of diagnosis, date of 
study entry and histologic diagnosis. 
• The results of the pretreatment and end of therapy evaluations, including the extent of 
disease evaluation (history, physical examination and imaging studies), baseline 
laboratory values, renal and hepatic function, as defined per protocol, will be recorded. 
• All study related treatment data and concomitant drugs will be recorded. 
• The presence of toxicity at baseline, during and for 30 days after administration of the 
investigational agent will be monitored and recorded. 
• The results of the extent of disease evaluation (history, physical examination and imaging 
studies) following each course of treatment will be recorded. 
• The patient's disease status and last follow-up will be recorded. If disease progresses or 
recurs, the results of the repeat extent of disease evaluation will be recorded. 
 
16.3 
Site Research Staff 
Research staff will be assigned at All Children’s Hospital, MD Anderson Cancer Center, Phoenix 
Children’s Hospital, Sidney Kimmel Cancer Center (Johns Hopkins Medical Center), Alberta Children’s 
Hospital, Children’s Hospital Colorado, Pennsylvania State University College of Medicine, Dana- 
Farber Cancer Institute, Children’s Mercy Hospital & Clinics and Arnold Palmer Hospital for Children/ 
MD Anderson Cancer Center Orlando. Their responsibilities will include project compliance, data 
collection, abstraction and entry, data reporting, regulatory monitoring, problems and prioritization, 
maintaining file documentation of data for the clinical trial, pharmacokinetic or other biologic 
correlative study collection, and analysis as outlined for each patient enrolled on study. They will also be 
responsible for maintaining a regulatory binder for each protocol. The designated research staff will also 


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be responsible for submitting the data on a weekly basis by fax or mail to the RSA at the DCC. Case 
report forms and required study tools along with supporting source documentation should be 
faxed/emailed or mailed to the address below, one week after the completion of each study cycle: 
 
POETIC Data and Coordinating Center 
Memorial Sloan-Kettering Cancer Center 
405 Lexington Avenue, Rm 3-512 
New York, NY 10174 
Telephone: 646-888-5714/5715 
FAX: 646-888-5726 
 
16.4 Administrative Support 
The protocol will be conducted as a single research study effort and data from each participating 
institution will be included in the analysis of results. 
The Study Principal Investigator will be responsible for the conduct of the study, the monitoring of the 
progress of the study, and review of all case report forms from each participating institution. 
Failure to submit required forms in the timelines requested will result in suspension of accrual privileges 
at a given site until data is updated, and/or withholding of contract payments if applicable. 
 
Initial Protocol Submission 
Prior to implementing this protocol, informed consent form, HIPAA authorization and any other 
information pertaining to participants must be approved by the MSKCC IRB/PB. Prior to implementing 
this protocol at the participating centers, approval must be obtained from the participating center’s Local 
IRB of Record. The following documents must be provided to MSKCC before the participating site can 
be initiated and begin enrolling participants: 
 
• Local IRB of Record approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 
• Local IRB of Record membership 
• Local IRB of Record’s Federal Wide Assurance number and OHRP Registration number 
• Curriculum vitae and medical license for each investigator and consenting professional 
• Documentation  of  Human  Subject  Research  Certification  and  HIPAA  training  for 
investigators and key staff members 
• Signed and dated FDA Related Forms 1572/1571 (if applicable) 
• Lab Certifications and Reference Ranges for each lab listed on the 1572 
•Appropriate financial disclosure forms. 
 
Protocol Amendments/Status Changes 
Each change to the protocol must be organized and documented by the POETIC DCC. After IRB 
approval at the lead institution, the POETIC DCC will distribute the amendment to the participating 
institutions, for submission to their local IRB within 60 days of the amendment date. The participating 


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sites will ensure that documentation for all IRB approved amendments are sent to the DCC and are 
maintained in the regulatory binder. This documentation will include the IRB approval letter referencing 
the protocol version date and amendment number, IRB approved protocol, IRB approved appendices 
and IRB approved consent forms. 
The amendment will be written so that no other institution will need to reformat the information but can 
simply copy and distribute. An amendment memo as well as highlighted and clean copies of the 
protocol, appendices and consent forms will be distributed to the participating sites. The consent form 
will be a sample which may be edited in order to adhere to local IRB guidelines. The amendment must 
be submitted at each site to the IRB for review and approval before patients can be enrolled on the study 
and within 60 days of the amendment version date. The amendment number and version date will also 
be displayed on each amendment. 
16.5 
Additional IRB Correspondence 
Annual re-approval 
Annual re-approval from the participating center’s Local IRB of Record must be submitted to the DCC 
at the time re-approval is granted. The most current approved version of the consent form should also be 
submitted to MSKCC at that time. Failure to submit the re-approval will result in suspension of accrual 
privileges. 
 
Deviations and Violations 
All deviations should be discussed with the Study Principal Investigator prior to submission to the Local 
IRB of Record. Deviation requests and approvals will then be forwarded to the DCC. 
For protocol violations, the participating site should report to the violation to Dr. Tanya Trippett, the 
Director of the POETIC DCC, as soon as possible. Dr. Trippett will in turn report the violation to the 
MSKCC IRB/PB. 
Participating sites should report deviations and violations to the Local IRB of Record as they occur, per 
institutional standards. Approvals/acknowledgments from the Local IRB of Record for protocol 
deviations and violations should be submitted to POETIC DCC as received. 
 
Other correspondence 
Participating sites should submit other correspondence to their local IRB of Record according to local 
guidelines, and submit copies of that correspondence to MSKCC. 
16.6 
Quality Assurance 
Quality assurance is a central responsibility of the POETIC DCC and it will be achieved by frequent 
review, constant oversight, and input from objective advisors. Each project will maintain a steering 
committee which will meet in conference call on a weekly basis to critically review the scientific 
progress of the clinical trial. The steering committee will include the principal investigators, research 
staff, and the biostatistical support team under the direction of Dr. Irina Ostrovnaya. Conference calls 
will also occur bi-weekly between the DCC and the Study Principal Investigator to discuss the trial. 
Case Report Forms with accompanying source documents must be provided to the DCC to ensure that 


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real-time monitoring can be accomplished. Queries will be generated by the DCC as needed if questions 
arise, and prompt responses are requested back to the DCC. Internal audits will be conducted by the 
DCC. Audits may be accomplished in one of two ways: (1) source documents and research records for 
selected patients are brought from participating sites to the DCC for audit, or (2) selected patient records 
may be audited on-site at participating sites. These audits will be performed by persons who are 
qualified by training and experience to monitor the progress of the investigation. During these audits the 
following activities will take place: 
 
 Review regulatory binders for protocol documentation; 
 Ensure that case report forms are source data verified according to the monitoring plan; 
 Verify drug accountability is complete and accurate; and 
 Verify compliance to GCPs, ICH guidelines, FDA regulations, and applicable SOPs. 
 
If there is ever an audit at the DCC, then the DCC is responsible for having all source documents, 
research records, all IRB approval documents, Drug Accountability Record Forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
 
16.7 
Data and Safety Monitoring 
The Data and Safety Monitoring Committee (DSMC) under the direction of Dr. Robert Motzer and 
Bonnie Edelman, Manager, will be responsible for monitoring the data safety of the open and closed to 
accrual protocols sponsored by POETIC. The DSMC meets quarterly, and will review data quarterly, 
semi annually or annually based on the risk level of the protocol. A copy of the MSKCC Data and 
Safety Monitoring Plans is on file at the Data and Coordinating Center. 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were initially 
created and approved by the National Cancer Institute in September 2001. The DSM Plans at MSKCC 
were established and are monitored by the Office of Clinical Research. The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data 
and 
Safety 
Monitoring 
of 
Clinical 
Trials” 
which 
can 
be 
found 
at:  
http://cancertrials.nci.nih.gov/clinicaltrials/conducting/dsm-guidelines. The MSKCC Data and Safety 
Monitoring Plans can be found on the MSKCC Intranet at: http://mskweb2.mskcc.org/irb/index.htm. 
The Data and Safety Monitoring Committee (DSMC) monitors all Phase I and II clinical trials and 
reports to the Research Council and Institutional Review Board. 
16.8 Therapeutic Response Review 
The Therapeutic Response Review Committee (TRRC) is MSKCC’s independent response review 
committee which annually evaluates therapeutic responses for participants in IRB/PB approved clinical 
trials where therapeutic efficacy is a stated primary objective, typically phase II and III trials. The 
process, done in an unbiased blinded fashion, ensures the data from the institution’s therapeutic trials 
clinical research program is verified and vetted. Studies monitored by the TRRC include NCI-NIH, in- 
house, industrial trials, and multi-center trials where MSKCC is the coordinating center, which are not 
reviewed by an outside independent therapeutic response review board. 
MSKCC’s  TRRC  review  will  serve  as  the  committee  that  may  review  and  confirm  responses  of 


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POETIC patients. The TRRC will possibly randomly select cases on an annual basis. If a patient is 
selected to be reviewed by the TRRC, the clinical site will be notified by the DCC with the required 
materials to be submitted to the committee and timeframe of submission. 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
17.2 
Privacy 
All institutional, FDA, and NCI requirements for human subjects must be met. This study will be carried 
out in compliance with the regulations of the Health Insurance Portability and Accountability Act 
(HIPAA). Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH. The POETIC DCC is responsible for assuring that each 
participating institution has an OHRP assurance and must maintain copies of IRB approvals from each 
participating site. The DCC is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
The risks and benefits of participation in this study will be reviewed with the patient and/or parent/legal 
guardian. 
Enrollment on this study is on a voluntary basis and every effort will be made to maintain privacy and 
confidentiality. The patient's records will be confidential. Only authorized individuals or agencies may 
inspect the records. No identifying information will be used in reports or publications resulting from this 
study. 
17.3 Serious Adverse Event (SAE) Reporting 
The Study Principal Investigator is responsible for monitoring the safety of patients who enroll in the 
study. All adverse events (AEs) and Serious Adverse Events (SAEs) occurring after any administration 
of the study drug regardless of drug attribution will be followed to the end of the study including 30 
days after the last administration of the study drug, as well as any SAEs designated possibly, probably, 
or definitely related to treatment that occur greater than 30 days. 
 
The descriptions and grading scales found in the revised NCI Common Terminology  Criteria  for 
Adverse Events (CTCAE) version 4.0 will be used for adverse event and serious adverse event 
reporting. All participating sites 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/reporting/ctc.html). 
The Study Principal Investigator is required to report all adverse events that occur during the clinical 
study starting with the first dose of study drug throughout 30 days of stopping the investigational agent. 
Severe adverse events must be reported to the appropriate protocol-defined study sponsors. Serious 
adverse events must be reported either by telephone or in person to the Study Principal Investigator, 
DCC, and local IRB within 24 hours of knowledge of their occurrence. A written SAE report including 
source documentation must be sent to the Study Principal Investigator and DCC within another 3 
calendar days, using the Serious Adverse Event case report form. Additionally, the Study Principal 
Investigator is responsible for submitting follow-up reports for all SAEs regarding the patient’s 
subsequent course until the SAE has resolved or until the patient’s condition stabilizes (in the case of 
persistent impairment), or the patient dies. 


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A serious adverse event (SAE) is any adverse drug experience that occurs at any dose that results in any 
of the following outcomes: 
 Death. 
 Life-threatening adverse drug experience. 
 Requires inpatient hospitalization or prolongation of existing hospitalization grade 2 and above. 
 For the purpose of this study, hospitalizations for protocol-scheduled procedures, blood 
product transfusions, or for social reasons (ie, awaiting transport home) will not be 
considered SAEs. 
 Persistent or significant disability/incapacity. 
 A congenital anomaly/birth defect. 
 Requires medical or surgical intervention to prevent one of the outcomes listed above. 
 
Reporting requirements for adverse events that occur on treatment and within 30 days1 of the last dose 
of study drug 
 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 
4 & 5 
Unexpected 
and Expected 
with or with-out 
hospitalization 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
and 
Expected 
with 
Hospitaliza 
tion 
without 
Hospitaliz 
ation 
with 
Hospitaliza 
tion 
without 
Hospitaliz 
ation 
with 
Hospitalizati 
on 
without 
Hospitalizati 
on 
with 
Hospitalizati 
on 
without 
Hospitalizati 
on 
Unrelated 
Unlikely 
Not 
Required 
SAE 
Report 
Required 
Not 
Required 
SAE 
Report 
Required 
Not 
Required 
SAE Report 
Required 
Not 
Required 
SAE Report 
Required 
Not 
Required 
SAE Report 
Required 
Possible 
Probable 
Definite 
Not 
Required 
SAE 
Report 
Required 
SAE 
Report 
Required 
SAE 
Report 
Required 
Not 
Required 
SAE Report 
Required 
SAE Report 
Required 
SAE Report 
Required 
Not 
Required 
SAE Report 
Required 
1    Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of study treatment require an SAE 
report as follows: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 4 unexpected events 
• 
Grade 5 expected events and unexpected events 
 
Initial notification for all SAEs must include: 
 Grade of event 
 Date of event 
 A brief description of the event 
 Attribution to the investigational agent 
 Patient Status 
Relationship of any adverse event to study drug should use the following criteria: 
 Definite - The adverse event is clearly related to protocol therapy. 
 Probable - The adverse event is likely related to protocol therapy. 
 Possible - The adverse event may be related to protocol therapy. 
 Unlikely - The adverse event is doubtfully related to protocol therapy. 


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 Unrelated - The adverse event is clearly NOT related to protocol therapy. 
SAEs must be reported within 24 hours by phone or e-mail to: 
 DCC 
 Study Principal Investigator of the protocol (Dr. Tanya Trippett) 
 Local IRB 
SAE contact information for the POETIC DCC is listed below: 
POETIC Data and Coordinating Center 
Memorial Sloan-Kettering Cancer Center 
405 Lexington Avenue, Rm 3-512 
New York, New York 10174 
Telephone: 646-888-5714 
Fax: 646-888-5726 
 
Contact information for the Primary Investigator is listed below: 
 
Study Principal Investigator 
Tanya Trippett, MD 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021 
Telephone (212) 639-8267 
Fax (212) 717-3239 
E-mail: Trippet1@mskcc.org 
 
Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215-993-1220) will be provided with the 
copies of all serious adverse experiences, within two working days. Additionally, any pregnancy 
occurring in association with use of a Merck Product will be reported to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-993-1220. 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European 
Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators by the 
investigator. The investigator will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. Additionally, a 
copy of these reports will be submitted to Merck & Co., Inc (Attn: Worldwide Product Safety; FAX 
215-993-1220) at the time of the submission. 
In the event of an AE, appropriate medical and supportive care will be administered. All efforts will be 
made to minimize the side effects and to support the patient until the toxicity resolves. 
17.2.1 Agent-Specific Expected Adverse Events List 
The list below guides the investigator in determining which AEs require expedited reporting. Those AEs 
that do not require expedited reporting are reported in routine study data submissions. 


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Expected adverse events for Vorinostat include: 
 
Likely ( > 20%) 
Less Likely ( ≤ 20%) 
Rare but Serious ( < 3%) 
• Anemia 
• Diarrhea 
• Nausea 
• Vomiting 
• Fatigue 
• Platelet count 
decrease 
• Anorexia 
• Abdominal Pain 
• Constipation 
• Dry mouth 
• Dyspepsia 
• Fever 
• Infection2 
• Constipation 
• Alanine aminotransferase increased 
• Alkaline phosphatase increased 
• Aspartate aminotransferase increased 
• Blood bilirubin increased 
• Creatinine increased 
• Lympocyte count increased 
• Neutrophil count decreased 
• Weight loss 
• White blood cell decreased 
• Dehydration 
• Hyperglycemia 
• Hypoalbuminemia 
• Hypocalcemia 
• Hypokalemia 
• Hyponatremia 
• Hypophosphatemia 
• Musculoskeletal and connective 
tissue disorder- other (muscle 
spasms) 
• Muscle weakness3 
• Dizziness 
• Dysgeusia 
• Cough 
• Dyspnea 
• 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. 


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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) trials but with the relationship to vorinostat (SAHA) still 
undetermined: 
 
Blood and lymphatic system disorders - Febrile neutropenia 
Cardiac disorders - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Left ventricular systolic 
dysfunction; Myocardial infarction; Palpitations; Pericardial effusion; Sinus bradycardia; Sinus 
tachycardia; Ventricular fibrillation 
Ear and labyrinth disorders - Tinnitus; Vertigo 
Eye disorders - Blurred vision 
Gastrointestinal disorders - Abdominal distension; Anal hemorrhage; Bloating; Cheilitis; Colitis; 
Dysphagia; Esophageal hemorrhage; Esophagitis; Flatulence; Gastric hemorrhage; Gastritis; Gingival 
pain; Lower gastrointestinal hemorrhage; Mucositis oral; Oral hemorrhage; Small intestinal obstruction; 
Stomach pain; Upper gastrointestinal hemorrhage 
General disorders and administration site conditions - Chills; Death NOS; Edema limbs; Gait 
disturbance; General disorders and administration site conditions - Other (angioedema); General 
disorders and administration site conditions - Other (failure to thrive); Malaise; Multi-organ failure; 
Non-cardiac chest pain; Pain 
Hepatobiliary disorders - Hepatic failure 
Infections and infestations - Infections and infestations - Other (Herpes zoster) 
Injury, poisoning and procedural complications - Bruising; Vascular access complication; Wound 
dehiscence 
Investigations - Activated partial thromboplastin time prolonged4; Cardiac troponin I increased; 
Electrocardiogram QT corrected interval prolonged; GGT increased; INR increased4; Investigations - 
Other (elevated LDH); Lipase increased 
Metabolism and nutrition disorders - Acidosis; Hypercalcemia; Hyperkalemia; Hypermagnesemia; 
Hypernatremia; Hypoglycemia; Hypomagnesemia; Tumor lysis syndrome 
Musculoskeletal and connective tissue disorders - Arthralgia; Back pain; Chest wall pain; 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 - 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; Syncope; Tremor 
Psychiatric disorders - Agitation; Anxiety; Confusion; Depression; Insomnia; Personality change; 
Psychosis 


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Renal and urinary disorders - Acute kidney injury; Hematuria; Proteinuria; Urinary  frequency; 
Urinary incontinence; Urinary retention; Urinary tract pain 
Reproductive system and breast disorders - Pelvic pain; Uterine hemorrhage 
Respiratory, thoracic and mediastinal disorders - Bronchopulmonary hemorrhage; Epistaxis; 
Hypoxia; Nasal congestion; Pharyngeal mucositis; Pharyngolaryngeal pain; Pleural effusion; Pleuritic 
pain; Pneumonitis 
Skin and subcutaneous tissue disorders - Dry skin; Hyperhidrosis; Nail loss; Palmar-plantar 
erythrodysesthesia syndrome; Pruritus; Purpura; Rash maculo-papular 
Vascular disorders - Flushing; Hematoma; Hot flashes; Hypertension; Hypotension; Thromboembolic 
event; Vascular disorders - Other (arterial thrombosis); Vasculitis 
 
Note: Vorinostat (SAHA) 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. 
The effects of vorinostat on a fetus and reproductive organs have not been studied and are therefore 
unknown. It is not known whether vorinostat can cause teratogenic changes to the fetus or the 
consequences to an unborn child. Patients who are pregnant or nursing, planning to become pregnant or 
to father a child are not permitted to enroll on this study. Women of childbearing potential must have a 
negative pregnancy test before the start of treatment on the study. 
An adequate form of contraception must be used by both male and female patients and their partners 
during therapy with vorinostat. It is recommended that two forms of birth control be used 
simultaneously unless abstinence is the chosen method. 
 
 
 
 
 
 
Expected adverse events for Etoposide include: 
Likely ( > 20%) 
Less Likely ( ≤ 20%) 
Rare but Serious ( < 3%) 
• Nausea and vomiting 
• Hair loss 
• Feeing of weakness or 
tiredness 
• Fewer white blood 
cells, red blood cells 
and platelets in the 
blood. 
○ A low number of 
red blood cells 
can make you feel 
tired and weak 
• Loss of appetite 
• Decreased blood pressure during 
the infusion which may require 
treatment 
• Rashes 
• Diarrhea 
• Pain in the abdomen 
• Mouth sores 
• Tingling sensation or loss of 
sensation in fingers or toes 
• A feeling of extreme tiredness or 
weakness 
• Damage to the liver 
• Severe allergic reaction which 
can be life threatening with 
shortness of breath, low blood 
pressure, rapid heart rate, 
chills and fever 
• New cancer or leukemia 
resulting from this treatment 
• Severe rashes which can 
result in loss of skin and 
damage to mucous 
membranes 


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○ A low number of 
white blood cells 
can make it easier 
to get infections 
○ A low number of 
platelets may 
cause you to 
bruise and bleed 
more easily 
• Loosening of the fingernails or 
toenails from their nail beds 
• Inflammation of the vein through 
which the medication was given 
• Chest pain 
• Absence or decrease monthly 
periods which may be 
temporary or permanent and 
may make it difficult to have 
children 
• Damage to the heart muscle 
which may make you feel 
tired, weak, feel short of 
breath, and retain fluid 
 
17.2.2 SAE Reporting (This section pertains to guidelines for Memorial Sloan-Kettering only) 
The DCC RSA must submit any SAEs to the MSKCC IRB/PB as soon as possible but no later than 5 
calendar days. The MSKCC IRB/PB requires a Clinical Research Database (CRDB) SAE report be 
submitted electronically to the SAE Office at sae@mskcc.org. The report will be generated by the DCC 
RSA, and should contain the following information: 
Fields populated from the CRDB: 
• Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
 
 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 


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The CRDB AE report should be completed as above and the FDA assigned IND/IDE number written at 
the top of the report. If appropriate, the report will be forwarded to the FDA by the SAE staff through  
the IND Office. 
18.1 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain full details of 
the protocol and study procedures as well as the risks involved to participants prior to their inclusion in 
the study. Participants will also be informed that they are free to withdraw from the study at any time. 
All participants must sign an IRB/PB-approved consent form indicating their consent to participate. This 
consent form meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care 
for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional  will  fully 
explain the aspects of patient privacy concerning research specific information. In addition to signing 
the IRB Informed Consent, all patients must agree to the Research Authorization component of the 
informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must receive a 
copy of the signed informed consent form. 


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19.0    REFERENCE(S) 
 
1. Vorinostat Clinical Investigators Brochure, MERCK Research Laboratories, Edition 8.0. 
 
2. Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, et al. J Clin Oncol 2005;23: 
3923-3931. 
 
3. Richardson, P, Schlossman, R, Mitsiades, CS, Munshi, N, Colson, K et al. Phase I clinical trial of 
oral administration of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid 
(SAHA) in patients with relapsed/refractory multiple myeloma (MM). The American Society of 
Hematology 46th Annual Meeting and Exposition, 2004. Abstract 1503. 
 
4. Duvic M, Talpur R, Zhang C, Goy A, Richon V, Frankel SR. Phase II trial of oral suberoylanilide 
hydroxamic acid (SAHA) for cutaneous T-cell lymphoma (CTCL) unresponsive to conventional 
therapy. Proc Am Soc Clin Oncol 2005.Abstract 6571. 
 
5. Garcia-Manero, G, Issa, JP, Cortes, J, Koller, C, O’Brien, S. et al. Phase I study of oral 
suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, in patients with advanced leukemia or 
myelodysplastic syndrome. Proc ASCO 2004. 
 
6. Kim, MS, Blake M, Baek, J, Kohlhagen, G, Pommier, Y and Carrier, F. Inhibition of histone 
deacetylase increases cytotoxicity to anticancer drugs targeting DNA. 2003 Cancer Research 63:7291- 
7300. 
 
7. Fouladi M, Park J, Sun J, Fraga C, Ames M, Stewart CF, Gilbertson J et al. A phase I trial of 
vorinostat in children with refractory solid tumors: A Children’s Oncology Group Study. Proc ASCO 
2007, Abstract # 9569. 
 
8. Marks P, Rifknd R, Richon V, Breslov R, Miller T, and Kelly W. Histone deacetylases and cancer: 
causes and therapies. 2001 Nature Reviews Cancer 1:194-202. 
 
9. Marks P, Rifkind R, Richon V, and Breslow R. Inhibitors of histone deacetylase are potentially 
effective anticancer agents. 2001 Clinical Cancer Research 7:759-760. 
 
10. Kelly W, O’Connor O, and Marks P. Histone deacetylase inhibitors: from target to clinical trials. 
2002 Expert Opin Investig Drugs 11(12):1695-1713. 
 
11. Miller T, Witter D, and Belvedere S. Histone Deacetylase Inhibitors. 2003 Journal of Medicinal 
Chemistry 46(24): 5097-5116. 
 
12. Richon VM. Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide 
hydroxamic acid), a novel histone deacetylase inhibitor. 2006 Br  J Cancer 95 Suppl 1:S2-6. 
 
13. Mehnert JM, Kelly WK. Histone deacetylase inhibitors: biology and mechanism of action. 2007 


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- 70 - 
 
 
 
Cancer J 13(1):23-9. 
 
14. Hsi LC, Xi X, Lotan R, Shureiqi I, Lippman SM. The histone deacetylase inhibitor suberoylanilide 
hydroxamic acid induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells. 2004 
Cancer Res. 64(23):8778-81. 
 
15. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or 
apoptosis of transformed cells. J Natl Cancer Inst. 2000 Aug 2;92(15):1210-6. 
 
16. Yoshida M, Furumai R, Nishiyama M, Komatsu Y, Nishino N, Horinouchi S. Histone deacetylase as 
a new target for cancer chemotherapy. 2001Cancer Chemother Pharmacol. 48 Suppl 1:S20-6. 
 
17. Chen CS, Wang YC, Yang HC, Huang PH, Kulp SK, Yang CC, Lu YS, Matsuyama S, Chen CY,  
Chen CS. Histone Deacetylase Inhibitors Sensitize Prostate Cancer Cells to Agents that Produce DNA 
Double-Strand Breaks by Targeting Ku70 Acetylation. 2007 Cancer Res 67(11):5318-27. 
 
18. Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F. Inhibition of histone deacetylase 
increases 
cytotoxicity 
to 
anticancer 
drugs 
targeting 
DNA. 
2003 
Cancer Res 63(21):7291-300. 
 
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