Conditions: Neoplasms Lymphomas
Keywords: Histone Deacetylase Inhibitor Liver Dysfunction Pharmacokinetics UGT1A1 Polymorphisms Solid Tumor Cancer Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 72
Healthy volunteers: no

Brief summary:
Background:

\- Belinostat is an experimental cancer treatment drug that works by helping to turn on genes that limit cell growth and survival of cancer cells. These genes are often switched off in tumors. Belinostat has been given to patients with different types of cancer to measure its safety and effectiveness, but it has not been given in a formal trial to cancer patients who have abnormal liver function. Because belinostat is processed by the liver, its safety and effectiveness needs to be established in individuals who have abnormal liver function. Researchers are interested in comparing the effects of belinostat as a cancer treatment drug in individuals with normal and abnormal liver function.

Objectives:

* To test the safety and effectiveness of belinostat in individuals who have solid tumors and lymphomas and who also have abnormal liver function.
* To compare the results of belinostat treatment in individuals with normal and abnormal liver function.

Eligibility:

* Individuals at least 18 years of age who have been diagnosed with solid tumors or lymphomas that have not responded to standard treatment.
* Individuals with normal liver function and varying degrees of abnormal liver function (mild, moderate, severe) are eligible.

Design:

* Participants will be screened with a full medical history and physical examination, as well as blood and urine tests, and tumor imaging studies. Participants will then be divided into study groups based on their liver function.
* Participants will receive belinostat in cycles of treatment. Except for cycle 1, all cycles will last 21 days. Cycle 1 will last 28 days. For cycle 1 only, participants will receive a single dose of belinostat 1 week before the regular 21-day treatment cycle starts.
* In each cycle, participants will receive belinostat once a day for 5 days, and will be asked to keep a medication diary to record any side effects.
* Participants will have regular clinic visits with blood and urine sample collection and imaging studies to evaluate the cancer's response to treatment.
* Participants may continue to take belinostat for as long as the cancer responds to the treatment.

Detailed description:
Background:

* Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs are frequently deregulated in cancer cells, leading to an increase in deacetylation and the silencing of genes that normally control cell cycle arrest and apoptosis.
* Belinostat has growth inhibitory activity in several malignancies in vitro and in vivo, both as a single agent and in combination with chemotherapeutic agents. Several Phase I and II clinical trials have been conducted to date in patients with solid tumor and hematologic malignancies; belinostat has been generally well tolerated.
* Belinostat is metabolized in the liver and therefore, the safety and dosing of belinostat needs to be established in patients with varying degrees of hepatic dysfunction.

Objectives:

* Establish the safety and tolerability of belinostat given on days 1 through 5 of 21-day cycles to patients with varying degrees of liver dysfunction.
* Define the maximum tolerated dose (MTD) and recommended dose of belinostat given on days 1 through 5 of 21-day cycles to patients with varying degrees of liver dysfunction.
* Evaluate the pharmacokinetics (PK) of one dose of belinostat (400 mg/m(2)) in patients with varying degrees of liver dysfunction.
* Obtain preliminary evidence of anti-tumor activity at tolerable doses of belinostat in patients with varying degrees of liver dysfunction.
* Measure direct versus indirect bilirubin levels and correlate these with observed toxicities, PK.

Eligibility:

-Adults with solid tumors or lymphomas whose disease has progressed after standard therapy or who have no acceptable standard treatment options. Patients with normal and varying degrees of hepatic dysfunction (mild, moderate, and severe) are eligible.

Study Design:

-Patients will be divided into 4 dose escalation cohorts based on their level of liver dysfunction. Belinostat will be administered intravenously (IV) over 30 minutes. On day -7 (Cycle 1 only), all patients will receive a single dose of 400 mg/m(2) belinostat. On days 1 through 5 of each cycle, patients will receive belinostat at a dose dependent on the level of hepatic dysfunction and dose level. Mild, moderate, and severe liver dysfunction cohorts will begin on dose level 1; patients with normal hepatic function will not have their dose escalated (see below). The total length of Cycle 1 will be 28 days; all other cycles will be 21 days. No more than 12 evaluable patients with normal hepatic function will be accrued.

Arms:
arm 1: Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. arm 2: Mild Liver Dysfunction was defined as bilirubin \>Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) \> ULN. arm 3: Mild Liver Dysfunction was defined as bilirubin \>Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) \> ULN. arm 4: Moderate Liver Dysfunction was defined as bilirubin \>1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). arm 5: Moderate Liver Dysfunction was defined as bilirubin \>1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). arm 6: Severe Liver Dysfunction was defined as bilirubin \>3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). arm 7: Severe Liver Dysfunction was defined as bilirubin \>3 but ≤ 10 x ULN and any aspartate aminotransferase (AST).

Interventions: intervention 1: Belinostat
Intervention descriptions: intervention 1: Belinostat was administered intravenously (IV) over 30 minutes on days 1 through 5 of a 21-day cycle. All patients were administered a single dose of 400 mg/m(2) of belinostat on Cycle 1 Day -7 for pharmacokinetic analysis (the total length of Cycle 1 was 28 days).

Protocol document:
Prot_SAP_000.pdf: 
CTEP #8846 
Clinical Center #11-C-0060 
 
 
 
1
Phase I Pharmacokinetic Study of Belinostat for Solid Tumors and Lymphomas in Patients 
with Varying Degrees of Hepatic Dysfunction 
 
Abbreviated Title:  
PhI Belinostat ODWG 
 
Coordinating Center: 
Developmental Therapeutics Clinic (DTC) 
 
National Cancer Institute  
 
10 Center Drive, 12N226 
 
Bethesda, MD 20892 
 
Principal Investigator: 
Naoko Takebe, MD, PhDA-E, DTC 
 
Bldg 31 Room 3A44  
Bethesda, MD 20892 
Phone: (240) 781-3398; Fax: (240) 541-4515 
 
takeben@mail.nih.gov  
 
NIH Co-Investigators: 
James H. Doroshow, MDA-E, DCTD 
 
Alice P. Chen, MDA-E, DCTD 
 
Howard Streicher, MDA-E, CTEP/DCTD 
 
Geraldine O’Sullivan Coyne, MDA-E, DCTD 
 
 
 
Non-NCI  
Co-investigators  
Lamin Juwara, CRNPA,B,E, Leidos Biomed/FNLCR 
 
 
 
 
Participating Centers: 
NCI Organ Dysfunction Working Group (ODWG):  
 
Albert Einstein College of Medicine 
University of California Davis Cancer Center 
Emory University 
University of Southern California/Norris 
Karmanos Cancer Institute 
Comprehensive Cancer Center 
City of Hope Comprehensive Cancer Center 
 
 
Referral Contact:  
Nancy Moore, RNA,B,E 
Bldg 10/RM 8D53 
National Cancer Institute 
Phone: (240) 760-6045; Fax: (301) 451-5625 
nancy.moore@nih.gov 
 
 
 
Roles: Aobtains information by intervening or interacting with living individuals for research purposes; 
Bobtains identifiable private information about living individuals; Cobtains the voluntary informed consent 
of individuals to be subjects; Dmakes decisions about subject eligibility; Estudies, interprets, or analyzes 
identifiable private information or data/specimens for research purposes 
 


CTEP #8846 
Clinical Center #11-C-0060 
 
 
 
2
CoH 
 
FWA#: 00000692 
 
PI: Vincent Chung, MD, FACP 
(626) 471-9200 
Fax: (626) 301-8233 
VChung@coh.org 
 
PI: Edward Newman, Ph.D. 
City of Hope Comprehensive Cancer Center 
1500 East Duarte Road 
Duarte, CA. 91010 
(626) 256-4673 x 62566 
Fax: (626) 301-8654 
enewman@coh.org 
 
IRB Contact: Amanda Hammond 
IRB of Record Name: City of Hope Natl Med 
Ctr & the Beckman Rsch Inst IRB#1 
IRB IORG#: IORG0000042 
1500 E. Duarte Rd. 
Duarte, CA 91010 
Phone: (626) 256-4673 X 89084  
Fax: (626) 245-8695 
ahammond@coh.org 
 
 
Pharmacy Contact: Timothy Synold, Pharm D 
(626) 256-4673 x 62110 
Fax: (626) 471-9376 
tsynold@coh.org  
 
Cecilia Lau, Clinical Pharmacist 
(626) 256-4673 x 64165 
Fax: (626) 301-5237 
clau@coh.org 
 
Regulatory Coordinator:  
Stella Chen Khoo, MBA 
Project Administrator 
Data Coordinating Center 
California Cancer Consortium 
Phone: (626) 256-4673 ext. 60094 
Fax: (626) 256-8654 
Pager: (626) 423-5365 
cccp@coh.org and skhoo@coh.org 
USC 
 
FWA#: 00005906 
 
PI: Heinz-Josef Lenz, M.D. 
USC/Norris Comprehensive Cancer Center 
1441 Eastlake Avenue 
Los Angeles, CA 90033 
Phone: 323-865-3955, Fax: 323-865-0061 
lenz@usc.edu 
 
PK Coordinator: Isabell Nungaray 
Nungaray_I@ccnt.usc.edu 
Shipping Address: 
USC/Norris Comprehensive Cancer Center 
1441 Eastlake Ave., Room 7408 
Los Angeles, CA 90033 
 
 
IRB Contact: Sandy Jean 
IRB of Record Name: University of Southern 
California Health Sciences Institutional Review 
Board 
IRB IORG #: IRB00000484 
LAC+USC Medical Center 
General Hospital Suite 4700  
1200 North State St.  
Los Angeles, CA 90033  
Phone Number: (323) 276-2231 
HUsjean@usc.eduU 


CTEP #8846 
Clinical Center #11-C-0060 
 
 
 
3
UCD 
 
FWA#: 00004557  
 
PI: David Gandara, MD 
UC Davis Cancer Center 
45021 X Street, Suite 3016 
Sacramento, CA 95817 
Phone: 916-734-3772, Fax: 916-734-7946 
david.gandara@ucdmc.ucdavis.edu 
 
PK Coordinator: Leslie Snyder-Solis, MS 
UC Davis Cancer Center 
Clinical Trials Support Unit 
4501 X Street Suite 1009 
Sacramento, CA 95817 
Phone: 916-734-6447, Fax: 916-734-4177 
ljsnyder@ucdavis.edu  
 
 
Clinical Research Coordinator: 
Corinne Turrell, CCRP 
UC Davis Comprehensive Cancer Center 
4501 X Street, Suite 1009 
Sacramento, CA 95817 
Phone: 916-734-3089, Fax: 916-734-4177 
ceturrell@ucdavis.edu 
 
IRB Contact: Cynthia Gates, JD, RN, CIP 
Director of IRB Administration  
IRB of Record Name:  UC Davis Office of Research, 
IRB Administration  
IRB IORG #:  0000251  
2921 Stockton Blvd., Suite 1400, Room 1429  
Sacramento, CA  95817  
Phone Number: (916) 703-9154 
cmgates@ucdavis.edu 
 
NYC 
 
FWA#: 00000140 
 
PI: Sanjay Goel, M.D., M.S. 
Albert Einstein College of Medicine  
Montefiore Medical Center 
1825 Eastchester Road 
Bronx, NY 10461 
Ph: 718-904-2488, Fax: 718-904-2830 
sgoel@montefiore.org 
 
 
 
 
PK Coordinator: Mohammed Ghalib 
mhghalib@montefiore.org 
Shipping Address: 
1695 Eastchester Rd 
Oncology 1st FL/AECOM 
Bronx, NY 10461 
Phone: 718-405-8515 
 
IRB Contact: David Wallach 
IRB of Record Name: Albert Einstein College of 
Medicine Institutional Review Board 
IRB IORG #:IRB00000081; IORG0000058 
1300 Morris Park Avenue, Bronx, NY 10461 
Phone: 718-430-2237 
irb-east@einstein.yu.edu 


CTEP #8846 
Clinical Center #11-C-0060 
 
 
 
4
WSU 
 
FWA#:00002460 
 
PI: Ulka Vaishampayan, MD 
Wayne State University/Karmanos Cancer 
Institute 
4HWCRC, 4100 John R HW04HO 
Detroit, MI 48201 
Phone: 313-576-8718, Fax: 313-576-8487 
vaishamu@karmanos.org 
 
PK Coordinator: Nikita Patel, MSc 
Karmanos Cancer Institute 
87 E. Canfield MM05P1 
Detroit, MI 48201 
Phone:  313-576-9723; Fax:  313-576-9684 
pateln@karmanos.org 
 
 
 
Regulatory Coordinator: 
Rachelle Zeleny 
Karmanos Cancer Institute  
87E. Canfield MM05P1 
Detroit, MI 48201 
Phone: 313-576-9811; Fax: 313-576-9684 
zelenyr@karmanos.org 
 
IRB Contact: Rozelle Copeland 
IRB of Record Name: Wayne State University IRB 
IRB IORG #:IRB00006856 
(for the Phase I IRB at WSU) 
Address: 87 E. Canfield, 2nd Floor 
Detroit, MI 48201 
Phone: (313) 577-1628 
ph1board@wayne.edu 
 
EMY 
 
FWA#: 00005792 
 
PI: Bassel F. El-Rayes, MD 
Emory University School of Medicine 
Building C, Room 2080 
Atlanta, GA 30322 
Phone: 404-778-3882, Fax: 404-778-5676 
bassel.el-rayes@emoryhealthcare.org 
 
Co-PI: Donald Harvey, PharmD 
Emory University School of Medicine 
Building C, Room CPL017B 
Atlanta, GA 30322 
Phone: 404-778-4381, Fax: 404-778-7720 
Donald.harvey@emory.edu 
 
 
 
 
PK Coordinator: Rijalda Deovic 
Emory University School of Medicine 
rijalda.deovic@emory.edu 
1365-C Clifton Road NE 
Suite C3012-C 
Atlanta, GA 30322 
Phone:404-778-5849 
 
Eligibility Coordinator:  
Meredith Renfroe, CCRP 
Emory University Winship Cancer Institute 
1365-C Clifton Road NE 
Suite C3012-B 
Atlanta, GA 30322 
Phone: 404-778-1802 
marenfr@emory.edu 
 
IRB Contact: Rebecca Rousselle, BA, CIP 
IRB of Record Name: Emory University IRB 
IRB IORG #: #0000267 
Address: 1599 Clifton Road NE, 5th Floor  
Atlanta, GA 30322 
Phone Number: 404-712-0720 
IRB@emory.edu 
 
 


CTEP #8846 
Clinical Center #11-C-0060 
 
 
 
5
Statistician: 
 
 
Larry Rubinstein, PhDE  
Biometric Research Branch, NCI  
9609 Medical Center Drive 
Rockville, MD  20850 
Phone: (240) 276 6026  
rubinsteinl@ctep.nci.nih.gov 
 
NCI-Supplied Agent: 
Belinostat (NSC 726630)  
 
IND Number:  
72990 
 
CTEP Drug Monitors: 
Richard Piekarz, MD, PhD 
 
S. Percy Ivy, MD 
 
Protocol Version Date: 
October 25, 2018  


CTEP #8846 
Clinical Center #11-C-0060 
 
 
 
6
 
PRÉCIS 
 
Background:  
 Belinostat is a histone deacetylase (HDAC) inhibitor.  HDACs are frequently deregulated 
in cancer cells, leading to an increase in deacetylation and the silencing of genes that 
normally control cell cycle arrest and apoptosis.   
 Belinostat has growth inhibitory activity in several malignancies in vitro and in vivo, both 
as a single agent and in combination with chemotherapeutic agents.  Several Phase I and 
II clinical trials have been conducted to date in patients with solid tumor and hematologic 
malignancies; belinostat has been generally well tolerated.     
 Belinostat is metabolized in the liver and therefore, the safety and dosing of belinostat 
needs to be established in patients with varying degrees of hepatic dysfunction. 
Objectives: 
 Establish the safety and tolerability of belinostat given on days 1–5 of 21-day cycles to 
patients with varying degrees of liver dysfunction.   
 Define the maximum tolerated dose (MTD) and recommended dose of belinostat given 
on days 1–5 of 21-day cycles to patients with varying degrees of liver dysfunction. 
 Evaluate the pharmacokinetics (PK) of one dose of belinostat (400 mg/m2) in patients 
with varying degrees of liver dysfunction 
 Obtain preliminary evidence of anti-tumor activity at tolerable doses of belinostat in 
patients with varying degrees of liver dysfunction. 
 Correlate observed toxicities with PK of belinostat in patients with varying degrees of 
liver dysfunction. 
 Measure direct versus indirect bilirubin levels and correlate these with observed toxicities 
and PK. 
Eligibility: 
 Adults with solid tumors or lymphomas whose disease has progressed after standard 
therapy or who have no acceptable standard treatment options.  Patients with normal and 
varying degrees of hepatic dysfunction (mild, moderate, and severe) are eligible.  
Study Design:  
 Patients will be divided into 4 cohorts based on their level of liver dysfunction.  
Belinostat will be administered IV over 30 minutes.  On day -7 (Cycle 1 only), all patients 
will receive a single dose of 400 mg/m2 belinostat.  On days 1–5 of each cycle, patients 
will receive belinostat at a dose dependent on the level of hepatic dysfunction (see 
below).  The total length of Cycle 1 will be 28 days; all other cycles will be 21 days.  No 
more than 12 patients with normal hepatic function will be accrued. 


CTEP #8846 
Clinical Center #11-C-0060 
 
 
 
7
SCHEMA 
  
 
Liver Dysfunction Groups 
Cohort 1: Normal hepatic function: bilirubin ≤ upper limit of normal (ULN) and AST ≤ ULN 
Cohort 2: Mild hepatic dysfunction: bilirubin > ULN but ≤ 1.5 x ULN and/or AST > ULN 
Cohort 3: Moderate hepatic dysfunction: bilirubin > 1.5 x ULN to ≤ 3 x ULN and any AST 
Cohort 4: Severe hepatic dysfunction: bilirubin > 3 x ULN but ≤ 10 x ULN and any AST 
 
Dose Escalation Scheme 
Dose Level of Belinostat (mg/m2/day) 
 
-1 
1 
2 
3 
4 
Cohorts: 
Normal 
750 
1000 
No 
escalation 
No 
escalation 
No 
escalation  
Mild 
Dysfunction 
500 
750 
1000 
No 
escalation 
No 
escalation 
Moderate 
Dysfunction 
250 
500 
750 
1000 
No 
escalation 
Severe 
Dysfunction 
125 
250 
350 
500 
750 
 
The initial cohorts of patients will begin on dose level 1 based on their level of hepatic dysfunction.  
Patients with normal hepatic function will not have their dose escalated.  
B = Belinostat, administered IV over 30 minutes.  On Day -7 (Cycle 1 only), all patients will receive a 
single dose of 400 mg/m2 belinostat.   
Starting on Day 1, patients will receive the assigned dose of belinostat, according to the dose 
escalation scheme, for Days 1–5 of each cycle. 
Blood samples for correlative PK studies will be collected from all patients on Cycle 1 D-7 before 
the administration of belinostat, 15 minutes after starting infusion, and then at the following time 
points after the end of infusion: 5, 10, 15, 30, 60, 90 minutes, 2, 4, 6, 8, and 24 hours 
PK 
sampling 
D21 
D1 
D5 
D -7 
Cycle 1 
(total duration 28 days) 
Cycle 2 and beyond 
(total duration 21 days) 
B 
 
B 
 
D21 
D1 
D5 
B 


CTEP #8846 
Clinical Center #11-C-0060 
 
 
 
8
TABLE OF CONTENTS 
PRÉCIS ........................................................................................................................................... 6 
SCHEMA ........................................................................................................................................ 7 
1 
OBJECTIVES ........................................................................................................................ 11 
1.1 
Primary Objectives ......................................................................................................... 11 
1.2 
Secondary Objectives ..................................................................................................... 11 
2 
BACKGROUND ................................................................................................................... 11 
2.1 
Belinostat ........................................................................................................................ 11 
2.2 
Rationale......................................................................................................................... 18 
3 
PATIENT SELECTION ........................................................................................................ 18 
3.1 
Eligibility Criteria........................................................................................................... 18 
3.2 
Exclusion Criteria ........................................................................................................... 20 
3.3 
Inclusion of Women and Minorities ............................................................................... 22 
3.4 
Research Eligibility Evaluation ...................................................................................... 22 
4 
REGISTRATION PROCEDURES ....................................................................................... 23 
4.1 
Registration Process ....................................................................................................... 23 
5 
TREATMENT PLAN ............................................................................................................ 25 
5.1 
Belinostat Administration .............................................................................................. 25 
5.2 
Definition of Dose-Limiting Toxicity ............................................................................ 27 
5.3 
Design ............................................................................................................................. 28 
5.4 
Supportive Care Guidelines ........................................................................................... 29 
5.5 
General Concomitant Medication .................................................................................. 29 
5.6 
Duration of Therapy ....................................................................................................... 30 
5.7 
Duration of Follow Up ................................................................................................... 30 
5.8 
Criteria for Removal From Study ................................................................................... 30 
6 
DOSING DELAYS/DOSE MODIFICATIONS .................................................................... 31 
6.1 
Intrapatient Dosing, Non-Hepatic Toxicities ................................................................. 31 
6.2 
Intrapatient Dosing, Hepatic Toxicities .......................................................................... 32 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ................................ 33 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ............................. 33 
7.2 
Adverse Event Characteristics........................................................................................ 35 
7.3 
Expedited Adverse Event Reporting .............................................................................. 36 
7.4 
Routine Adverse Event Reporting .................................................................................. 42 
7.5 
Secondary AML/MDS.................................................................................................... 43 
8 
PHARMACEUTICAL INFORMATION .............................................................................. 43 
9 
CORRELATIVE/SPECIAL STUDIES ................................................................................. 46 


CTEP #8846 
Clinical Center #11-C-0060 
 
 
 
9
9.1 
Pharmacokinetic Studies ................................................................................................ 46 
9.2 
Analysis of Pharmacokinetic Data ................................................................................. 48 
9.3 
Sample Handling ............................................................................................................ 48 
10 
STUDY CALENDAR........................................................................................................ 50 
11 
MEASUREMENT OF EFFECT ........................................................................................ 52 
11.1 
Antitumor Effect – Solid Tumors ............................................................................... 52 
11.2 
Antitumor Effect – Lymphomas ................................................................................. 59 
12 
DATA REPORTING / REGULATORY CONSIDERATIONS ....................................... 62 
12.1 
Data Reporting ............................................................................................................ 62 
12.2 
Data Monitoring and Safety Plan................................................................................ 63 
12.3 
Multi-Institutional Guidelines .................................................................................... 63 
12.4 
Clinical Trials Agreement (CTA) ............................................................................... 65 
13 
STATISTICAL CONSIDERATIONS ............................................................................... 66 
13.1 
Sample Size/Accrual Rate .......................................................................................... 67 
13.2 
Stratification Factors ................................................................................................... 68 
14 
HUMAN SUBJECTS PROTECTIONS ............................................................................ 68 
14.1 
Rationale for Subject Selection .................................................................................. 68 
14.2 
Participation of Children ............................................................................................ 68 
14.3 
Evaluation of Benefits and Risks/Discomforts ........................................................... 68 
14.4 
Risks/Benefits Analysis .............................................................................................. 69 
14.5 
Consent Process and Documentation ......................................................................... 69 
15 
REFERENCES .................................................................................................................. 71 
APPENDIX A: GI50 MEAN GRAPH FOR NSC 726630 (BELINOSTAT) ............................... 73 
APPENDIX B: PERFORMANCE STATUS CRITERIA ............................................................ 74 
APPENDIX C: MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL  AND/OR 
INDUCE TORSADES DE POINTES .......................................................................................... 75 
APPENDIX D: CYP450 INTERACTIONS ................................................................................. 78 
APPENDIX E: CTEP MULTICENTER GUIDELINES .............................................................. 81 
APPENDIX F: PHARMACOKINETIC SAMPLE ACQUISITION FORM................................ 83 
APPENDIX G: MULTICENTER INFORMED CONSENT TEMPLATE .................................. 85 
APPENDIX H: REGISTRATION PROCEDURES ..................................................................... 95 
APPENDIX I: ORGAN DYSFUNCTION CONFERENCE CALL POLICIES .......................... 98 


CTEP #8846 
Clinical Center #11-C-0060 
 
 
 
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APPENDIX J: FORMS ................................................................................................................. 99 
APPENDIX K: OFF STUDY/DEATH NOTIFICATION FORM ............................................. 107 
APPENDIX L: STUDY DIARY ................................................................................................ 108 
APPENDIX M: CHILD-PUGH CLASSIFICATION (CPC) OF LIVER DYSFUNCTION ...... 109 
 
 


CTEP #8846 
Clinical Center #11-C-0060 
 
11 
 
1 OBJECTIVES 
1.1 
Primary Objectives 
1.1.1 Establish safety and tolerability of belinostat given on days 1–5 of 21-day cycles to 
patients with varying degrees of liver dysfunction.   
1.1.2 Define the maximum tolerated dose (MTD) and recommended dose of belinostat 
given on days 1–5 of 21-day cycles to patients with varying degrees of liver 
dysfunction. 
1.1.3 Evaluate the pharmacokinetics (PK) of one dose of belinostat (400 mg/m2) in 
patients with varying degrees of liver dysfunction. 
1.2 
Secondary Objectives 
1.2.1 Obtain preliminary evidence of anti-tumor activity at tolerable doses of belinostat 
in patients with varying degrees of liver dysfunction. 
1.2.2 Correlate observed toxicities with PK of belinostat in patients with varying 
degrees of liver dysfunction. 
1.2.3 Measure direct versus indirect bilirubin levels and correlate these with observed 
toxicities and PK. 
 
2 BACKGROUND 
2.1 
Belinostat 
Belinostat (N-hydroxy-3-[phenylsulphamoylphenyl] acryl amide) is a novel, achiral, low 
molecular weight inhibitor of histone deacetylase (HDAC) activity.1-3  The structural design of 
belinostat was based on natural products that were known inhibitors of HDAC.4  It contains a 
zinc-chelating hydroxamic acid moiety that contributes to high levels of potency similar to other 
low molecular weight HDAC inhibitors, such as trichostatin A (TSA), oxamflatin, and 
suberoylanilide hydroxamic acid (SAHA).5  Molecular modeling studies predict that belinostat 
binds within the active sites of HDAC class I and II enzymes, in a similar manner to that 
described for TSA and SAHA.6, 7 
 
Mechanism of Action 
 
HDACs exert their action during post-translational acetylation of core nucleosomal histones, 
which affects chromatin structure and thus regulates gene expression.  Acetylation and 
deacetylation of histones is controlled by the activity of histone acetyltransferases (HATs) and 
HDACs.  Acetylation of the e-amino groups of lysine residues in the N-terminal tails of histones 
is associated with transcriptional activation, while deacetylation is associated with condensation 
of chromatin and transcriptional repression.  HDAC inhibitors, such as the natural product TSA 
and SAHA, induce the expression of genes associated with cell cycle arrest and tumor 


CTEP #8846 
Clinical Center #11-C-0060 
 
12 
 
suppression.8-10  Phenotypic changes induced by HDAC inhibitors include G1 and G2/M cell 
cycle arrest and apoptosis in tumor cells.  There are also data to suggest that HDAC inhibitors 
possess antiangiogenic properties.  HDAC inhibitors deplete vascular endothelial cell growth 
factor (VEGF) concentrations and inhibit the proliferation of endothelial cells.11 
 
DNA methylation and hypoacetylation of core nucleosome histone proteins leads to the tight 
coiling of chromatin, thus silencing the expression of a variety of genes.12  HDAC inhibitors 
alone or in combination with DNA hypomethylating agents, such as 5-azacytidine or decitabine, 
restore expression of silenced genes, leading to cell differentiation and subsequent cell cycle 
arrest or apoptosis.  Reports also suggest that HDAC inhibitors repress some genes, e.g., the gene 
for thymidylate synthetase, which may explain the reports of synergistic interaction between 5-FU 
and these inhibitors.13, 14  Gene expression analyses with human HL-60 promyelocytic leukemia 
cells and HCT116 colon cancer cells, after exposure to belinostat (1 µM), TSA (1 µM), or FK228 
(10 nM) suggest that belinostat may have similar gene induction and repression effects as other 
HDAC inhibitors (Investigator communication).  HDAC inhibition also depleted the levels of 
several oncoproteins that are normally stabilized by binding to the 90 kD heat shock protein 
(Hsp90) in cancer cells, e.g., mutant p53 and Raf-1 proteins.15  Concurrent administration of 
marginally toxic concentrations of 17-AAG, an Hsp90 inhibitor, with sublethal concentrations of 
HDAC inhibitors resulted in synergistic induction of apoptosis.16 
 
Nonclinical Activity 
 
Belinostat induced a concentration-dependent increase in acetylation of histones H3 and H4 in 
various tumor cell lines (ovarian, colon, lung, breast, prostate, and melanoma), with IC50 values 
varying from about 10 to 100 nM.2, 17  In these same tumor cell lines, belinostat induced apoptosis 
or was cytotoxic with IC50 values varying from 0.2 to 3.4 µM.2, 3, 7  Activity against the NCI 60 
cancer panel is included as Appendix A.  Other human tumor cell lines reported to be sensitive to 
belinostat are T-cell leukemia (Jurkat); small cell lung cancer (SCLC) (H69, GLC2, and GLC4); 
and multiple myeloma (JNN-2, LP-1, RPMI-8226, and U-266).3,7  Belinostat also has activity in 
preclinical models of hepatocellular carcinoma (HCC), especially in combination with sorafenib.  
HDAC inhibitors have been shown to restore sensitivity to sorafenib in sorafenib-resistant HCC 
cell lines.   
 
The antitumor activity of belinostat was demonstrated in several in vivo xenograft models, 
including human A2780 ovarian cancer cells, cisplatin-resistant A2780/cp70 ovarian cancer cells, 
HCT116 colon cancer cells, and murine P388 leukemia cells.  Tumor-bearing mice were treated 
intraperitoneally (IP) with belinostat once daily for 7 days.  Delay of tumor growth was observed 
at a dose of 10 mg/kg/day in A2780 and A2780/cp70 xenografts.  Growth delay was dose 
dependent up to a belinostat dose of 40 mg/kg/day.  Growth inhibition was also observed in 
xenografts of HCT116 cells at 40 mg/kg/day.  Belinostat treatment did not affect body weight of 
the mice, nor were there apparent signs of toxicity.  Hyperacetylated histone H4 was detected in 
peripheral blood mononuclear cells (PBMC) at 1 and 2 hours after a single IP injection of 
40 mg/kg belinostat,2 and acetylation returned to baseline levels by 3 hours.  Histone 
hyperacetylation was dose dependent, with marked acetylation in both PBMCs and tumor tissue 
apparent at doses of belinostat ≥ 10 mg/kg. 


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The efficacy of various schedules of belinostat was evaluated in the murine P388 leukemia IP 
tumor model.7  A schedule of 40 mg/kg/day × 5 days (from day 3) proved superior to the same 
total dose (200 mg/kg) administered in a bolus on day 3 (P < 0.0001).  Fractionation of the daily 
dose (20, 40, or 80 mg/kg for 5 days) into two doses per day instead of one daily dose did not 
improve survival.  Mice given a cumulative dose of 200 mg/kg over a 10-day period (day 3 to day 
12) fractionated as 20 mg/kg/day for 10 days exhibited better survival than mice receiving 
40 mg/kg every two days (day 3, 5, 7, 9, 11) (P = 0.009).  Treatment every second day three times 
was compared with the same cumulative dose of 270 mg/kg belinostat administered every day in 
a 5-day period (day 3 to 7), and no significant differences were found in survival rates (P = 0.49). 
 In general, daily doses appeared to be superior to bolus injections; fractionation of the daily dose 
into two did not result in any advantage; and experiments comparing alternating day to daily 
treatments favored the daily treatment, but not substantially. 
 
Nonclinical Pharmacology and Toxicology 
 
Due to the low intrinsic aqueous solubility of belinostat, the early in vivo studies were primarily 
carried out using a co-solvent formulation of ethanol and polyethylene glycol fractions (PEG) in 
Tris buffer (known as the co-solvent-Tris formulation).7  However, this preparation proved 
unsuitable due to injection site reactions, and a new formulation was developed, which utilized 
the solubility-enhancing effects of arginine and led to the identification of the belinostat 
50 mg/mL injection formulation.  The in vitro studies were carried out using belinostat in a final 
concentration of < 1% DMSO, while the in vivo studies used the new injection formulation, after 
demonstration of bioequivalence. 
 
The cardiovascular effects of belinostat were examined in dogs.  The high dose (35 mg/kg) of 
belinostat elicited a small transient increase in heart rate.7  Anticipated changes in the 
electrocardiogram waveform—such as decrease in the RR, PR, and QT intervals—were also 
observed.  However, these changes were not substantially different from the control group.  
Increases in the rate of respiration following administration of the intermediate (15 mg/kg) and 
the high (35 mg/kg) doses of belinostat were not significantly different from those observed with 
the control group.  The hemolytic potential and plasma compatibility of belinostat (in the arginine 
formulation) in human blood were examined ex vivo.  No hemolysis was detected. 
 
Pharmacokinetic (PK) studies were undertaken in mice, rats, and dogs.7  The majority of the 
metabolite-profiling studies, coupled with preliminary investigation of excretion routes, were 
undertaken in rats and dogs.  Plasma concentrations of belinostat in mice, determined after a 
single IP injection of 20 mg/kg, reached a mean concentration of 3.3 ± 0.7 µM after 0.5 hour, and 
decreased to 0.042 ± 0.002 µM by 2 hours.  In general, the Cmax was achieved at the first time 
point after the end of infusion and increased with dose.  It then declined very rapidly with a t1/2 of 
0.5 to 1 hour.  With daily administration, t1/2 did not vary from day 1 to day 5.  With few 
exceptions, the PK parameters did not vary from day 1 to day 5 (or 7) of a treatment cycle and did 
not vary from cycle 1 to cycle 2 where two cycles were administered over 4 weeks.  There was no 
clear indication of drug accumulation following 5 or 7 days of treatment.  Acetylation of histones 
H3 and H4 was also determined in canine PBMCs taken at various times after a 45-minute 


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intravenous (IV) infusion of 50 mg/kg belinostat.2  At the end of the infusion, the plasma 
concentration of belinostat was between 20 and 30 µM, and the plasma t1/2 was estimated at 
approximately 40 minutes. 
 
In an exploratory in vivo study, metabolic profiling was undertaken in pooled samples from 
mouse, rat, and dog plasma following administration of belinostat.  The study suggested that rapid 
and extensive metabolism took place, producing a variety of metabolites that differed in rodents 
and dogs.  Since there was no consistency of either dose or sampling time, no further conclusions 
could be drawn.  The overall metabolic profile observed in the two species appeared to be similar. 
 The principal degradation product and a secondary metabolite were tested in the HDAC 
biochemical and cell proliferation assays and found to be inactive.  Elimination of belinostat and 
its metabolites occurred by both urinary and fecal routes in both rats and dogs.  Concentrations of 
parent drug cleared by either route were low when calculated as a percentage of the original dose, 
implying that the bulk of parent drug is cleared following primary and secondary metabolic 
conversion. 
 
Toxicology studies were performed with both formulations of belinostat.  Overall, in rats, the 
maximum tolerated dose (MTD) was considered to be between 100 and 200 mg/kg/day.  Due to 
local irritation at injection sites, it was not possible to assign a no-observable-effect-level (NOEL) 
in rats.  Systemic effects, however, even at the 100 mg/kg/day level, were mild with both 
formulations.  Signs of local irritation at the injection sites with both formulations were observed 
in dogs as well, although a NOEL of 10 mg/kg/day was assigned in one study.  Systemic and local 
irritation adverse events (AEs), such as lymphopenia, lymphoid atrophy, and injection site 
reactions, were observed at a dose of 50 mg/kg/day, but these were considered mild and fully 
reversible for the arginine formulation. 
 
The potential for drug interactions of belinostat was determined in vitro in CYP inhibition, 
induction, and metabolism studies.  Results indicate that belinostat is a weak/moderate inhibitor 
of CYP2C8 and CYP2C9, and may be a weak inducer of CYP1A2.  CYP3A4 appears to 
contribute to the metabolism of belinostat; CYP isoforms are not responsible for the formation of 
the two major metabolites in humans.7  
 
Phase I/II Clinical Experience 
 
TopoTarget and the NCI have conducted 22 clinical trials to evaluate the IV formulation of 
belinostat alone and in combination with approved chemotherapeutic agents, including 5-FU, 
carboplatin and paclitaxel, doxorubicin, idarubicin, bortezomib, 5-azacytidine, 13-cis-retinoic 
acid, and dexamethasone.  A total of 529 patients with advanced solid tumors and hematologic 
malignancies have been accrued as of January 2009; there is also one ongoing trial of the single-
agent oral formulation (101 patients).  Multiple dosing schedules are being investigated in these 
studies (Table 1; data from Investigators Brochure, and specified references).  A dose of 
1000 mg/m2/day IV over 30 minutes on days 1–5 in a 21-day cycle is the most widely 
recommended Phase II dose.3, 18-20 
 


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Table 1: Doses and Schedules Used for Clinical Administration of Belinostat by IV Infusion 
 
Belinostat 
monotherapy 
The recommended Phase II dose established in the initial Phase I study in patients with solid 
tumors is 1000 mg/m²/day by 30-minute intravenous infusion once daily on days 1-5 of a 21-
day cycle.19   
The same recommended Phase II dose has also proved to be tolerated in patients with 
hematological malignancies.18 
An alternative recommended Phase II dose has been established in an NCI-sponsored 
Phase I study including patients with hepatocellular carcinoma.  The Phase II dose used is 
1400 mg/m²/day by 30-minute intravenous infusion once daily on days 1-5 of a 21-day 
cycle.   
Evaluation of a 48-hour belinostat monotherapy continuous infusion administered every 
2 weeks is part of an ongoing Phase Ib study (800 mg/m²/24h for 48 hours as 
monotherapy, and 1000 mg/m²/24h for 48 hours has been applied in combination with 
idarubicin).   
Belinostat in 
combination 
with other 
antitumor 
therapies 
The recommended schedule of belinostat in combination with 5-FU is belinostat 
1000 mg/m²/day by 30-min infusions once daily days 1-5 every 21 days in combination 
with 5-FU 750 mg/m²/24h by a 96-hour continuous infusion starting day 2.   
The recommended schedule of belinostat in combination with carboplatin and paclitaxel is 
1000 mg/m²/day by 30-minute intravenous infusion once daily days 1-5 every 21 days, in 
combination with paclitaxel 175 mg/m² (started 2-3 hours after end of belinostat infusion 
on day 3) and carboplatin AUC 5 (chrome-EDTA clearance estimated GFR; following 
immediately after delivery of paclitaxel on day 3).   
The combination of belinostat with carboplatin and paclitaxel using an infusion time of up 
to 6 hours for belinostat rather than 30 minutes has been shown to be generally well 
tolerated.   
The recommended schedule of belinostat in combination with dexamethasone for patients 
with multiple myeloma is 1000 mg/m²/day by 30-minute intravenous infusion once daily 
days 1-5 every 21 days, in combination with dexamethasone administered orally (40 mg 
daily on cycle days 2-5 and 10-13).   
 
Clinical benefit has been reported from both monotherapy and combination therapy with 
belinostat in solid and hematologic malignancies.  Durable complete responses have been seen in 
patients with peripheral and cutaneous T-cell lymphoma; patients with peripheral T-cell 
lymphomas have also had persistent complete responses (CRs), and patients with multiple 
myeloma have had stable disease with belinostat alone.  Belinostat combination therapy including 
carboplatin and paclitaxel has shown encouraging activity in previously treated patients with 
different types of solid tumors, including platinum-resistant ovarian cancer and transitional cell 
carcinoma of the bladder.  Ovarian cancer patients (platinum-sensitive and platinum-resistant) 
treated with belinostat in combination with paclitaxel and carboplatin had CRs, partial responses 
(PRs), and a progression-free survival of 5.4 months; a CR and PRs were reported in patients with 
transitional cell bladder cancers.  The combination of dexamethasone with belinostat in patients 
with myeloma has resulted in PRs, objective responses, and stable disease.  Complete remissions 
were seen in patients with refractory acute myelogenous leukemia in combination with idarubicin. 
 Long periods of stabilization have been seen in patients with thymoma and soft tissue sarcomas.  
 


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PK and pharmacodynamic (PD) information for belinostat has been obtained.  The mean half-life 
is 0.6-2 hours.  Most of the drug is out of the system within 8-10 hours after administration of 
1000 mg/m2 IV over 30 minutes.  The PK for Cmax and AUC were linear with varying doses 
(Fig. 1).  AUC and elimination were not affected by height, weight, age, or gender.   
 
Fig. 1 Pharmacokinetic Data of Belinostat (150-1200 mg/m2 IV) Derived From the Phase I Study 
in Patients With Solid Tumors 
 
 
 
 
As a correlative PD study, changes in levels of histone H3 and H4 acetylation in patient PBMCs 
were also measured by Western blot following drug administration.  As illustrated in Fig. 2, 
histone H4 hyperacetylation was sustained for 4-24 hours, despite the rapid decreases in drug 
concentration measured in Fig. 1.  The level and the duration of histone acetylation were dose 
dependent, but approached plateaus by the MTD (Fig. 3; data from 2 representative patients in 
Fig. 2A).  This would suggest that the maximum effect on the tumor can be achieved at the MTD; 
however, it is unclear if the acetylation in human PBMCs correlates with effect on tumor.   
 
 
 
 
 


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Fig. 2 Changes in PBMC Protein Histone H4 Acetylation Before and After Belinostat 
Administration in Patients With Solid Tumors 
A 
 
 
 
 
 
 
B 
 
A: Western blot showing histone H4 acetylation in PBMC extract for 2 patients treated with belinostat (150 
and 900 mg/m2, respectively) pre-dose, and at defined time points afterward (5, 15, 30, 60, 90, 
120 minutes, 4, 6, and 24 hours).  B: Mean (+/- SE) for each dose:  ●, 150mg/m2 (n = 2) or 300 mg/m2  
(n = 4); ■, 600 mg/m2 (n = 4); □, 900 mg/m2 (n = 2); ▲ 1000 mg/m2 (n = 11); ◊, 1200 mg/m2 (n = 4).  
 
Fig. 3 PK/PD Relationship for Belinostat in Patients With Solid Tumors 
 
 
 
 
Relationship between relative histone H4 
acetylation in PBMCs and belinostat 
plasma concentration in 2 patients 
receiving single 150 mg/m2 (top) and 
900 mg/m2 (bottom) doses.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Based on information received to date, belinostat has been generally well tolerated.  The most 
common side effects of any grade have been nausea, vomiting, and fatigue, and the most frequent 
grade 3/4 event has been fatigue.7 
 
Serious AEs (SAEs) have been reported in 225 of the 420 patients exposed to belinostat in all 
clinical trials.  The most frequent SAEs (reported in more than 2% of patients receiving IV 
belinostat irrespective of causal relationship) were disease progression (5.6%), febrile neutropenia 
(3.8%), infection (4.1%), pneumonia (2.5%), dyspnea (2.2%), and pyrexia (3.2%).  The 
Comprehensive Adverse Event and Potential Risks (CAEPR) list for belinostat is included in 
Section 7.1.  
 
Out of 420 patients who received belinostat in studies conducted by TopoTarget, 
7 cardiotoxicities were attributed to the drug (2 atrial fibrillation events, 1 tachycardia, 
1 ventricular fibrillation, 1 chest pain, 1 angina pectoris, and 1 myocardial ischemia).  It is not 
clear whether these events were incidental in a group at high risk or if they were from the drug; 
however, specific exclusionary criteria regarding preexisting cardiac conditions and dose 
modifications if any events occur while on therapy are included in this protocol.   
 
Study Considerations 
 
There may be interactions with drugs that also affect CYP 450, especially CYP 2C9, which 
includes Coumadin.  Forty-one patients on Coumadin have received belinostat.  From what is 
known to date, warfarin is not contraindicated, but should be monitored.    
 
Cytopenias were a rare and minor when belinostat is given as a single agent, though severe AEs 
were seen when it was used in combination with cytotoxic chemotherapy.   
2.2 
Rationale   
Belinostat looks promising for the treatment of patients with cancer, having activity in several 
malignancies as monotherapy and in combination.  Exploring appropriate dosing for patients with 
varying degrees of hepatic dysfunction would be beneficial for patients with many malignancies.  
Belinostat is metabolized in the liver into less active metabolites and is also excreted primarily 
through the liver.  Therefore, belinostat dosing in patients with hepatic dysfunction should be 
explored in a clinical trial to establish dosing guidelines.  
 
 
3 PATIENT SELECTION 
3.1 
Eligibility Criteria  
3.1.1 Patients (except those with hepatocellular carcinoma) must have histologically or 
cytologically confirmed (at original diagnosis or subsequent recurrence or 
progression) solid tumor or lymphoma that is metastatic, unresectable, progressive, 
or recurrent, and for which standard curative or palliative measures do not exist or 


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are no longer effective.  Patients with hepatocellular carcinoma do not require 
biopsy confirmation.  A liver mass with raised α-fetoprotein level (≥500 ng/mL), 
consistent radiographic changes, and serology and viral DNA/RNA measurements 
consistent with chronic hepatitis25 (see Section 3.1.9) will be sufficient to identify 
hepatocellular carcinoma without the need for pathologic confirmation of the 
diagnosis.  Patients with hepatocellular carcinoma must still, however, have 
disease that has failed standard therapy.  Having chronic hepatitis B or C will not 
exclude patients from participating.   
3.1.2 No radiation, major surgery, chemotherapy or biologic therapy within 4 weeks 
prior to entering the study (6 weeks for nitrosoureas or mitomycin C); ≥ 2 weeks 
since any prior administration of study drug in an exploratory IND/Phase 0 study 
(also referred to as an “early Phase I study” or “pre-Phase I study” where a sub-
therapeutic dose of drug is administered) at the PI’s discretion.  Patients must have 
recovered to at least eligibility levels due to adverse events and/or toxicity of prior 
chemotherapy or biologic therapy.   
3.1.3 Age ≥ 18 years.  Because no dosing or adverse event data are currently available 
on the use of belinostat in patients < 18 years of age, children are excluded from 
this study but will be eligible for future pediatric Phase I single-agent trials. 
3.1.4 ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix B). 
3.1.5 Life expectancy of greater than 3 months. 
3.1.6 Patients must have acceptable renal and marrow function as defined below: 
- leukocytes 
≥3,000/mcL 
- absolute neutrophil count 
≥1,500/mcL 
- platelets 
≥100,000/mcL 
- serum creatinine 
within normal institutional limits 
 
OR 
-    creatinine clearance  
 
≥60 mL/min for patients with creatinine levels 
above institutional normal, as determined by a 
measured 24-hour creatinine clearance  
Baseline evaluations should be conducted within 7 days of treatment start date. 
3.1.7 Patients with abnormal liver function will be eligible and will be grouped 
according to the criteria described in Section 5.1.  Patients with active hemolysis 
should be excluded.  No distinction will be made between liver dysfunction due to 
metastases and liver dysfunction due to other causes.   
3.1.8 Patients with biliary obstruction for which a stent has been placed are eligible, 
provided the stent has been in place for at least 10 days prior to the first dose of 
belinostat and the liver function has stabilized.  Two measurements at least 2 days 
apart that put the patient in the same hepatic dysfunction stratum will be accepted 


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as evidence of stable hepatic function.  There should be no evidence of biliary 
sepsis. 
3.1.9 For patients with hepatocellular carcinoma secondary to hepatitis B or C, test 
results should be indicative of chronic viral hepatitis infection: 
3.1.9.1 Patients with hepatitis B 
 Antibodies: HepBsAg and HepBcAb should be elevated and HepBsAb and 
HepBeAb low, indicating chronic infection.  If the pattern is different from 
this, please notify the PI.   
 Viral load: COBAS TaqMan test26 measuring HBV DNA is reduced in 
chronic phase hepatitis B.  The baseline value as the patient enters this 
study will be useful to discriminate between drug, disease progression, or 
increased viral load as possible attributions for worsening symptoms.   
3.1.9.2 Patients with hepatitis C 
 Antibodies: Anti-HCV testing—specific tests used will be based on the 
site’s standard procedure for identifying hepatitis C.27-29 
 Viral load: HCV-RNA should be relatively constant in chronic phase of 
disease, though the level is typically higher than in the acute phase.27-29  
The baseline value as the patient enters this study will be useful to 
discriminate between drug, disease progression, or increased viral load as 
possible attributions for worsening symptoms.   
3.1.10 Patients with gliomas or brain metastases who require corticosteroids or 
anticonvulsants must be on a stable dose of corticosteroids and seizure free for 
1 month prior to enrollment.  Patients with known brain metastases should have 
had brain irradiation (whole brain or gamma knife) more than 4 weeks before 
starting the protocol.  Note that patients should have had their steroids tapered to 
low dose (i.e., < 1.5 mg of dexamethasone/day). 
3.1.11 The effects of belinostat on the developing human fetus are unknown.  For this 
reason and because HDAC inhibitors are known to be teratogenic, women of 
child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and 
for the duration of study participation.  Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she should inform her 
treating physician immediately. 
3.1.12 Ability to understand and the willingness to sign a written informed consent 
document. 
3.2 
Exclusion Criteria 
3.2.1 Prior therapy with belinostat.  
3.2.2 Patients may not be receiving any other investigational agents. 


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3.2.3 Patients with history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to belinostat, including hydroxamate compounds 
or arginine. 
3.2.4 Patients should not have taken valproic acid, another HDAC inhibitor, for at least 
2 weeks prior to enrollment. 
3.2.5 Patients with uncontrolled intercurrent illness including, but not limited to ongoing 
or active infection, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
3.2.6 Pregnant women are excluded from this study because belinostat is an HDAC 
inhibitor with the potential for teratogenic or abortifacient effects.  Because there 
is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with belinostat, breastfeeding should be discontinued if 
the mother is treated with belinostat. 
3.2.7 Having chronic hepatitis B or C will not exclude patients from participating if they 
are otherwise eligible; however, requiring treatment with interferon is an 
exclusion.  Patients must be stable without having received interferon in at least 4 
weeks. 
3.2.8 HIV positive patients who are not on retroviral therapy will not be excluded from 
cohort 1, the normal liver function cohort.   
HIV positive patients who are not on retroviral therapy will be excluded from 
cohorts 2-4 because of confounding effects from potential complications from HIV 
and opportunistic infections. 
3.2.9 HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for the increased risk of liver dysfunction from the antiretroviral 
therapies themselves and because of potential PK interactions with belinostat.  
Appropriate studies will be undertaken in these groups of patients when indicated.  
3.2.10  Patients with significant cardiovascular disease (New York Heart Association 
Class III or IV cardiac disease), symptomatic congestive heart failure, myocardial 
infarction within the past 6 months, unstable angina, unstable arrhythmia or a need 
for anti-arrhythmic therapy (use of frequency adjusting medication for atrial 
fibrillation is allowed, if stable medication for at least last month prior to initiation 
of belinostat treatment and medication not listed as causing Torsades de Points), or 
evidence of acute ischemia on ECG.  Marked baseline prolongation of QT/QTc 
interval, e.g., repeated demonstration of a QTc interval > 450 msec; Long QT 
Syndrome.  Concomitant use of drugs known to prolong the QT interval and/or 
cause Torsades de Pointes (Table 1, Appendix C) is not allowed during the study 
or within 2 weeks of study entry.  These drugs should also be avoided for up to 
4 weeks following discontinuation of study treatment.  Drugs that may be 
associated with Torsades de Pointes but lack substantial evidence (Table 2, 
Appendix C) will be allowed at the discretion of the PI (although it is preferable to 
substitute an alternate medication), and patients will be closely monitored. 


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3.3 
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
3.4 
Research Eligibility Evaluation  
3.4.1 History and Physical Examination: Complete history and physical examination 
(including height, weight, vital signs, EKG, and performance score) will be 
conducted prior to starting study drug administration. 
3.4.2 Imaging Studies (Baseline): Every participant should have a clinical evaluation of 
known sites of disease as part of the baseline evaluation.  All patients will be 
required to undergo a CT scan of the chest/abdomen/pelvis to evaluate sites of 
disease within 28 days prior to start of study drug administration.   
3.4.3 Laboratory Evaluation: Baseline laboratory data are to be obtained within 1 week 
prior to starting study drug. 
3.4.3.1 Hematological Profile: CBC with differential and platelet count. 
3.4.3.2 Coagulation Studies: PT*/INR/aPTT* is required to be checked at baseline 
*=as clinically indicated 
3.4.3.3 Biochemical Profile: electrolytes, BUN, creatinine, glucose, AST, ALT, 
bilirubin, calcium, phosphorous, albumin, magnesium, alkaline 
phosphatase. 
3.4.3.4 Serum pregnancy test for female participants of childbearing age and 
anatomic ability. 
3.4.4 Histologic confirmation will be required prior to enrollment (except for patients 
with hepatocellular carcinoma; see Section 3.1.1).  A pathology report from the 
time of diagnosis will be required from each participant to confirm diagnosis.  A 
pathology report from a known recurrence will be accepted if the original report is 
not available.  
3.4.5 Laboratory evaluation for patients with hepatocellular carcinoma secondary to 
hepatitis B or C: 
3.4.5.1 For patients with hepatitis B:  
 HepBsAg, HepBcAb, HepBsAb, and HepBeAb; results may be from 
within 3 months before starting on study. 
 COBAS TaqMan; results must be from within 1 month before starting 
on study. 


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3.4.5.2 For patients with hepatitis C:  
 anti-HCV; results may be from within 3 months before starting on 
study. 
 HCV-RNA; results must be from within 1 month before starting on 
study. 
 
3.4.6 Child-Pugh Classification (CPC) of liver dysfunction: each patient’s CPC score 
should be calculated during the eligibility assessment and submitted with the 
protocol registration at enrollment.  See Appendix M for instructions on CPC 
calculation. 
 
4 REGISTRATION PROCEDURES 
4.1 
Registration Process 
Registrations for the trial must be made through the Coordinating Center at the National Cancer 
Institute.  Patients are registered Monday through Friday between the hours or 8:30am through 
4:30pm, excluding Federal Holidays.  Prior to patient registration, documentation of IRB 
approval by collaborating institutions must be on file.  
 
Slot Reservation 
Once a patient has been identified for potential enrollment, the participating site’s data manager 
or research nurse must contact the Developmental Therapeutics Clinic (DTC) Research Nurse at 
(301) 435-4949.  (See Appendix H for slot reservation procedures). 
4.1.1 Coordinating Site Registration Process 
Authorized staff must register an eligible candidate with the NCI Central Registration Office 
(CRO).  A registration Eligibility Checklist from the Web site (http:// 
home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via encrypted 
email to:  NCI Central Registration Office (HOIS) (ncicentralregistration-l@mail.nih.gov).  After 
confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise 
them of the acceptance of the patient on the protocol prior to the release of any investigational 
agents.  Verification of Registration will be forwarded electronically via e-mail.   


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4.1.2 Participating Site Registration (Appendix H) 
Registration will be done centrally by the Coordinating Center at the NCI per the detailed 
instructions in Appendix H.  A protocol registration form and a cover memo will be supplied by 
the Coordinating Center, NCI DTC (See Appendix J for Eligibility/Pre-Registration Worksheet) 
and updates will be provided as needed.  Patient eligibility and demographic information is 
required for registration.  To register a patient, fax copies of the following pre-registration 
documents, signed informed consent, HIPAA authorization form, required pre-study tests 
(baseline laboratory and pathology reports), and the completed Eligibility/Pre-Registration form 
to the Coordinating Center’s Research Nurse Nancy Moore, RN, phone (240) 760-6045 
(nancy.moore@nih.gov).  The Coordinating Center will notify the participating site by e-mail to 
confirm that the protocol registration documents have been received.  
 
All eligible patients will be registered though the NCI Center Registration Office (CRO).  The 
CRO is open from 8:30 am to 5:00 pm EST Monday through Friday, excluding federal holidays.  
The Coordinating Center’s research nurse will complete and fax a registration Eligibility 
Checklist from the web site (http:// home.ccr.cancer.gov/intra/eligibility/welcome.htm).  After 
confirmation of eligibility at the Central Registration Office, CRO staff will assign a unique 
patient/subject ID number for each patient that will be used to enter data into the C3D database.  
An encrypted electronic verification of registration form will be sent to the NCI research nurse.  
The Coordinating Center’s research nurse will assign a dose, and a patient study ID number.  This 
information will be included on the confirmation of registration form.  The confirmation form 
will be sent to the data manager or research nurse by email.  The assigned patient ID will be used 
to code research samples and reference patients during the Organ Dysfunction Working Group 
conference call (See Appendices H and I for Registration Procedures and Conference Call 
Procedures).  Questions about eligibility should be directed to the Coordinating Center’s Research 
Nurse. 
 
Following registration, patients should begin protocol treatment within 72 hours.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
4.1.3 Off-Study Procedure 
Off-Study Procedure: Authorized staff must notify the Coordinating Center’s Research Nurse 
when a patient is taken off study.  The off study form is included in Appendix K and must be 
completed and sent via encrypted email to:  NCI Central Registration Office (HOIS) 
(ncicentralregistration-l@mail.nih.gov).   
 
 


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5 TREATMENT PLAN 
5.1 
Belinostat Administration 
Treatment will be administered on an outpatient basis.  On days when belinostat is given, it will 
be administered IV over 30 minutes.  Either peripheral or central IV can be used.  Reported 
adverse events and potential risks are described in Section 7.  Appropriate dose modifications for 
belinostat are described in Section 6.  No investigational or commercial agents or therapies for the 
purpose of treating the malignancy may be administered while the patient receives belinostat.  
5.1.1  Stratification by Hepatic Dysfunction Group 
Patients will be divided into 4 cohorts based on their level of liver dysfunction: 
Cohort 1: Normal hepatic function: bilirubin ≤ ULN and AST ≤ ULN  
Cohort 2: Mild hepatic dysfunction: bilirubin > ULN but ≤ 1.5 x ULN and/or AST > 
ULN  
Cohort 3: Moderate hepatic dysfunction: bilirubin > 1.5 x ULN to ≤ 3 x ULN and any 
AST 
Cohort 4: Severe hepatic dysfunction: bilirubin > 3 x ULN but ≤ 10 x ULN and any 
AST 
5.1.2 Schedule 
On Day -7 (Cycle 1 only), patients in all cohorts will receive belinostat 400 mg/m2 and 
have baseline and post-dose blood samples collected for PK measurements (Section 9.1;  
post-dose samples collected 15 and 25 minutes after starting infusion, and then at the 
following time points after the end of infusion: 5, 10, 15, 30, 60, 90 minutes, 2, 4, 6, 8, 
and 24 hours).  
 
On Days 1–5 of each cycle, patients in all cohorts will receive their assigned dose of 
belinostat based on their level of hepatic toxicity, according to the table below.  Dose 
escalation will begin at dose level 1.   
 
Including Day -7, the total duration of Cycle 1 will be 28 days.  All other cycles will be 
21 days. 
 
A new cycle may begin 1 day earlier or 1 day later than it would otherwise be scheduled 
based on the 28 days for cycle 1 and the 21 days for the other cycles, i.e., the second cycle 
may begin on day 27, 28, or 29 and the third and later cycles may begin on day 20, 21, or 
22, to allow for flexibility for days the clinic is closed and other unexpected events.   
 
Although belinostat’s effect on cardiovascular safety parameters is not assessed as a major 
concern, for patient safety, an EKG will be done after 5 days of belinostat at the cohort-


CTEP #8846 
Clinical Center #11-C-0060 
 
26 
 
assigned dose (Cycle 1 Day 5) and again pre-Cycle 2 to evaluate for any elevation in QTc 
after cumulative exposure. 
5.1.3 Dose Escalation Scheme 
 
Dose Level of Belinostat (mg/m2/day) 
 
-1 
1 
2 
3 
4 
Cohorts: 
Normal 
750 
1000 
No 
escalation 
No 
escalation 
No 
escalation  
Mild 
Dysfunction 
500 
750 
1000 
No 
escalation 
No 
escalation 
Moderate 
Dysfunction 
250 
500 
750 
1000 
No 
escalation 
Severe 
Dysfunction 
125 
250 
350 
500 
750 
 
Each patient’s starting dose will be assigned by the Coordinating Center at the time of 
registration according to the dose escalation scheme and hepatic dysfunction criteria 
outlined above.  Patients whose degree of hepatic dysfunction changes (becomes worse or 
better) between registration and initiation of protocol therapy may be re-assigned to a 
different dysfunction group and dose level.  This change should be discussed with the 
Principal Investigator.  The Coordinating Center must document reassignments with 
notification to Theradex. 
 
All cohorts can accrue simultaneously.  Doses in more severe cohorts will not be escalated 
beyond doses being tested in less severe cohorts.  If DLT-level toxicity is noted in dose 
level 1, then dose de-escalation to level -1 may occur.  A patient will be dose reduced to 
the next lowest dose level if they experience and recover from a Grade 4 adverse event 
(see Section 6.1.1.). 
5.1.4 Definition of Evaluable and Complete Cycle 
A cycle is defined as 21 days, with Day 1 starting the first day of the 5-day treatment 
period.  If a patient receives the total dose of belinostat as planned over the course of 
5 days and remains in the study until Day 21, unless taken off treatment for toxicity, the 
patient will be considered to have completed a cycle of therapy and will be considered 
evaluable.  Patients who do not complete a cycle of therapy for reasons other than toxicity 
will be replaced.  Patients who experience a DLT on day -7 will be taken off treatment.  
They will not be treated with the 5-day course.  This will be considered a DLT for study 
purposes and will affect dose escalation for that cohort. 
5.1.5 Maintaining Consistent Dosing Across the Hepatic Dysfunction Groups 
In general, results from each hepatic dysfunction group will have implications for the 
other groups based upon the assumption that at any given dose level, the dysfunction-


CTEP #8846 
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27 
 
toxicity response gradient is monotonic.  In other words, patients in a particular group will 
not tolerate a dose not tolerated by a group with lesser dysfunction and conversely, will 
tolerate a dose tolerated by a group with greater dysfunction.  When discrepancies arise 
between observed results and this principle, they will be resolved in the direction of 
conservative practice.  That is, the lower dose will be recommended for both groups if a 
higher dose is tolerated in a group of greater dysfunction, but not in the group of lesser 
dysfunction.  In particular, dose level assignments and MTD determination will be made 
consistent across the various hepatic dysfunction groups as follows: 
 
Observation for a Particular Dysfunction Group 
Resulting Action for other Dysfunction Groups 
MTD has been exceeded at a dose level. 
Accrual at that dose level or higher is terminated for 
all cohorts with greater hepatic dysfunction. 
MTD has been established at a dose level. 
Accrual at lower dose levels is terminated for all 
cohorts with lesser hepatic dysfunction.  New 
patients will be enrolled at the dose found to be safe 
in the higher hepatic dysfunction cohort.* 
MTD has been established in one cohort while 
simultaneously the MTD has been exceeded at that 
dose in a cohort with lesser dysfunction.   
The MTD in both cohorts is determined to be the 
dose of the cohort with the lesser hepatic 
dysfunction.   
* For example, if a dose of 1000 mg/m2 is found to be safe for the moderate dysfunction cohort, then enrollment will 
be terminated to the 750 mg/m2 cohorts of the mild dysfunction cohort and all subsequent patients will be enrolled at 
the 1000 mg/m2 cohort.  No changes will be made to the enrollment for the severe dysfunction cohort. 
 
5.2 
Definition of Dose-Limiting Toxicity 
DLT will be a toxicity that occurs during Cycle 1 and is felt to be possibly, probably, or definitely 
related to the study drug and meets the following criteria: 
5.2.1 Grade ≥3 non-hematologic toxicity will be considered dose-limiting, with the 
following exceptions:  
 Allergic reaction/hypersensitivity will not be considered dose limiting. 
 Alopecia will not be considered dose limiting. 
 Grade ≥3 diarrhea will only be considered dose limiting if, after 24 hours, it is 
refractory to treatment. 
 Grade ≥3 nausea and vomiting will only be considered dose limiting if after 
24 hours it is refractory to maximal anti-emetic therapy and unable to be 
corrected to Grade 1 or baseline. 
 Grade 3 rise in creatinine, not corrected to Grade 1 or baseline after fluids 
within 24 hours, will be considered dose limiting.  All Grade 4 rises in 
creatinine will be dose limiting. 
 Grade ≥3 electrolyte toxicities unable to be corrected to Grade 1 or baseline 
within 48 hours will be considered dose limiting.  


CTEP #8846 
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28 
 
 Elevated bilirubin will be defined as DLT by the criteria as specified in 
Section 5.2.4. 
5.2.2 Grade 4 hematological toxicity  
 Neutropenia: Drug-related Grade 4 neutropenia for >5 days without fever or 
infection will be considered dose limiting.  Grade 4 neutropenia of any 
duration accompanied by fever or infection will be considered dose limiting.  
 Grade 4 thrombocytopenia. 
 Grade 4 lymphopenia, anemia, or leucopenia without neutropenia will NOT 
constitute a DLT.   
5.2.3 Any neurotoxicity Grade ≥ 2 that is not reversible to a Grade ≤ 1 or baseline within 
2 weeks will be considered dose limiting.  For patients with neuropathy at 
baseline, an increase in grade that does not reverse within 2 weeks and is felt to be 
drug related will be considered a DLT.  
5.2.4 Liver toxicity as described: 
Worsening liver function, as defined by a rise in serum bilirubin, not related to 
tumor progression, stent occlusion, or worsening viral hepatitis will constitute a 
DLT if a patient in the mild group progresses into the severe dysfunction range for 
1 week, or if a patient in either the moderate or severe groups has a > 1.5 times 
increase in bilirubin lasting 1 week.  (Note: In the moderate cohort, a > 1.5 times 
increase over baseline level of total bilirubin that does not put a patient in the 
severe group does not constitute a DLT). 
5.2.5 Delays in new treatment cycles by ≥ 2 weeks due to treatment-related toxicity will 
constitute a DLT. 
Management and dose modifications associated with the above AEs are outlined in Section 6.   
5.3 
Design   
Twelve patients will be enrolled on the normal hepatic function cohort (cohort 1).  Cohort 2 will 
undergo dose escalation according to a 3+3 design.  The remaining cohorts (cohort 3 and 4) will 
undergo a similar dose escalation design to cohort 2, but with the flexibility to over accrue an 
additional 1 or 2 patients per dose level.  See Section 6 for intrapatient dose modification 
guidelines. 
 
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥ 2 
Dose escalation will be stopped.  This dose level will be 


CTEP #8846 
Clinical Center #11-C-0060 
 
29 
 
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 out 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.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out 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 the recommended phase 2 
dose. 
 
5.4 
Supportive Care Guidelines 
Patients should be provided supportive care as medically indicated.  This includes blood product 
support, antibiotic treatment, and management of any other medical conditions. 
 
Prophylactic measures for nausea/vomiting are allowed.  
 
If diarrhea develops and does not have an identifiable cause other than study drug administration, 
anti-diarrheals such as Lomotil (diphenoxylate HCl 2.5 mg + atropine sulfate 0.025 mg/tablet) 
dosed according to package insert or loperamide 4 mg po after the first unformed stool with 2 mg 
po every 2 hours as long as unformed stools continue (4 mg every 4 hours while asleep).  No 
more than 16 mg of loperamide should be taken in during a 24-hour period.  This regimen can be 
repeated for each diarrheal episode.  Diarrhea will be considered refractory if it does not resolve 
within 24 hours = to Grade 2 with the above regimen (16 mg, or less if there is resolution of the 
symptoms, of loperamide in a 24-hour period). 
5.5 
General Concomitant Medication  
All concurrent medications should be documented prior to initiation of treatment, and be 
periodically reviewed with the patient.  Particular attention must be paid to medications which 
may prolong the QTc interval (Appendix C) and agents that interact with CYP450 isoenzymes 
(Appendix D).   
 
QTc Prolongation: 
Caution should be exercised when administering belinostat to patients with a history of QTc 
interval prolongation, in patients taking anti-arrhythmics or other medications that may prolong 
the QTc interval, and those with relevant pre-existing cardiac disease.  As Appendix C/Table 1 
includes medications that are generally accepted to carry the risk of causing QTc prolongation and 
Torsades de Pointes, patients requiring those medications will not be eligible for this protocol.  


CTEP #8846 
Clinical Center #11-C-0060 
 
30 
 
Use of these drugs is not allowed within 2 weeks of study entry, while the patient is on protocol, 
and within 4 weeks of ending protocol treatment.  Those medications listed in 
Appendix C/Table2 as reported but lacking substantial evidence for causing QTc prolongation 
and Torsades de Pointes will be allowed at the discretion of the PI, although if an alternative 
medication can be substituted, that would be preferable.  If the patient remains on a medication in 
Table 2, they should have an EKG prior to each cycle.   
 
CYP450 Interactions: 
At the present time, no in vivo human studies have been conducted to elucidate the metabolic and 
drug interaction profiles of belinostat.  In vitro data indicate that belinostat is an inhibitor of 
CYP2C8 and CYP2C9.  Belinostat is a potential inducer of CYP1A2, CYP2B6, CYP2C9, 
CYP2C19 and CYP3A4.  There is evidence that belinostat is a substrate of CYP2D6 and 
CYP3A4.  Attention and caution must be used when patients are on belinostat and another 
medication that might affect any of these isoenzymes (Appendix D).   
5.6 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue 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, or 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
5.7 
Duration of Follow Up 
Patients will be followed for 30 days after the last dose is administered or until one of the 
following occurs: patient enrolls on another protocol (phase 0 or early phase I), patient receives 
standard of care, or death, whichever comes first.  The follow-up will consist of a phone call 
between Days 27-30 after the last dose to evaluate adverse events that were ongoing and any new 
events that might be deemed related to the therapy.  Unacceptable toxicities (i.e., AEs related to 
the intervention) that have not resolved by Day 30 post-treatment will be followed via biweekly 
phone calls until stabilization or resolution. 
5.8 
Criteria for Removal From Study 
Patients will be removed from study for one of the following reasons:  
 patient completed 30-day follow-up period,  
 patient experiences an infusion or allergic reaction to belinostat which consists of 
bronchospasm, shortness of breath, hypoxia, or hypotension, 
 toxicities are unresolved but stabilized,  


CTEP #8846 
Clinical Center #11-C-0060 
 
31 
 
 patient enrolls on another protocol (phase 0 or early phase I), or  
 patient receives standard of care.   
 
The reason for study removal and the date the patient was removed must be documented in the 
medical record. 
 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
6.1 
Intrapatient Dosing, Non-Hepatic Toxicities 
There will be no dose modification for lymphopenia, anemia, or leucopenia without 
neutropenia of any grade.   
6.1.1 Patients who experience a non-hepatic toxicity > Grade 1 but < Grade 4 may 
proceed to a subsequent cycle at the same dose level if the toxicity improves to 
Grade 1 or to baseline within 2 weeks of the previous cycle.  Patients who 
experience a Grade 4 dose limiting toxicity may proceed to a subsequent cycle at 
the next lower dose level if their toxicity improves to Grade 1 or to baseline within 
2 weeks of the previous cycle.  If any toxicity > Grade 1 does not improve to 
Grade 1 or baseline within 2 weeks, the patient will come off treatment.   
6.1.2 In the case of a single occurrence of grade 4 QTc prolongation (QTc > 500 msec in 
combination with life-threatening signs or symptoms, e.g., arrhythmia, CHF, 
hypotension, shock, syncope; Torsades de pointes), belinostat should be 
discontinued permanently.  
6.1.3 In the event of a Grade 3 QTc prolongation (QTc >500 msec; without life-
threatening symptoms described above), study treatment should be temporarily 
withheld until the QTc interval returns below 500 msec.  Patients should be 
monitored with daily ECGs until the QTc interval returns below 500 msec. 
Treatment may then be resumed at the next lower dose level.  
In the event of a subsequent prolongation of QTc interval >500 msec after 2 dose 
reductions according to above, further treatment with belinostat should be 
discontinued. 
6.1.4 In the event of an infusion reaction or allergic reaction to belinostat, the patient 
will be treated with antihistamines, steroids, and/or epinephrine, as appropriate.  
a. Patients who experience an infusion or allergic reaction to belinostat consisting 
of rash, itchy throat, or mild cough can remain on study and be premedicated 
for all future doses.  If a similar or worse reaction occurs when the patient 


CTEP #8846 
Clinical Center #11-C-0060 
 
32 
 
receives belinostat after being premedicated, the patient will not be re-exposed, 
and will come off study.   
b. Patients who experience an infusion or allergic reaction to belinostat consisting 
of bronchospasm, shortness of breath, hypoxia, or hypotension will not be re-
exposed, and the patient will come off study.   
6.2 
Intrapatient Dosing, Hepatic Toxicities   
6.2.1 Treatment for an individual patient will stop immediately when the bilirubin rises 
to the level of a DLT.  Treatment for that patient can resume after a DLT under the 
following conditions:   
 The bilirubin of a patient in the mild cohort returns to at least the moderate 
dysfunction range within 2 weeks.  The patient will be treated at one dose level 
lower (unless they are already on dose level -1, in which case they will be 
taken off treatment) or at the dose for moderate dysfunction, whichever is 
lower.   
 The bilirubin of a patient in the moderate cohort returns to the range of 
moderate dysfunction within 2 weeks.  The patient will be treated at one dose 
level lower unless they are already on dose level -1, in which case they will be 
taken off treatment.    
 The bilirubin of a patient in the severe cohort returns to ≤ 1.2 x baseline 
bilirubin within 2 weeks.  The patient will be treated at one dose level lower 
unless they are already on dose level -1, in which case they will be taken off 
treatment.    
 
If the bilirubin does not return to within the above-stated ranges within 2 weeks, 
the patient will be taken off treatment.   
6.2.2 If a patient has worsening liver function that leads to a cohort change but does not 
constitute a DLT, they will be treated according to the dose level being used for 
their new cohort, except if that dose is the same or higher than the dose on which 
they have already been treated.  If the dose of their new cohort is the same or 
higher, they will be treated at one dose level lower than the previous dose that they 
received.    
6.2.3 If a patient experiences an improvement in liver function during treatment, there 
will be no change in dose during an ongoing cycle, but treatment may resume at a 
new dose level determined by the cohort that would apply based on their liver 
function, if there is continued improvement at the time of the next cycle. 
 
 


CTEP #8846 
Clinical Center #11-C-0060 
 
33 
 
7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event monitoring and reporting is a routine part of every clinical trial.  The following list 
of adverse events (Section 7.1) and the characteristics of an observed adverse event (Section 7.2) 
will determine whether the event requires expedited (via CTEP-AERS; Section 7.3) or routine 
(via CTMS; Section 7.4) reporting.   
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Belinostat (PXD 101, 
NSC 726630) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the Agent 
Specific Adverse Event List (ASAEL), appears in a separate column and is identified with bold 
and italicized text.  This subset of AEs (ASAEL) contains events that are considered 'expected' 
for expedited reporting purposes only.  Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification.  Frequency is provided based on 583 patients.  Below is the CAEPR for 
belinostat (PXD 101). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.6, September 12, 20161 
 Adverse Events with Possible  
 Relationship to Belinostat (PXD-101) 
 (CTCAE 4.0 Term) 
[n= 583] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
  
INFECTIONS AND INFESTATIONS 
  


CTEP #8846 
Clinical Center #11-C-0060 
 
34 
 
 Adverse Events with Possible  
 Relationship to Belinostat (PXD-101) 
 (CTCAE 4.0 Term) 
[n= 583] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Infection2 
 
 Infection2 (Gr 3) 
INVESTIGATIONS 
  
 
Creatinine increased 
 
  
 
Electrocardiogram QT corrected interval 
prolonged 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 4) 
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Dysgeusia 
 
  
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Dyspnea 
 
 Dyspnea (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
  
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing (Gr 2) 
 
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 may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on belinostat (PXD-101) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that belinostat (PXD-101) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac disorders - Other (bundle branch 
block left); Heart failure; Left ventricular systolic dysfunction; Myocardial infarction; Palpitations; Sinus 
bradycardia; Sinus tachycardia; Supraventricular tachycardia; Ventricular fibrillation 
EYE DISORDERS - Eye disorders - Other (visual acuity reduced); Eye disorders - Other (visual loss) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Dyspepsia; Gastroesophageal reflux disease; 
Mucositis oral; Rectal hemorrhage; Small intestinal obstruction; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Flu like symptoms; General 
disorders and administration site conditions - Other (general physical health deterioration); Infusion related reaction; 
Malaise; Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (hepatic cirrhosis) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Tracheal hemorrhage 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; CPK increased; Cardiac troponin I increased; Cholesterol 


CTEP #8846 
Clinical Center #11-C-0060 
 
35 
 
high; Ejection fraction decreased; INR increased; Investigations - Other (electrocardiogram T wave inversion); 
Investigations - Other (prothrombin time shortened); Investigations - Other (total protein decrease); Lipase increased; 
Weight gain; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; Hypermagnesemia; 
Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hyponatremia; Hypophosphatemia; Tumor 
lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Bone pain; Chest 
wall pain; Generalized muscle weakness; Musculoskeletal and connective tissue disorder - Other (muscle spasms); 
Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Depressed level of consciousness; Dysesthesia; Encephalopathy; 
Lethargy; Nervous system disorders - Other (apraxia); Nervous system disorders - Other (burning sensation); 
Peripheral sensory neuropathy; Seizure; Stroke; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Depression; Insomnia; Psychosis 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other (azotemia); 
Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema; Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Hiccups; Hypoxia; Nasal 
congestion; Pneumonitis; Pulmonary hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Pruritus; Urticaria 
VASCULAR DISORDERS - Hematoma; Hypertension; Hypotension; Phlebitis; Thromboembolic event; Vasculitis 
 
Note: Belinostat (PXD-101) 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. 
 
7.2 
Adverse Event Characteristics  
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for expedited 
reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold and italicized in the CAEPR 
(Section 7.1). 
Attribution of the AE: 
– Definite – The adverse event is clearly related to the study treatment. 
– Probable – The adverse event is likely related to the study treatment. 
– Possible – The adverse event may be related to the study treatment. 
– Unlikely – The adverse event is doubtfully related to the study treatment. 
– Unrelated – The adverse event is clearly NOT related to the study treatment. 


CTEP #8846 
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7.3 
Expedited Adverse Event Reporting 
7.3.1 Expedited adverse event reporting for this study is via CTEP-AERS (CTEP 
Adverse Event Expedited Reporting System), accessed via the CTEP homepage 
(http://ctep.cancer.gov).  The reporting procedures to be followed are presented in 
the “NCI Guidelines: Expedited Adverse Event Reporting Requirements for NCI 
Investigational Agents” which can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification is 
to be made to NCI by telephone at:  301-897-7497, or 301-897-7402 for CIP 
studies.  An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy 
feature for other e-mail recipients.  
7.3.2 Expedited Reporting Guidelines – CTEP-AERS Reporting Requirements for 
Adverse Events That Occur Within 30 Days1 of the Last Dose of the 
Investigational Agent on Phase 1 Trials 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Unexpected  
and Expected 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  
and 
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
 
Grade 4 unexpected events  
 
Grade 5 expected events and unexpected events 
 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report 
is required as outlined in the table. 
December 15, 2004 
 
Note:  All deaths on study must be reported using expedited reporting regardless of 
causality.  Attribution to treatment or other cause should be provided. 
 


CTEP #8846 
Clinical Center #11-C-0060 
 
37 
 
 Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE 
via CTEP-AERS within 24 hours of learning of the event followed by a 
complete CTEP-AERS report within 5 calendar days of the initial 24-hour 
report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event.  
 Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of designation as expected or unexpected and attribution with the 
exception of events identified as protocol-specific expedited adverse event 
reporting exclusions. 
 Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS if the 
event occurs following treatment with an agent under a CTEP IND. 
 Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports. 
7.3.3 Protocol-Specific Expedited Adverse Event Reporting Exclusions   
 
 
 
For this protocol only, certain adverse events/grades are exceptions to the 
Expedited Reporting guidelines and do not require expedited reporting.  The following 
adverse events should be reported through the routine reporting mechanism (Section 7.4): 
any grade lymphopenia, Grade 2 electrolyte abnormalities, alopecia (any grade), 
anemia (grade 2), albumin (grade 2), hyperuricemia (grade 3), INR (grade 2), and 
PTT (grade 2) will NOT be reported through CTEP-AERS but will be reported in 
the routine data submissions.  
 Events that are clearly consequences of the “main” event (e.g., hypokalemia 
associated with diarrhea or the arrhythmias, hypotension, hypoxia, etc. that are known 
to occur concurrently with sepsis) may be noted in the Description of Event in the 
CTEP-AERS report and do not require separate CTEP-AERS reports. 
 The possibility of the contribution of comorbid conditions to the event should be 
considered when reporting adverse events.  Examples include hyperglycemia in 
patients with diabetes, or headaches and seizures in patients with brain tumors. 
7.3.4 Pregnancy, Fetal Death and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or 
“Neonatal loss”, the Pregnancy Information Form should also be completed for 
patients who became pregnant on study, and faxed along with any additional 
medical information to 301-230-0159.  The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 


CTEP #8846 
Clinical Center #11-C-0060 
 
38 
 
the “Description of Event” section of the CTEP-AERS report. 
 
7.3.4.1 Pregnancy 
 Because patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic, DCTD/DCP is requesting that pregnancy 
should be reported in an expedited manner via CTEP-AERS as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other (pregnancy)” under the 
Pregnancy, puerperium and perinatal conditions SOC. 
 
 The pregnancy outcome for patients on study should be reported via CTEP-AERS 
at the time the outcome becomes known, accompanied by the same Pregnancy 
Report Form used for the initial report. 
 
7.3.4.2 Fetal Death 
 
 Fetal death is defined in CTCAE as “A disorder characterized by death in utero; 
failure of the product of conception to show evidence of respiration, heartbeat, or 
definite movement of a voluntary muscle after expulsion from the uterus, without 
possibility of resuscitation.” 
 Any fetal death should be reported expeditiously, as Grade 4 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC. 
 A fetal death should NOT be reported as “Fetal death,” a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-AERS 
recognizes this event as a patient death. 
 
7.3.4.3 Death Neonatal 
 
 Neonatal death, defined in CTCAE as “A disorder characterized by cessation of 
life occurring during the first 28 days of life” that is felt by the investigator to be at 
least possibly due to the investigational agent/intervention, should be reported 
expeditiously. 
 A neonatal death should be reported expeditiously as Grade 4 “General disorders 
and administration - Other (neonatal loss)” under the General disorders and 
administration SOC. 
 Neonatal death should NOT be reported as “Death neonatal” under the General 
disorders and administration SOC, a Grade 5 event.  If reported as such, the 
CTEP-AERS interprets this as a death of the patient being treated. 


CTEP #8846 
Clinical Center #11-C-0060 
 
39 
 
7.3.5 NCI-IRB Expedited Reporting of Adverse Events, Unanticipated Problems, 
and Deaths 
7.3.5.1 Definitions 
Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that 
occurs during the course of the clinical trial associated with the use of a drug in 
humans, whether or not the event is considered related to the treatment or 
clinically significant.  For this study, AEs will include events reported by the 
patient, as well as clinically significant abnormal findings on physical examination 
or laboratory evaluation.  A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is 
considered an AE.  All AEs must be recorded on the AE case report form unless 
otherwise noted.  
 
All AEs, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until satisfactory resolution.  
AEs should be reported up to 30 days following the last dose of study drug.  AEs 
that are considered treatment related, expected, continuing, but not resolvable by 
30 days after treatment completion (e.g., alopecia) will not be followed after the 
30-day period. 
 
An abnormal laboratory value will be considered an AE if the laboratory 
abnormality is characterized by any of the following: 
 
Results in discontinuation from the study 
 
Is associated with clinical signs or symptoms  
 
Requires treatment or any other therapeutic intervention 
 
Is associated with death or another serious adverse event, including 
hospitalization.  
 
Is judged by the Investigator to be of significant clinical impact 
 
If any abnormal laboratory result is considered clinically significant, the 
investigator will provide details about the action taken with respect to the 
test drug and about the patient’s outcome. 
Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  For the purposes of 
IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a 
causal relationship between the drug and the adverse event.  A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug. 
 


CTEP #8846 
Clinical Center #11-C-0060 
 
40 
 
Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is 
not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or available, 
is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application.  “Unexpected”, also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the 
definition of a Serious Adverse Event or if it compromises the safety, welfare, or 
rights of subjects or others. 
Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view 
of the investigator or the sponsor, it results in any of the following: 
 
Death, 
 
A life-threatening adverse drug experience 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
Disability 
 A substantial disruption of a person’s ability to conduct normal life functions. 
Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, 
in the view of the investigator or sponsor, at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction that had it occurred in a 
more severe form, might have caused death. 


CTEP #8846 
Clinical Center #11-C-0060 
 
41 
 
Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB approved study procedures in a 
research protocol   
 
Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program 
(HRPP) policies, IRB requirements, or regulatory requirements for the protection 
of human research subjects. 
Unanticipated Problem 
Any incident, experience, or outcome that: 
 Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol 
and informed consent document; Investigator’s Brochure or other study 
documents, and 
(b) the characteristics of the subject population being studied; AND 
 Is related or possibly related to participation in the research; AND 
 Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
7.3.5.2 NCI-IRB and Clinical Director Reporting 
NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths 
The NCI-IRB requires that the following language be used for reporting events to 
the NCI-IRB and the Clinical Director: 
 
The Coordinating Center PI will report to the NCI-IRB: 
 All unexpected serious adverse events that are possibly, probably, or definitely 
related to the research  
 All deaths, except deaths due to progressive disease  
 All Protocol Deviations 
 All Unanticipated Problems 
 All non-compliance 
 
Reports must be received within 7 days of Coordinating Center PI awareness via 
iRIS. 


CTEP #8846 
Clinical Center #11-C-0060 
 
42 
 
7.3.5.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of unanticipated problem will 
need to be reported to the NCI IRB. 
7.3.6 Multicenter Guidelines for Expedited Adverse Event Reporting 
7.3.6.1 Expedited Adverse Event Reporting for Participating Sites 
Adverse Event Reporting via CTEP-AERS: 
Participating sites are responsible for submitting any expedited adverse event 
reports directly to CTEP.  Follow sponsor expedited AE reporting requirements in 
Section 7.3.2.  Copy Nancy Moore (nancy.moore@nih.gov) and Naoko Takebe, 
MD (takeben@mail.nih.gov) on all CTEP-AERS reports. 
 
 
Adverse Event Reporting to NCI IRB: 
The site PI must immediately report to the Coordinating Center PI any serious 
adverse event, whether or not considered drug related, including those listed in the 
protocol or investigator brochure and must include an assessment of whether there 
is a reasonable possibility that the drug caused the event within 24 hours of PI 
awareness of the event.  The site PI must also report any protocol deviations or 
violations to the Coordinating Center PI within 7 days of PI awareness.  
Participating centers must also submit the report to their IRB in accordance with 
their institutional policies. 
 
7.4 
Routine Adverse Event Reporting 
Those adverse events that do not require expedited reporting must be reported in routine study 
data submissions via CTMS (see Section 12.1).  Adverse events reported through CTEP-
AERS must also be reported in routine study data submissions. 
7.4.1 NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing 
Review: 
Please use the following table for reporting adverse events at time of CR: 
System Organ 
Class 
CTCAE 
Term 
Grade 
# of Events 
since last CR 
Total # of 
Events 
Attribution 
to Research 
Serious? 
Unexpected? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the 
 
deviation occurred, a brief description of the deviation and any corrective action. 


CTEP #8846 
Clinical Center #11-C-0060 
 
43 
 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
 All Grade 2 unexpected events that are possibly, probably or definitely related 
to the research;  
 All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research; 
 All Grade 5 events regardless of attribution;  
 All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.5 
Secondary AML/MDS 
AML/MDS events are to be reported via CTEP-AERS (in addition to your routine AE reporting 
mechanisms).  In CTCAE v4.0, the event(s) may be reported as either: 1) Leukemia secondary to 
oncology chemotherapy, 2) Myelodysplastic syndrome, or 3) Treatment related secondary 
malignancy. 
 
8 PHARMACEUTICAL INFORMATION 
Chemical Name:  
N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide 
  
Other Names: 
 
 
PXD101 
 
Classification:  
 
 
Histone deacetylase (HDAC) inhibitor 
 
CAS Registry Number: 
 
414864-00-9 
 
Molecular Formula: 
C15H14N2O4S  
M.W.: 318.35 
 
Approximate Solubility:  Water 0.14 mg/mL; ethanol >200 mg/mL; polyethylene glycol 400 
~ 1.5 mg/mL; 1,2-propanediol ~ 0.2 mg/mL 
 
Mode of Action:     
Histone deacetylases (HDACs) are a family of enzymes that 
regulate chromatin remodeling and gene transcription via the 
dynamic process of acetylation and deacetylation of core histones. 
Belinostat is a novel and potent HDAC inhibitor of the 
hydroxymate class. It alters acetylation levels of histone and non-
histone proteins, thus influencing chromatin accessibility and 
ultimately gene transcription. Additionally, recent data reveals that 
HDAC inhibitors reduce vascular endothelial growth factor 
(VEGF) production and directly inhibit the endothelial cells 
proliferation.  
 


CTEP #8846 
Clinical Center #11-C-0060 
 
44 
 
Description:  
 
A yellow solid powder  
 
How Supplied:   
TopoTarget A/S supplies and the CTEP, DCTD, NCI distributes 
belinostat in single-use 30 mL clear glass vials with coated stoppers 
and aluminum crimp seals with “flip-off” caps containing 500 mg 
belinostat For Injection. The lyophilized product also contains 
arginine, Ph. Eur/USP.   
 
Preparation:  
 
Reconstitute the lyophilized product with 9 mL Sterile Water for 
Injection to yield a concentration of belinostat of 50 mg/mL.  
Before intravenous administration, further dilute in 250 mL 0.9 % 
Sodium Chloride Injection. 
 
Storage:   
 
Store intact vials of belinostat at ambient room temperature (15-
25°C; 59- 77°F); brief excursions permitted (15-30°C; 59-86 °F). 
Leave intact vials of belinostat in the secondary packaging until 
use. 
 
Stability:  
 
Shelf life stability studies of intact vials of belinostat are on-going; 
once the lyophilized product is reconstituted, use it immediately. 
 
Once further diluted in 250 mL of 0.9% sodium chloride, belinostat 
may be stored at ambient room temperature (15-25°C) for up to 24 
hours, including the infusion time. 
 
Route of Administration: Intravenous 
 
Method of Administration: Infuse belinostat intravenously over 30 minutes through an in-line 
0.22 micron low protein binding filter. 
 
Drug Interactions:  
Belinostat and its metabolites are a weak to moderate inhibitor of 
CYP2C8 and a moderate to strong inhibitor of CYP2C9.  
Additionally, CYP3A4 contributes to belinostat metabolism.  
Avoid moderate to strong CYP3A4 inhibitors or inducers and 
CYP2C8 and CYP2C9 substrates during belinostat treatment unless 
deemed medically necessary.  As glucuronidation is the major route 
of elimination for belinostat, caution should be exercised when 
using concomitant medications that are inhibitors of the UGT1A1 
enzyme. 
 
Patient Care Implications: Patients must not use concomitant medication on belinostat 
infusion days that may cause Torsade de Pointes. 
 


CTEP #8846 
Clinical Center #11-C-0060 
 
45 
 
Availability 
 
Belinostat is an investigational agent supplied to investigators by 
the Division of Cancer Treatment and Diagnosis (DCTD), NCI.  
Belinostat is provided to the NCI under a Clinical Trials Agreement 
(CTA) between TopoTarget and the DCTD, NCI (see Section 12.3).  
 
Agent Ordering   
NCI-supplied agents may be requested by the Principal Investigator 
(or their authorized designees) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that the 
agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of investigational agents 
between institutions (unless prior approval from PMB is obtained). 
 The CTEP-assigned protocol number must be used for ordering all 
CTEP-supplied investigational agents.  The responsible investigator 
at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 
(Statement of Investigator), Curriculum Vitae, Supplemental 
Investigator Data Form (IDF), and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one 
institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that 
institution.  
 
 
Active CTEP-registered investigators and investigator-designated 
shipping designees and ordering designees can submit agent 
requests through the PMB Online Agent Order Processing (OAOP) 
application: https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx.  
Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account (https://eapps-
ctep.nci.nih.gov/iam/) and the maintenance of an “active” account 
status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday 
through Friday between 8:30 am and 4:30 pm (ET) or e-mail 
PMBAfterHours@mail.nih.gov anytime. 
 
Agent Accountability  
Agent Inventory Records – The Investigator, or a responsible party 
designated by the Investigator, must maintain a careful record of the 
inventory and disposition of all agents received from DCTD using 
the NCI Drug Accountability Record Form (DARF).  (See the 
CTEP home page at http://ctep.cancer.gov for the Procedures for 
Drug Accountability and Storage and to obtain a copy of the DARF 
and Clinical Drug Request form.) 
Investigator Brochure Availability  –  The current versions of the 
IBs for PMB-supplied agents will be accessible to site investigators 
and research staff through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment 


CTEP #8846 
Clinical Center #11-C-0060 
 
46 
 
of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” 
password.  Questions about IB access may be directed to the PMB 
IB coordinator at IBCoordinator@mail.nih.gov.  
 
 
9 CORRELATIVE/SPECIAL STUDIES 
Pharmacokinetic studies will be done on all patients at all participating sites.  This can be waived 
at the Principal Investigator’s discretion for patient hardship, including lack of venous access.  In 
this event, patients will be replaced to ensure that adequate PK data are obtained for each group 
(i.e., at least 3 patients per group and at least 6 patients at the MTD level). 
9.1 
Pharmacokinetic Studies 
All PK measurements for this study will be performed and analyzed by the Clinical Pharmacology 
Analytical Facility at the University of Pittsburgh Cancer Institute.  All data and results will be 
made available to the investigators on this study, to the industrial collaborator, and to CTEP.  PK 
sampling will be performed on day -7 of the first cycle for all patients. 
9.1.1 Specimen Collection / Documentation 
Prior to drug administration on day -7 of treatment, an indwelling heparin lock should be placed 
so that serial specimens can be collected.  At each sampling time, 1 mL of blood will be 
withdrawn and discarded to assure that the solution used to maintain catheter patency does not 
dilute the sample.  Even if a patient has a central venous catheter, it is preferable for day -7 PK 
samples to be withdrawn through a peripheral heparin lock.  However, if the patient objects or has 
problems with peripheral venous access, the central venous catheter may be used for PK 
sampling.  In the event that the central venous catheter is used, sufficient blood should be 
withdrawn before each PK sample to assure that the solution used to maintain catheter patency 
does not dilute the PK sample.  It is important to document whether the sample was collected 
through a heparin lock or central venous catheter. 
9.1.2 Pharmacokinetic Sampling Schedule 
On day -7 of cycle 1, belinostat will be administered at a dose of 400 mg/m2 to all patients, under 
supervision in the outpatient/inpatient research center.  The time of belinostat administration 
should be documented.  Blood samples will be drawn at the following time-points for PK studies: 
 
1. 
Before administration of belinostat 
2. 
15 minutes after start of infusion of belinostat 
3. 
25 minutes after start of infusion of belinostat 
4. 
5 minutes after end of infusion of belinostat 
5. 
10 minutes after end of infusion of belinostat 
6. 
15 minutes after end of infusion of belinostat 
7. 
30 minutes after end of infusion of belinostat 


CTEP #8846 
Clinical Center #11-C-0060 
 
47 
 
8. 
60 minutes after end of infusion of belinostat 
9. 
90 minutes after end of infusion of belinostat 
10. 
2 hours after end of infusion of belinostat 
11. 
4 hours after end of infusion of belinostat 
12. 
6 hours after end of infusion of belinostat 
13. 
8 hours after end of infusion of belinostat* 
14. 
24 hours after end of infusion of belinostat 
 
*It may not always be feasible to obtain the 8 h sample for logistical reasons. 
9.1.3 Blood Sample Processing Procedures 
1. 4 mL of blood will be collected in a green-top vacutainer tube (heparin anticoagulated) 
(BD Franklin Lakes, NJ) at the above-mentioned time-points.   
2. Centrifuge the sample at 1,000 X g for 10 minutes at 4°C. 
3. The resulting plasma samples will be transferred to 3.6 mL NUNC internal thread round 
bottom cryotubes (NUNC 366524) with labels attached. 
4. Samples will be immediately stored at –70 °C until transfer to central PK lab on DRY 
ICE. 
 
Care must be taken to ensure that labels are carefully attached to tubes and are not likely to fall 
off when frozen or during shipping.  Sample acquisition should be documented on the appropriate 
sample acquisition form that documents the patient identifier, date, the time that belinostat was 
administered, the theoretical time of correct sample acquisition, the actual time of sample 
acquisition, and any problems with sample acquisition (Appendix F: Sample Acquisition Form).   
 
Samples should be stored at –70ºC until shipment to the University of Pittsburgh Cancer Institute. 
 Samples should be shipped to the following name and address: 
 
Clinical Pharmacology Analytical Facility 
Attention: Dr. Jan H. Beumer 
University of Pittsburgh Cancer Institute 
Room G28, Hillman Research Pavilion 
5117 Centre Avenue 
Pittsburgh, PA 15213-1863 
 
Samples should be shipped on dry ice without thawing.  Samples should be wrapped in paper 
toweling or absorbent underpadding (benchkote); at no point should they come into direct contact 
with dry ice, which might lead to cracking of the tubes.  Samples should be accompanied by the 
appropriate sample acquisition and shipping form that indicates the material indicated in the 
above section of the protocol and also indicates the condition of the sample upon shipment, the 
name of the individual shipping the samples and a phone number, fax number and e-mail contact 
for confirmation of sample receipt in Pittsburgh.   
 


CTEP #8846 
Clinical Center #11-C-0060 
 
48 
 
Samples should be shipped to Pittsburgh by overnight express mail and should only be shipped 
on Monday, Tuesday, or Wednesday to ensure that samples do not arrive on Saturday or Sunday.  
Before shipping samples, please notify the Clinical Pharmacology Analytical Facility by calling 
(412) 623-1213 or (412) 623-3248 or by faxing Dr. Beumer at (412) 623-1212. 
9.2 
Analysis of Pharmacokinetic Data  
Concentrations of belinostat and metabolites will be quantitated with a liquid chromatography-
electrospray ionization tandem mass spectrometric method developed and validated in the 
Clinical Pharmacology Analytical Facility.  Plasma concentration versus time data for belinostat 
and metabolites will be analyzed non-compartmentally using PK solutions and/or 
compartmentally using ADAPT5.  Pharmacokinetic parameters such as Cmax, Tmax, AUC, Cl, 
Vd and t½ will be calculated and reported. 
9.3 
Sample Handling 
Biospecimens will be collected and processed using validated SOPs that will ensure both 
specimen quality and patient confidentiality pursuant to informed consent provisions.  
 
Using a computerized inventory system and a backup hardcopy process, all specimen collection 
and processing steps will be documented and the specific location of each specimen will be 
tracked.  Each new specimen collected will be assigned a unique barcode identifier that can be 
linked to the original specimen collected and other relevant information within the inventory 
system.  To ensure patient confidentiality, only containers used for the initial specimen 
collections will be labeled with patient identifiers.   
 
Only the barcode identifier will be applied to all subsequent specimen containers.  When 
specimens are processed and aliquoted, no patient information will be included on the new 
containers.  Original specimen containers will be discarded.  Only barcode-labeled specimens 
without patient identifiers will be shipped for analysis and/or storage.  Specimen labels will 
indicate: protocol number, order in which the patient enrolled on the trial, type of sample, 
collection time, and total volume collected, as appropriate.  Samples from sets of at least three 
patients will be grouped for scientific analysis.   
 
The inventory process contains other security provisions sufficient to safeguard patient privacy 
and confidentiality.  Access to the inventory system and associated documents will be restricted to 
appropriate individuals.  Requests to use specimens stored in the repository must be approved.  
The only patient information available in the inventory system will be the patient sex, diagnosis, 
and level of informed consent given.  SOPs ensure that any changes in informed consent made by 
a patient and relayed to the PI will be reflected in the inventory system to ensure that specimens 
are destroyed as appropriate.  All laboratory personnel will be trained to adhere to SOPs and will 
be monitored for high-quality performance. 
 


CTEP #8846 
Clinical Center #11-C-0060 
 
49 
 
Any new use of these samples will require prospective IRB review and approval.  Access to these 
samples will only be granted following IRB approval of an additional protocol, granting the rights 
to use the material. 
 
 
 
If at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request.  Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB.  Any samples lost (in transit or by a researcher) or destroyed due to unknown sample 
integrity (i.e., broken freezer allows for extensive sample thawing, etc.) will be reported as such 
to the IRB. 


CTEP #8846 
Clinical Center #11-C-0060 
 
50 
 
 
10 STUDY CALENDAR 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy unless 
otherwise indicated.  Patients may be registered onto protocol based on labs done within 7 days 
prior to entry onto study.  If there is a clinical deterioration prior to day -7, repeat chemistries.  
Then document stability of labs with repeat chemistries 48 hours later, prior to dosing.   
 
Repeat labs within 3 days prior to Cycle 1 Day 1.  Labs need to be obtained prior to the start of 
each cycle (can be done up to 3 days before start of a new cycle).   
 
Scans and x-rays must be performed within 28 days prior to the start of therapy.  


CTEP #8846 
Clinical Center #11-C-0060 
 
51 
 
 
 
Pre-
Study 
C1  
D-7 
C1  
D-6 
C1 
Wk 1 
C1 
Wk 2 
C1  
Wk 3 
C2 on 
Wk 1 
C2 on 
Wk 2 
C2 on 
Wk 3 
Off  
Treatment 
Belinostata 
 
X 
 
X 
 
 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Child-Pugh 
classification (CPC)  
X 
 
 
 
 
 
 
 
 
 
Concurrent medsm 
Xm  
Xm----------------------------------------------------------------Xm 
 
Physical exam 
X 
X 
 
 
 
 
X 
 
 
X 
Vital signs 
X 
X 
 
 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
X 
 
 
X 
Performance Status 
X 
X 
 
 
 
 
X 
 
 
X 
CBC w/diff, plts 
X 
Xd 
 
Xd 
Xd 
Xd 
X 
 
 
X 
Serum chemistryb 
X 
Xd 
 
Xd 
Xd 
Xd 
X 
 
 
X 
EKGe 
X 
 
 
X 
 
 
X 
 
 
 
AE evaluation 
 
X---------------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 2 cycles (about every 
6 weeks).  Documentation (radiologic) must be provided for 
patients removed from study for progressive disease. 
X 
Serum Magnesiumf 
Xf 
Xf 
 
 
 
 
 
 
 
 
B-HCG 
Xc 
 
 
 
 
 
 
 
 
 
PT*/INR/aPTT*g  
X 
 
 
 
 
 
 
 
 
 
Correlative studiesh 
 
X 
X 
 
 
 
 
 
 
 
HepBsAg,HepBcAb, 
HepBsAb, HepBeAbi,k 
X 
 
 
 
 
 
 
 
 
 
COBAS TaqMani,l 
X 
 
 
 
 
 
 
 
 
 
anti-HCVj,k 
X 
 
 
 
 
 
 
 
 
 
HCV-RNAj,l 
X 
 
 
 
 
 
 
 
 
 
a: Belinostat 400 mg/m2 administered Day -7 (Cycle 1 only) and at dose assigned on Day 1-5 of each 
cycle. 
b: Albumin, alkaline phosphatase, total and fractionated bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
c: Serum pregnancy test (women of childbearing potential). 
d: Weekly during Cycle 1 and at the beginning of each cycle (up to 3 days before start of new cycle) for 
the rest of the study.  If AEs are observed, these can be done more frequently at the discretion of the 
local PI.   
e: EKG will be done pre-study, on Cycle 1 Day 5 within 5 hours after the dose, and prior to the dose at the 
beginning of Cycle 2.  If QTc prolongation is observed, EKG will be done daily until QTc returns to < 
500 msec. 
f: Pre-cycle, Cycle 1 and as clinically indicated. 
g: PT*/INR/aPTT* is required to be checked at baseline in all patients.  Since belinostat might interact with 
CYP 450, patients on Coumadin should have their PT/INR monitored carefully by their local 
physicians. 


CTEP #8846 
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* = as clinically indicated. 
h: Blood samples for correlative studies will be collected from all patients on Cycle 1 D-7 before the 
administration of belinostat, 15 and 25 minutes after starting infusion, and then at the following time 
points after the end of infusion: 5, 10, 15, 30, 60, 90 minutes, 2, 4, 6, 8, and 24 hours (D-6). 
i: For patients with hepatocellular carcinoma secondary to hepatitis B. 
j: For patients with hepatocellular carcinoma secondary to hepatitis C. 
k: Results may be from within 3 months before starting on study. 
l: Results must be from within 1 month before starting on study.   
M Particular attention must be paid to medications which may prolong the QTc interval (Appendix C) and 
agents that interact with CYP450 isoenzymes (Appendix D). 
 
 
11 MEASUREMENT OF EFFECT 
11.1 
Antitumor Effect – Solid Tumors 
Although response is not the primary endpoint of this trial, patients with measurable disease will 
be assessed by standard criteria.  For the purposes of this study, patients should be reevaluated 
every 2 cycles (approximately every 6 weeks).  In addition to a baseline scan, confirmatory scans 
will also be obtained at least 4 weeks following initial documentation of an objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).30  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
 
Lymphoma response will be measured using the International Workshop Lymphoma Response 
Criteria.31 
11.1.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with belinostat. 
 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-evaluated 


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53 
 
will be considered evaluable for non-target disease.  The response assessment is 
based on the presence, absence, or unequivocal progression of the lesions.  
11.1.2 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
≥20 mm by chest x-ray, as ≥10 mm with CT scan, or ≥10 mm with calipers by 
clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or 
might not be considered measurable. 
 
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. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 


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baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these lesions are 
not required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow-up.  
11.1.3 Methods 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. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved 
in MRI, which greatly impact image quality, lesion conspicuity, and measurement. 
 Furthermore, the availability of MRI is variable globally.  As with CT, if an MRI 
is performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease.  Furthermore, as with 


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CT, the modality used at follow-up should be the same as was used at baseline and 
the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans.  Body scans should be performed with breath-
hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT performed 
as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the 
CT introduces additional data which may bias an investigator if it is not routinely 
or serially performed.   
 
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, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine relapse 
in trials where recurrence following complete response (CR) or surgical resection 
is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.  Specific guidelines for both 
CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent 
prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 
3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which 
are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 


CTEP #8846 
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56 
 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT scanning in assessment of progression (particularly possible 'new' disease).  
New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT  scans 
are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan).  
If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, 
this is not PD. 
 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought to 
represent fibrosis or scarring.  The use of FDG-PET in this circumstance 
should be prospectively described in the protocol and supported by disease-
specific medical literature for the indication.  However, it must be 
acknowledged that both approaches may lead to false positive CR due to 
limitations of FDG-PET and biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
11.1.4 Response Criteria 
11.1.4.1 
Evaluation of Target Lesions 
 


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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 progressions). 
 
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 
11.1.4.2 
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) 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
Non-CR/Non-PD:  
 
 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the 
normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase.     


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Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
11.1.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
        For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
        For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease as SD is 


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59 
 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
11.2 
Antitumor Effect – Lymphomas 
Response and progression will be evaluated in this study using the International Working Group 
recommendations.32 
11.2.1 CT Criteria of Nodal Involvement  
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm 
regardless of the short axis.  If a lymph node has a long axis of 1.1 to 1.5 cm, it should 
only be considered abnormal if its short axis is more than 1.0.  Lymph nodes 1.0 x 1.0 cm 
will not be considered as abnormal for relapse or progressive disease. 
11.2.2 Complete Remission (CR)  
 
1. Complete disappearance of all detectable clinical evidence of disease and disease-
related symptoms if present before therapy. 
 
2. In lymphoma that is FDG-avid prior to protocol treatment, a post-treatment residual 
mass of any size is permitted as long as it is PET negative. 
 
3. For FDG negative or variably FDG-avid lymphomas or if PET scan prior to therapy 
not done or results not known, all lymph nodes and nodal masses must have regressed 
on CT to normal size (1.5 cm in their greatest transverse diameter for nodes > 1.5 cm 
before therapy.  Previously involved nodes that were 1.1 to 1.5 cm in their long axis 
and more than 1.0 cm in their short axis before treatment must have decreased to 1.0 
cm in their short axis after treatment.) 


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4. The spleen and/or liver, if considered enlarged before therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical examination and 
should be considered normal size by imaging studies.  Nodules related to lymphoma 
should disappear.  However, determination of splenic involvement is not always 
reliable because a spleen considered normal in size may still contain lymphoma, 
whereas an enlarged spleen may reflect variations in anatomy, blood volume, the use 
of hematopoietic growth factors, or causes other than lymphoma. 
 
5. If the bone marrow was involved by lymphoma before treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy.  The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core).  If 
the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry.  A sample that is negative by immunohistochemistry but that 
demonstrates a small population of clonal lymphocytes by flow cytometry will be 
considered a CR until data become available demonstrating a clear difference in 
patient outcome. 
11.2.3 CRu (Unconfirmed Complete Response) 
The use of the above definition for CR and that below for PR eliminates the category of 
CRu. 
 
11.2.4 Partial Remission (PR) 
1. At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of 
the largest dominant nodes or nodal masses.  These nodes or masses should be 
selected according to all of the following: they should be clearly measurable in at least 
2 perpendicular dimensions; if possible they should be from disparate regions of the 
body; and they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved. 
2. No increase should be observed in the size of other nodes, liver, or spleen. 
 
3. Splenic and hepatic nodules must regress by 50% in their SPD or, for single nodules, 
in the greatest transverse diameter. 
 
4. With the exception of splenic and hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present.   
 
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment.  However, if positive, the cell type should be specified (e.g., 
large-cell lymphoma or small neoplastic B cells).  Patients who achieve a CR by the 
above criteria, but who have persistent morphologic bone marrow involvement will be 
considered partial responders.  When the bone marrow was involved before therapy 


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and a clinical CR was achieved, but with no bone marrow assessment after treatment, 
patients should be considered partial responders. 
 
6. No new sites of disease should be observed. 
 
7. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the 
PET scan was positive before therapy, the post-treatment PET should be positive in at 
least one previously involved site. 
 
8. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, CT criteria should 
be used.  In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is 
only indicated with one or at most two residual masses that have regressed by more 
than 50% on CT; those with more than two residual lesions are unlikely to be PET 
negative and should be considered partial responders. 
11.2.5 Stable Disease (SD)  
 
 
 
 
1. A patient is considered to have SD when he or she fails to attain the criteria needed for 
a CR or PR, but does not fulfill those for progressive disease (see Relapsed Disease 
[after CR]/Progressive Disease [after PR, SD]). 
 
2. Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease 
with no new areas of involvement on the post-treatment CT or PET. 
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan or if the pretreatment PET was negative, there must be no 
change in the size (> 50%) of the previous lesions on the posttreatment CT scan.   
11.2.6 Relapsed Disease (after CR)/Progressive Disease (after PR, SD) 
1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease 
after confirmation with other modalities.  In patients with no prior history of 
pulmonary lymphoma, new lung nodules identified by CT are mostly benign.  Thus, a 
therapeutic decision should not be made solely on the basis of the PET without 
histologic confirmation. 
 
2. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in 
a single involved node, or the size of other lesions (e.g., splenic or hepatic nodules).  
To be considered progressive disease, a lymph node with a diameter of the short axis 
of less than 1.0 cm must increase by 50% and to a size of 1.5 x 1.5 cm or more than 
1.5 cm in the long axis. 
 
3. At least a 50% increase in the longest diameter of any single previously identified 
node more than 1 cm in its short axis. 


CTEP #8846 
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4. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected 
with current PET systems (< 1.5 cm in its long axis by CT).  Measurable extra-nodal 
disease should be assessed in a manner similar to that for nodal disease.  For these 
recommendations, the spleen is considered nodal disease.  Disease that is only 
assessable (e.g., pleural effusions, bone lesions) will be recorded as present or absent 
only, unless, while an abnormality is still noted by imaging studies or physical 
examination, it is found to be histologically negative. 
 
 
12 DATA REPORTING / REGULATORY CONSIDERATIONS 
Adverse event lists, guidelines, and instructions for adverse event reporting can be found in 
Section 7.0 (Adverse Events: List and Reporting Requirements). 
12.1 
Data Reporting 
12.1.1 Method 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  
Information on CTMS reporting is available at 
http://www.theradex.com/CTMS/ctmsmenu.htm.  Data will be submitted to CTMS at 
least once every 2 weeks on the NCI/DCTD case report form or the electronic case report 
form (ACES).  CTEP will arrange for a bi-weekly toxicity report to be generated by 
Theradex, and this report will be provided to the Principal Investigator, all Co-
Investigators, and the Organ Dysfunction Working Group for the purposes of monitoring 
and coordination of this multicenter trial.  The final study report should contain all raw 
data collected during the trial including the case report forms as well as all clinical, 
laboratory, pharmacokinetic, and pharmacodynamic data collected.  This report will be 
made available to the FDA as well as all members of the Organ Dysfunction Working 
Group. 
12.1.2 Responsibility for Data Submission 
Study participants are responsible for submitting CTMS data and/or data forms to the 
Coordinating Center quarterly to allow time for Coordinating Center compilation, 
Principal Investigator review, and timely submission to CTEP (see Section 12.1.1.).  For 
trials monitored by CTMS, the monthly data submission to CTEP from Theradex should 
be copied to the Coordinating Center. 
 
The Coordinating Center is responsible for compiling and submitting CTMS data to 
CTEP for all participants and for providing the data to the Principal Investigator for 
review.   


CTEP #8846 
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63 
 
12.2 
Data Monitoring and Safety Plan 
A mandatory conference call will take place every other week on Friday at 1300 (Eastern Time) 
unless unforeseen events require postponement or cancellation (Appendix I).  The call will update 
participants on the current status of the trial and will include investigators from all participating 
centers, CTEP, and representatives from TopoTarget.  At this time, any serious toxicities 
encountered will be discussed and appropriate action taken, and issues relating to the protocol, 
treatment, management, or other matters of importance that arise during the conduct of the study 
will be discussed.  Between these regularly scheduled conference calls, unusual toxicities may be 
discussed among the Principal Investigator and CTEP senior investigators; however, all 
participants will routinely be updated on such calls via e-mail. 
 
All SAEs will be reported through CTEP-AERS to CTEP, to the Coordinating Center PI at NCI, 
and forwarded to the IRB per Section 7.  In all cases where the dose of the study treatment has 
been reduced/modified or the patient withdrawn due to unusual or unusually severe toxicity 
considered related to the study treatment, the investigator must contact and inform the 
Coordinating Center PI.  All sites will be monitored by the CTEP drug monitor who will receive 
data from all participating sites. 
 
Data will be monitored regularly by the principal investigator in order to identify significant 
toxicity trends.  Any new significant finding that may affect the patient’s willingness to continue 
in the study will be shared with patients.  The Coordinating Center is responsible for establishing 
bimonthly conference calls between participating sites to discuss protocol issues.  
 
Confidentiality will be maintained as much as possible, consistent with applicable regulations.  
Names of participants or identifying material will not be released without patient permission, 
except when such release is required by law.  No patient’s name or identifying information will 
be released in any publication or presentation.  Records are maintained according to current legal 
requirements, and are made available for review according to the requirements of the FDA or 
other authorized user, only under guidelines established by the Federal Privacy Act.  
12.3 
Multi-Institutional Guidelines 
This protocol will open initially at the NCI.  The NCI IRB will be notified once the participating 
centers’ IRBs have approved the study to open.   
12.3.1 IRB Approvals 
As the Coordinating Center for a trial, it is the PI’s responsibility to ascertain that no 
patients are entered on the trial at a participating institution without full IRB approval.  
Thus, the NCI IRB must approve the addition of each participating institution to the 
protocol and will require a copy of the local IRB approval from each participating 
institution before NCI IRB approval will be granted. 
  


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The PI will provide the NCI IRB with a copy of the participating institution’s approved 
yearly continuing review.  Registration will be halted at any participating institution in 
which a current continuing approval is not on file at the NCI IRB.  
12.3.2 Amendments and Consents 
The PI will provide the NCI IRB with copies of all amendments, consents, and approvals 
from each participating institution.  
12.3.3 Data Collection 
The investigators will be responsible for the collection, maintenance, and quality control of 
the study data.  All data collected for each study subject will be entered into the Cancer 
Central Clinical Database (C3D), an NCI electronic case report form/database, every 2 weeks. 
 Once a participating site has received IRB approval, data managers and research nurses will 
receive training on the C3D database.  Each participating site must electronically send the 
names and office contact information of all of the intended C3D users to NCI, DTC research 
nurse.  This information will be emailed to the C3D programmers for the scheduling of 
individualized virtual training.  The database programmers will coordinate the logistics of the 
virtual training with each site, and assign a user identification and password with the 
completion of training.  Once the intended users are trained, participating sites will be able to 
enroll patients and enter the data remotely into the web-based C3D system.  The electronic 
C3D instruction manual serves as a resource to assist with data entry into the NCI, CCR’s 
C3D electronic case report forms.  Each site investigator is responsible for maintaining all 
source documentation related to the study, including any films, tracings, computer discs or 
tapes.  NCI will be responsible for data management, data analysis, and reporting.  Data 
collection forms are provided for the participating institutions (Appendices J and K).  
Required data include, not exclusively: prior disease-related therapies, with dates, disease 
type, stage, disease sites, with measurements, and concurrent medications.  
12.3.4 Data and Center Audits 
Audits will be conducted yearly to ensure data integrity and provide quality control.  
These audits will be conducted by the NCI research team.  Selected patient charts should 
be audited as well as the participating institution’s Standard Operating Procedures (SOP) 
at the time of the visit.  Data from participating institutions should be available when the 
protocol is audited at the NCI. 
12.3.5 CTEP Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the CTEP Multicenter 
Guidelines.  The specific responsibilities of the Principal Investigator and the 
Coordinating Center (NCI, DTC) and the procedures for auditing are presented in 
Appendix E. 
 The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from CTEP to all participating institutions 
for submission to their individual IRBs for action as required. 


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 Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site 
only after the initial IRB approval for the site has been forwarded by the Coordinating 
Center to the CTEP PIO (PIO@ctep.nci.nih.gov).  
12.4 
Clinical Trials Agreement (CTA) 
The agent(s), supplied by CTEP, DCTD, NCI, used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CTA) between the Topo Target [hereinafter referred to as 
“Collaborator(s)”] and the NCI Division of Cancer Treatment and Diagnosis.  Therefore, the 
following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option 
to Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained within the terms of award, apply to the use of Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained 
as such by the investigators.  The protocol documents for studies utilizing investigational 
agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient participating on the 
study or patient’s family member, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different  collaborative agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as “Multi-Party Data”.): 
 
a. NCI must provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NIH, the design of 
the proposed combination protocol, and the existence of any obligations that would 
tend to restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval, or commercialize its own 
investigational agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational agent. 
 


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3. Clinical Trial Data and Results and Raw Data developed under a collaborative agreement will 
be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate.  All 
data made available will comply with HIPAA regulations. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP for 
immediate delivery to Collaborator(s) for advisory review and comment prior to submission 
for publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an additional 
30 days to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must be 
provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to presentation 
at the meeting or publication in the proceedings.  Press releases and other media presentations 
must also be forwarded to CTEP prior to release.  Copies of any manuscript, abstract, and/or 
press release/ media presentation should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
9609 Medical Center Drive RM 5-W 
Rockville, MD 20850 (fed ex) 
Phone: 240-276-6580 
Fax: 240-276-7894 
E-mail: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/proprietary information. 
 
 
13 STATISTICAL CONSIDERATIONS 
This is a Phase I trial using a design including 4 cohorts of patients with varying degrees of 
hepatic dysfunction, including one group with normal hepatic function (see Section 5.1.1).  The 
study incorporates a 3+3 design.  The dose recommended for cohorts with greater liver 
dysfunction cannot be greater than the dose for cohorts of lesser dysfunction (see Section 5.1.5).  
Furthermore, the highest dose to be explored is no greater than the recommended dose for 
patients with normal liver function.  These restrictions will compensate in part for patient 


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heterogeneity and yield more accurate final recommended doses in liver dysfunction groups.  
Further rules for dose escalation and MTD determination are given in Sections 5.1 and 5.2. 
 
Patients in cohort 1 are included in this study to obtain PK data in the same manner as for the 
patients with liver dysfunction.  This group will also be followed for toxicity.  Occasionally a 
patient consented for a group with liver dysfunction will present with normal liver function tests 
on the day of treatment initiation.  These patients may be entered into cohort 1 on a case-by-case 
basis. 
 
 
Toxicity will be graded according to the NCI CTCAE v4.0 and relationship to the study drug; 
results will be tabulated by liver dysfunction group.  All patients who receive any amount of 
belinostat will be evaluable for toxicity, but patients who receive other than the prescribed dose 
and do not experience a DLT will be considered inevaluable for DLT.  Patients who are not 
evaluable for DLT will be replaced. 
 
The PK variables described in Section 9.1 will be tabulated and descriptive statistics calculated 
for each function group.  Geometric means and coefficients of variation will be presented for Cmax 
and AUCINF for each group. 
 
In addition, indirect bilirubin levels will be evaluated to see if there is a correlation between those 
results and toxicity or activity of belinostat.   
13.1 
Sample Size/Accrual Rate 
A minimum of 2 and a maximum of 6 patients will be accrued in each liver dysfunction cohort 
(2-4) at each dose level, and 12 patients will be entered at the recommended dose level in 
cohort 1.  MTD will not be established for the normal cohort as that is already known.  Patients in 
this cohort are being enrolled to obtain PK data in the same manner as for the patients with liver 
dysfunction.  Three additional patients will be accrued to the MTD levels (following 
establishment of MTD for that cohort in the first 6 patients at that dose level) for each liver 
dysfunction cohort to allow additional information to be gained at these levels.  Therefore, the 
minimum number of patients will be 24 patients.  The maximum would include the 12 patients in 
cohort 1, 6 patients for all other non-MTD levels (up to 6 such), and 9 patients for the MTD 
levels (3 such), bringing the total to 75 patients.  We do not expect all dose levels to have 6 
patients and recognize that some patients may need to be replaced if they are not evaluable based 
on protocol guidelines.  As long as < 33% of the patients treated at a given dose level experience 
a DLT, that dose level will be considered the MTD. 
 
 The estimated monthly accrual is 4 patients/month, and the accrual ceiling for this trial is 
80 patients.  


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13.2 
Stratification Factors 
Patients will be stratified according to the level of hepatic dysfunction as described in 
Section 5.1.1.  Dose escalation and MTD determination will be performed separately for each 
stratum.   
 
14 HUMAN SUBJECTS PROTECTIONS 
14.1 
Rationale for Subject Selection   
This study will be open to all individuals regardless of gender, ethnicity, or race, provided that the 
aforementioned inclusion and exclusion criteria are met.  Patients for this study will be recruited 
through internal referral, our physician referral base, and through various cancer information 
hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer).  To date, there is no information 
that suggests that differences in drug metabolism or effect on tumor would be expected in one 
ethnic group compared to another.  Efforts will be made to extend accrual to each representative 
population, but a balance must be struck between participant safety considerations and limitations 
on the number of individuals exposed to potentially ineffective treatments on the one hand and 
the need to explore racial/ethnic aspects of clinical research on the other hand.  If differences in 
outcome that correlate to ethnic identity are noted, a follow-up study may be written to investigate 
those differences more fully. 
 
Due to lack of knowledge of the effects of belinostat on the fetus or infants, as well as the 
possibility of teratogenic effects, pregnant and nursing women will be excluded from this trial.  
Patients with unstable or serious medical conditions are excluded due to the possibility that 
belinostat may worsen their condition and the likelihood that the underlying condition may 
obscure the attribution of adverse events with respect to belinostat.  HIV-positive patients on 
combination antiretroviral therapy are excluded from the study because of possible PK 
interactions with belinostat. 
14.2 
Participation of Children 
Children aged <18 years are excluded because of the lack of safety data of the compound in this 
population.  Appropriate studies in the pediatric age group may be undertaken in the future. 
14.3 
Evaluation of Benefits and Risks/Discomforts 
Patients will receive evaluation and treatment of their malignancy as a result of participating in 
this trial.  All the medications, tests, hospitalizations, and physician services during this trial 
within the NIH will be free of charge to the participant.  Imaging studies may help determine the 
extent of disease and or identify lesion not detected by conventional modalities.  The trial will 
help investigators learn the effects of the study medication, but may or may not be helpful for a 
specific patient.  The study treatment may offer temporary control of the disease, but is not 


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curative by this protocol.  Benefit cannot be promised nor can the chance of benefit be accurately 
predicted.  The risks and discomforts of the tumor biopsies will be slight pain, as well as the 
small possibility of bleeding or infection.  Alternative approaches other than entering this trial, 
including supportive care only, if it is available, will also be discussed before the verbal and 
written consent regarding the risk and benefits and the treatment requirements of this trial.   
 
14.3.1 Alternative Approaches or Treatments 
There are no effective alternative therapies.  Other investigational agents could be 
employed, or the patient may elect to be treated for symptomatic control alone or 
with agents of marginal or unknown clinical benefit. 
14.3.2 Procedure for Protecting Against or Minimizing Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in 
nature and severity.  This study may involve risks to patients, which are currently 
unforeseeable.  All patients will be monitored for side effects from taking study 
medication and from undergoing research-related procedures.  If patients suffer 
any physical injury as a result of the participation in this study, immediate medical 
treatment is available at the Clinical Center, National Cancer Institute, Bethesda, 
Maryland.  Although no compensation is available, any injury will be evaluated 
and treated in keeping with the benefits or care to which patients are entitled under 
applicable regulations.   
14.4 
Risks/Benefits Analysis  
There may or may not be any clinical benefit to a patient from participation in this trial.  Their 
participation will benefit future cancer patients.  Potential risks include the possible occurrence of 
any of a range of side effects that are listed in the consent document.  Clinical and laboratory data 
gathered in this trial will be analyzed frequently.  Any new or significant finding(s) found during 
the course of the research that may affect a patient’s willingness to participate further will be 
shared and explained to each participant. 
14.5 
Consent Process and Documentation 
An associate or principal investigator on the trial will inform patients of the purpose, alternatives, 
drug administration plan, research objectives and follow-up of this trial.  The patient will be 
provided an IRB-approved consent for review and signature and his/her questions will be 
answered.  After a decision is made to enroll into the study, a signature will be obtained from the 
patient.  The original signed consent goes to Medical Records; a copy is placed in the research 
record. 
 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study. 


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For NCI only: adults unable to give consent are excluded from enrolling in the protocol.  
However, re-consent may be necessary and there is a possibility, though unlikely, that subjects 
could become decisionally impaired.  For this reason and because there is a prospect of direct 
benefit from research participation, all subjects ≥ age 18 will be offered the opportunity to fill in 
their wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study.  Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures described 
in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who are (a) 
decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will 
be followed. 


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Di Gennaro E, Bruzzese F, Romano G, et al. Antitumor effect of histone deacetylase 
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Yu X, Guo ZS, Marcu MG, et al. Modulation of p53, ErbB1, ErbB2, and Raf-1 expression 
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Mackay HJ, Hirte H, Colgan T, et al. Phase II trial of the histone deacetylase inhibitor 
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Hasegawa Y, Sarashina T, Ando M, et al. Rapid Detection of UGT1A1 Gene 
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Assouline S, Meyer RM, Infante-Rivard C, et al. Development of adapted RECIST criteria 
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Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
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APPENDIX A: GI50 MEAN GRAPH FOR NSC 726630 (BELINOSTAT) 
 
Data from October 2009; average GI50 over all cell lines is 1.78E-7. 
 
 


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APPENDIX B: PERFORMANCE STATUS CRITERIA 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 


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APPENDIX C: MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL  
AND/OR INDUCE TORSADES DE POINTES 
 
It has been recognized for a number of years that certain prescription medications can prolong the 
QT/QTc interval and cause a form of acquired long QT syndrome, known as drug-induced LQTS. 
The drugs that prolong the QT interval and/or have a risk of inducing Torsades de Pointes (TdP) 
are listed below. We have divided these into two groups based on their known or perceived risk 
of causing TdP: 
Table 1. Group 1 Drugs That are Generally Accepted by Authorities to Have a Risk of 
Causing TdP* 
Drug (generic names) 
Drug class (clinical usage) 
Comments 
Albuterol (by parenteral 
administration) 
Bronchodilator (asthma) 
Inhaled albuterol at normal doses 
acceptable 
Amiodarone 
Anti-arrhythmic (heart rhythm) 
F >M, TdP cases in literature 
Arsenic trioxide 
Anti-cancer (leukemia) 
TdP cases in literature 
Bepridil 
Anti-anginal (heart pain) 
F >M 
Chlorpromazine 
Anti-psychotic/anti-emetic 
(schizophrenia/nausea) 
TdP cases in literature 
Chloroquine 
Anti-malaria (malaria infection) 
 
Disopyramide 
Anti-arrhythmic (heart rhythm) 
F >M 
Dofetilide 
Anti-arrhythmic (heart rhythm) 
 
Droperidol 
Sedative/hypnotic (anaesthesia 
adjunct) 
TdP cases in literature 
Erythromycin 
Antibiotic/GI stimulant 
(infection/GI motility) 
F >M 
Halofantrine 
Anti-malarial (malaria infection) 
F >M 
Haloperidol 
Anti-psychotic (schizophrenia, 
agitation) 
 
Ibutilide 
Anti-arrhythmic (heart rhythm) 
F >M 
Mesoridazine 
Anti-psychotic (schizophrenia) 
 
Methadone 
Opiate agonist (pain control/ 
narcotic dependence) 
F >M 
Pentamidine 
Anti-infective (pneumocystic 
pneumonia) 
F >M 
Pimozide 
Anti-psychotic (Tourette's tics) 
F >M, TdP cases in literature 
Procainamide 
Anti-arrhythmic (heart rhythm) 
 
Quinidine 
Anti-arrhythmic (abnormal heart 
rhythm) 
F >M 
Sotalol 
Anti-arrhythmic (heart rhythm) 
F >M 
Sparfloxacin 
Antibiotic (bacterial infection) 
 
Thioridazine 
Anti-psychotic (schizophrenia) 
 


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*Concomitant use of these drugs is not allowed during the study or within 2 weeks of study entry. 
 These drugs should also be avoided for up to 4 weeks following discontinuation of study 
treatment. 
 
Table 2. Group 2 Drugs That in Some Reports may be Associated With TdP but at This 
Time Lack Substantial Evidence of Causing It* 
Drug (brand names) 
Drug class (clinical usage) 
Comments 
Amantadine 
Dopaminergic/anti-viral/anti-
infective (Parkinson’s disease) 
 
Amitriptyline 
Tricyclic anti-depressant 
(depression) 
 
Amoxapine 
Tricyclic anti-depressant 
(depression) 
 
Azithromycin 
Antibiotic (bacterial infection) 
 
Citalopram 
Anti-depressant (depression) 
 
Clarithromycin 
Antibiotic (bacterial infection) 
TdP cases in literature 
Clomipramine 
Tricyclic antidepressant 
(depression) 
 
Chloral hydrate 
Sedative (sedation/insomnia) 
 
Clozapine 
Anti-psychotic (schizophrenia) 
 
Desipramine 
Tricyclic anti-depressant 
(depression) 
TdP cases in literature 
Dolasetron 
Anti-nausea (nausea and vomiting) 
 
Doxepin 
Anti-depressant (depression) 
TdP cases in literature 
Felbamate 
Anti-convulsant (seizures) 
 
Flecainide 
Anti-arrhythmic (heart rhythm) 
Association not clear 
Fluconazole 
Anti-fungal (fungal infection) 
 
Fluoxetine 
Anti-depressant (depression) 
Association not clear 
Foscarnet 
Antiviral (HIV infection) 
 
Fosphenytoin 
Anticonvulsant (seizures) 
 
Gatifloxacin 
Antibiotic (bacterial infection) 
 
Gemifloxacin 
Antibiotic (bacterial infection) 
 
Granisetron† 
Anti-nausea (nausea and vomiting) 
 
Imipramine 
Anti-depressant (depression, pain, 
other) 
TdP cases in literature 
Indapamide 
Diuretic (stimulates urine & salt 
loss) 
TdP cases in literature, QT in animals 
Isradipine 
Anti-hypertensive (high blood 
pressure) 
 
Levofloxacin 
Antibiotic (bacterial infection) 
Association not clear 
Lithium 
Anti-mania (bipolar disorder) 
 


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Drug (brand names) 
Drug class (clinical usage) 
Comments 
Mexiletine 
Anti-arrhythmic (abnormal heart 
rhythm) 
 
Moexipril/HCTZ 
Anti-hypertensive (high blood 
pressure) 
 
Moxifloxacin 
Antibiotic (bacterial infection) 
 
Nicardipine 
Anti-hypertensive (high blood 
pressure) 
 
Nortriptyline 
Tricyclic antidepressant 
(depression) 
 
Octreotide 
Endocrine (acromegaly/ carcinoid 
diarrhoea) 
 
Ofloxacin 
 
 
Ondansetron† 
Anti-emetic (nausea and vomiting) 
 
Paroxetine 
Anti-depressant (depression) 
 
Protriptyline 
Tricyclic antidepressant 
(depression) 
 
Quetiapine 
Anti-psychotic (schizophrenia) 
 
Risperidone 
Anti-psychotic (schizophrenia) 
 
Salmeterol 
Sympathomimetic (asthma, COPD) 
 
Sertraline 
Antidepressant (depression) 
Association not clear 
Solifenacin 
Muscarinic receptor antagonist 
(treatment of overactive bladder) 
 
Tacrolimus 
Immune suppressant 
TdP cases in literature 
Tamoxifen 
Anti-cancer (breast cancer) 
 
Telithromycin 
Antibiotic (bacterial infection) 
 
Tizanidine 
Muscle relaxant 
 
Trimipramine 
Tricyclic antidepressant 
(depression) 
 
Vardenafil 
Phosphodiesterase inhibitor 
(vasodilator) 
 
Venlafaxine 
Antidepressant (depression) 
 
Voriconazole 
Anti-fungal (fungal infection) 
 
Ziprasidone 
Anti-psychotic (schizophrenia) 
 
*Concomitant use of these drugs will be allowed at the discretion of the PI.  In such cases, the 
patient must be closely monitored, including regular checks of QTc and electrolytes.  Patients 
who are receiving a drug that has a risk of QTc prolongation are excluded if QTc is ≥460 msec. 
 
†Granisetron and ondansetron are acceptable antiemetics in this study.  In clinical use, QT interval 
changes do not exceed 15 msec, and consequently, the potential for induction of arrhythmias is 
low.33 


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APPENDIX D: CYP450 INTERACTIONS 
 
CTEP List of drugs that may have potential CYP3A4 interactions 
 
CYP3A4 Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amiodarone 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Budesonide 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazepine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cilostazol 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Dasatinib (1) 
Delavirdine 
Diazepam 
Dihydroergotamine  
Diltiazem  
Disopyramide  
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., 
synthetic 
Estrogens, conj., equine 
Estrogens, conj., 
esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestane 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fluticasone 
Fosamprenavir 
Gefitinib 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine  
Itraconazole 
Ketamine  
Ketoconazole 
Lansoprazole 
Letrozole 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pipotiazine 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole  
Ranolazine 
Repaglinide 
Rifabutin 
Ritonavir 
Salmeterol 
Saquinavir 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Spiramycin 
Sufentanil 
Sunitinib 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tipranavir 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 
 
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/. 


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CYP2C8 Substrates 
 
 
Other CYPs that contribute to metabolism are given in parenthesis. 
 
 
 


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CYP2C9 Substrates 
 
diclofenac 
losartan 
fluoxetine 
ibuprofen 
irbesartan 
fluvastatin 
lornoxicam 
glyburide 
glyburide 
meloxicam 
glibenclamide 
nateglinide 
S-naproxen_Nor 
glipizide 
phenytoin-4-OH2 
piroxicam 
glimepiride 
rosiglitazone 
suprofen 
tolbutamide 
tamoxifen 
tolbutamide 
amitriptyline 
torsemide 
glipizide 
celecoxib 
S-warfarin 
 
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/. 


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APPENDIX E: CTEP MULTICENTER GUIDELINES 
 
 
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
 The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
 The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
 The Protocol Chair is responsible for the timely review of adverse events to assure safety 
of the patients. 
 The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis. 
 
Responsibilities of the Coordinating Center 
 Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible for 
assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
  Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
 The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
 The Coordinating Center is responsible for the preparation of all submitted data for review 
by the Protocol Chair. 
 The Coordinating Center will maintain documentation of adverse event reports.  There are 
two options for adverse event reporting: (1) participating institutions may report directly 
to CTEP with a copy to the Coordinating Center, or (2) participating institutions report to 
the Coordinating Center who in turn report to CTEP.  The Coordinating Center will 
submit adverse event reports to the Protocol Chair for timely review. 
 
 


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 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 Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
 
Inclusion of Multicenter Guidelines in the Protocol 
 The protocol must include the following minimum information:  
 The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
 The Coordinating Center must be designated on the title page. 
 Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
 Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
 Describe how adverse events will be reported from the participating institutions, either 
directly to CTEP or through the Coordinating Center. 
 
 Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
 Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO.  
 


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APPENDIX F: PHARMACOKINETIC SAMPLE ACQUISITION FORM  
 
INSTRUCTIONS: This form should be completed as required per protocol.  Information in the upper box must be 
completed for this form to be accepted.  Do not leave any entries blank.  Enter all times in 24-hour format.  Enter - 1 
to indicate that an answer is unknown, unobtainable, not applicable, or not done.  Highlight or circle amended data.  
Include ORIGINAL form with sample shipment, retain a copy for your records. 
 
 
Patient’s Initials:  ___________________________   
Patient Accession Number:  ___________________   
Institution:  
 
 
DAY -7 Date Belinostat administered:  (mm/dd/yy) ⊔⊔/⊔⊔/⊔⊔ 
 
DOSING INFORMATION 
Belinostat Dose (mg/m2) ⊔⊔⊔  
BSA (m2) ⊔.⊔⊔ 
 
Belinostat Dose (mg) ⊔⊔⊔ 
Time Belinostat Started: (hh:mm) ⊔⊔:⊔⊔ 
 
Each timed sample will be noted with corresponding number (1-14) for labeling purposes 
 
BLOOD SAMPLES REQUIRED: 
 
# 
 
Projected Time 
Obtained (hh:mm) 
Actual Time 
Obtained (hh:mm) 
Problems? 
Specify 
1 
Pre-Belinostat (B) 
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
2 
15 min into infusion of B  ⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
3 
25 min into infusion of B  ⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
4 
5 min after end of 
infusion of B 
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
5 
10 min after end of 
infusion of B  
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
6 
15 min after end of 
infusion of B 
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
7 
30 min after end of 
infusion of B 
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
8 
1 h after end of infusion 
of B 
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 


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# 
 
Projected Time 
Obtained (hh:mm) 
Actual Time 
Obtained (hh:mm) 
Problems? 
Specify 
9 
1.5 h after end of 
infusion of B 
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
10 
2 h after end of infusion 
of B 
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
11 
4 h after end of infusion 
of B 
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
12 
6 h after end of infusion 
of B 
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
13 
8 h after end of infusion 
of B 
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
14 
24 h after end of infusion 
of B 
⊔⊔:⊔⊔ 
⊔⊔:⊔⊔ 
 
 
 
SHIPPING INFORMATION: 
 
SHIP TO: 
Clinical Pharmacology Analytical Facility 
 
Attention of Dr. Jan H. Beumer 
 
 
 
 UPCI Hillman Research Pavilion, G.28 
 
5117 Centre Avenue 
 
Pittsburgh, PA 15213 
 
*Prior to shipment of samples, please contact Clinical Pharmacology Analytical Facility by 
calling (412) 623-1213 or (412) 623-3248 or by sending a fax to Dr. Beumer at (412) 623-
1212. 
 
Condition of sample when shipped (1-frozen, 2-thawed) ⊔ 
 
 
Date sample shipped:  (mm/dd/yy) ⊔⊔/⊔⊔/⊔⊔ 
 
Shipper’s name:  __________________________ E-mail address or phone no.:  _____________  
 


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APPENDIX G: MULTICENTER INFORMED CONSENT TEMPLATE 
 
Phase I Pharmacokinetic Study of Belinostat for Solid Tumors and Lymphomas in Patients 
with Varying Degrees of Hepatic Dysfunction 
 
 
Introduction 
 
We invite you to take part in this research study. 
 
First, we want you to know that: 
Taking part in this research study is entirely voluntary. 
You may choose not to take part, or you may withdraw from the study at any time.  In either 
case, you will not lose any benefits to which you are otherwise entitled. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that may 
help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your doctors or research team before you agree to the 
study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with family, friends or your personal 
physician or other health professional. 
 
You have been asked to take part in a clinical research study testing an experimental drug, called 
belinostat, because you have an advanced cancer and your liver may or may not be working 
properly, and the standard drugs to treat your disease are no longer effective, or it may be that no 
effective treatment is known for your disease.  
 
Description of Research Study 
 
The purpose of this study is to test the safety of belinostat at different dose levels in patients with 
cancer who have different degrees of liver function.  Belinostat is an experimental drug that 
works by helping to turn on genes that control cell growth and survival that are switched off in 
cancer cells.  This is the first study in which belinostat will be given systematically to patients 
with different degrees of liver function.  We already know the safe dose for patients with normal 
liver function.  Other purposes of this study are to find out what side effects occur when 
belinostat is given to patients with different degrees of liver function, how much belinostat is in 
your blood at specific times, and whether or not belinostat is effective in treating your cancer.  We 
will compare how the patients with abnormal liver function do in comparison with patients with 


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normal liver function.  That is the reason that a group of patients with normal liver function will 
also be included on this trial.   
 
How many people will take part in this study? 
Up to 80 patients will take part in this study at multiple centers across the United States.  Out of 
this, about ___ patients will take part in this study at ________________ [name of center].   
 
Has this drug been given to other people?  
Belinostat has been given to about 500 patients with different types of cancer to measure its safety 
and how the body handles this drug.  Belinostat has not been given in a formal trial to patients 
with cancer who have abnormal liver function to learn how these patients tolerate and respond to 
the drug.     
 
What will happen if I take part in this study? 
Before you begin the study 
You will need to have the following examinations, tests, or procedures to find out if you can be in 
the study.  These examinations, tests, or procedures are part of your regular cancer care and 
should be done by your health care team even if you do not join the study.  If you have had them 
recently, they may not need to be repeated.  This will be up to your study doctor. 
 
If you decide that you would like to participate in this study, you will be asked to sign this consent 
form.  You will then have the examinations, tests, and procedures listed below done to see if you 
can take part in the study (this is called the screening/baseline evaluation).  
 
 Complete medical history. 
 Physical examination, including height, weight, blood pressure, pulse, and temperature. 
 Standard blood tests (requiring about 1 tablespoon of blood total), which include 
measurement of your white blood cells, red blood cells, platelets, blood sugar and 
electrolytes, how your liver and kidneys work, and how well your blood clots. 
 Urine tests: Depending on the results of blood tests, you may be asked to give a collect 
your urine for 24 hours for further testing. 
 Pregnancy test: A blood test will be done to check for pregnancy in women who are able 
to become pregnant.   
 EKG to check your heart. 
 CT scans of your chest, abdomen, and pelvis to measure your tumor(s).  Other imaging 
tests may be done as needed. 
 
During the Study 
After you are accepted for this study and you choose to take part, you will begin taking the study 
drug, belinostat.  Belinostat is given through a vein for 30 minutes.  Belinostat will be given in 
cycles.  Except for cycle 1, all cycles are 3 weeks long.  Cycle 1 is 4 weeks long.  Now, we will 
describe what will happen during each cycle.   
 


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For cycle 1 only, you will receive one extra dose of belinostat 1 week before the regular 
treatment starts (Day -7).  In each cycle, belinostat will be given once a day for 5 days (Day 1-5).  
 
For some study procedures we will need you to come to ________________ [name of center].  
You will also have tests performed because you are in the study to see how the study drugs are 
affecting your body.  This will include imaging studies (for example, CT scans) every 2 cycles 
(about every 6 weeks) to find out if your cancer has responded.   
 
Clinical Center Visits: We will ask that you come to ________________ [name of center] each 
day you receive belinostat (6 days in cycle 1 and 5 days in all other cycles) and on other days 
during cycle 1 when samples are collected for research (see Study Chart).  While you are at 
________________ [name of center], we will also perform study tests and procedures to see how 
the study drugs are affecting your body. 
 
Standard procedures being done because you are in this study; these may be done more 
often because you are in the study: 
 Clinic visit to ask how you are feeling and to evaluate you with a physical examination at 
the beginning of each cycle. 
 Vital signs: You will need to have your vital signs, including your temperature, heart rate, 
blood pressure, and respiratory rate, measured each time you are seen in the outpatient 
clinic. 
 Blood tests: Measurement of your white blood cells, red blood cells and platelets, and 
measurements of your blood sugar and electrolytes and of how your liver and kidneys 
work will be done each time you are seen in the outpatient clinic.  All of these blood tests 
combined will require 1-2 tablespoons (20-30 mL) of blood each time. 
 Urine test: Depending on the results of blood tests, you may be asked to give a urine 
sample for testing or to collect your urine for 24 hours for further testing. 
 EKG to check your heart on Day 5 of cycle 1, at the beginning of cycle 2, and more often 
if needed. 
 CT scans or other imaging tests such as ultrasound (an examination using sound waves) 
or MRI (an examination using magnetic field and radio waves) that detect your tumor will 
be done every 2 cycles (about every 6 weeks) while you are receiving treatment.  This is 
done so that any benefit of the treatment can be determined, and so that if your cancer is 
not responding to the treatment, the study team can tell you and help you move to a 
different treatment program (discussed further below). 
 
Tests and procedures that are either being tested in this study or being done to see how the 
study is affecting your body: 
 
 Measurements of the drug in your blood and urine: We will collect blood samples to 
measure amounts of belinostat in your blood several times during the first cycle.  Because 
we will collect several blood draws, a thin, flexible plastic tube (called a “catheter”) will 
be placed in your arm, and all blood samples would be taken from this tube.  Using a 


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catheter will reduce the number of times a needle would be placed in your vein.  The total 
amount of blood that we collect will be about 4 tablespoons (52 mL).  
 
 
Patients in this study will be divided into 4 groups.  You will be placed in one of these groups 
based on how your liver is functioning (determined from the results of the blood tests done to 
check your liver).  Up to 12 patients with normal liver function will be included in the study.  All 
of the patients with normal liver function will receive the same dose of belinostat.  For each group 
of patients with abnormal liver function, 3 patients will be enrolled and will begin with a low 
dose of belinostat.  If no serious side effects are reported, the next set of 3 patients enrolled in that 
group will receive a higher dose of belinostat.  This will continue as long as belinostat is well 
tolerated, or the dose reaches the level that caused side effects in patients with normal liver 
function.  The dose level of the study drug you receive will depend on when you enter the study, 
and whether patients enrolled before you had any serious side effects at their dose levels.  If 
serious side effects are seen, the dose of the study drug may be lowered or stopped depending on 
the severity of the side effects.  
 
Study Chart 
The chart below shows what will happen to you while you take part in this study.  The left-hand 
column shows the day in the cycle, and the right-hand column tells you what will happen on that 
day.   
 
Day 
What to do and what will happen to you 
 
Before starting 
study drug 
 
Check in at Outpatient Clinic 
 
Get routine blood tests 
 
EKG will be done to check your heart 
 
Pregnancy test 
 
Have a history taken of how you feel and undergo a physical examination by 
a Health Care Provider 
 
CT scan will be done 
Cycle 1, Day -7 
 
Check in at Outpatient Clinic 
 
Have a history taken of how you feel and undergo a physical examination 
 
Get routine blood tests 
 
Receive belinostat through a vein for 30 minutes 
 
Have blood samples taken for research 
Cycle 1, Day -6 
 
Have blood samples taken for research 
Cycle 1, Days 1-5 
 
Check in at Outpatient Clinic 
 
Have a history taken of how you feel and undergo a physical examination  
 
Receive belinostat through a vein once a day for 30 minutes 
 
EKG will be done on Day 5 to check your heart 
 
Get routine blood tests 
Cycle 1, Days 6-21 
 
Get routine blood tests once a week 
Cycle 2 and 
onwards, Days 1-5 
 
Check in at Outpatient Clinic 
 
Have a history taken of how you feel and undergo a physical examination  


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Day 
What to do and what will happen to you 
 
 
Get routine blood tests 
 
Receive belinostat through a vein once a day for 30 minutes 
 
EKG will be done on Day 1 of cycle 2 only to check your heart 
Cycle 3 onwards 
 
CT scans to determine how your tumor is responding to the treatment will be 
done every 2 cycles (about every 6 weeks). 
 
 
Alternative Approaches or Treatments 
 
What other choices do I have if I do not take part in this study? 
Talk to your doctor about your choices before you decide if you will take part in this study.  Your 
other choices may include: 
 Getting treatment or care for your cancer without being in a study. 
 Taking part in another study.  However, if you have moderate or severe abnormal liver 
function, you may not be eligible for most other studies. 
 Getting comfort care, also called palliative care.  This kind of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by cancer.  It does not treat the 
cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible.  
 
Risks or Discomforts of Taking Part 
What side effects or risks can I expect from being in this study? 
 
If you choose to take part in this study, there is a risk that you may: 
 Lose time at work or home and spend more time in the hospital or doctor’s office than 
usual 
 Be asked sensitive or private questions which you normally do not discuss 
 
The agents used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood.  The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health.  There is also a risk that you could have side effects 
from the study drug(s)/study approach.  Here are important points about side effects: 
 The study doctors do not know who will or will not have side effects. 
 Some side effects may go away soon, some may last a long time, or some may never go 
away. 
 Some side effects may interfere with your ability to have children. 
 Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
 Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 


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 The study doctor may be able to treat some side effects. 
 The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about.  There might be other side effects that researchers do not yet know about.  If important new 
side effects are found, the study doctor will discuss these with you. 
  
It is important to remember that this is a dose-ranging study, meaning that the dose of belinostat 
will increase between groups of patients until notable side effects are seen.  Because of this, some 
patients may have severe side effects as the study investigators find the highest dose of belinostat 
can be given safely to patients with different degrees of liver function.  We already know the 
“safe dose” for patients with normal liver function and will not give you a dose bigger than this.  
If a dose has too many or certain unacceptable side effects, a lower dose may be recommended as 
the “safe dose” for future testing in patients with abnormal liver function. 
 
Risks and side effects observed with belinostat include: 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving belinostat, more than 20 and up to 100 may have: 
 Diarrhea, nausea, vomiting 
 Tiredness 
 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving belinostat, from 4 to 20 may have: 
 Anemia which may require blood transfusion 
 Belly pain 
 Constipation 
 Dry mouth 
 Swelling of arms, legs 
 Fever 
 Swelling and redness at the site of the medication injection 
 Infection 
 Change in the heart rhythm 
 Bruising, bleeding 
 Weight loss, loss of appetite 
 Dehydration 
 Dizziness, headache 
 Changes in taste 
 Shortness of breath 
 Rash 
 Flushing 
 


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Side Effects of Blood Draw: 
Infrequent (occurs in 1 to 10 out of 100 people): persistent pain and discomfort at the injection 
or needle insertion site as well as possible infection, bleeding, bruising, and soreness.  
 
 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how belinostat would affect your baby or your unborn child.  If you are a woman 
who can become pregnant, or are the partner of a woman who can become pregnant, you will 
need to practice an effective form of birth control before starting study treatment and for the 
entire time you are in the study.  If you think that you or your partner is pregnant, you should tell 
your study doctor or nurse at once.   
 
Effective forms of birth control include: 
• abstinence  
 intrauterine device (IUD) 
• hormonal (birth control pills, injections, or implants) 
• tubal ligation 
• vasectomy 
 
Potential Benefits of Taking Part 
Are there benefits to taking part in this study?  
We hope that you will get personal medical benefit from taking part in this study, but we cannot 
be certain.  These potential benefits could include shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.  Because there is not much information 
about the drug’s effect on your cancer, we do not know if you will benefit from taking part in this 
study, although the knowledge gained from this study may help others in the future who have 
cancer.   
 
Research Subject’s Rights 
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
this study.  If you decide to participate, you may leave the study at any time.  No matter what 
decision you make, there will be no penalty to you, and you will not lose any of your regular 
benefits.  Leaving the study will not affect your medical care.  You can still get your medical care 
from our institution if you are eligible and choose to participate in another trial.  We will tell you 
about new information or changes in the study that may affect your health or your willingness to 
continue in the study.  In the case of injury resulting from this study, you do not lose any of your 
legal rights to seek payment by signing this form. 
 
What are the costs of taking part in this study?  
The National Cancer Institute will supply the Belinostat at no charge while you take part in this 
study.  The NCI does not cover the cost for getting the Belinostat ready and giving it to you, so 


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you or your insurance company may have to pay for this.  Even though it probably won’t happen, 
it is possible that the manufacturer may not continue to provide the Belinostat to the NCI for 
some reason.  If this would occur, other possible options are: 
 You may be able to get the Belinostat from the manufacturer or your pharmacy but you or 
your insurance company may have to pay for it. 
 If there is no Belinostat available at all, no one will be able to get more and the study 
would close. 
If a problem with getting Belinostat occurs, your study doctor will talk to you about these 
options. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons: 
 if he/she believes that it is in your best interest 
 if your disease gets worse during treatment 
 if you have side effects from the treatment that your doctor thinks are too severe 
 if new information shows that another treatment would be better for you 
 if too many patients in the study experience severe side effects 
 
In this case, you will be informed of the reason therapy is being stopped. 
 
You can stop taking part in the study at any time.  However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.   
 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you.  However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the Cancer Therapy 
Evaluation Program (CTEP) at the National Cancer Institute (NCI) or designated representatives. 
 If you withdraw your consent and leave the trial, any samples of yours that have been obtained 
for the study and stored at the NCI can be destroyed upon request. However, any samples and data 
generated from the samples that have already been distributed to other researchers or placed in the 
research databases cannot be recalled and destroyed. 
 


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Will my medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. 
 
Organizations that may look at and/or copy your medical records, including research records, for 
research, quality assurance, and data analysis include: 
 
 The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people. 
 Qualified representatives from the drug company sponsor may also review the medical 
records. 
 Designees from cancer centers participating in this study.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the Web 
site will include a summary of the results.  You can search this Web site at any time. 
 
[Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation 
found at 21 CFR 50.25(c) and must be included verbatim in all informed consent documents.  The 
text in this paragraph cannot be revised.] 
 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed by 
the local institution.  The regulations may or may not be included in the informed consent form 
depending on local institutional policy.] 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor in 
person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study will not pay for medical 
treatment.   
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ (telephone number).  


CTEP #8846 
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[Note to Local Investigator: Contact information for patient representatives or other individuals 
in a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can be listed here.]    
 
 
Where can I get more information? 
You may call the National Cancer Institute’s Cancer Information Service at: 1-800-4-CANCER 
(1-800-422-6237).  You may also visit the NCI Web site at http://cancer.gov/. 
 For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
 For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor.  
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I have 
read it or it has been read to me.  I understand the information and have had my questions 
answered.  I agree to take part in this study. 
 
Participant ________________________________ 
 
Date _____________________________________     


CTEP #8846 
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APPENDIX H: REGISTRATION PROCEDURES 
 
I. 
Registration Policies 
A. 
Registrations for the Liver Dysfunction Trial must be made through the 
Coordinating Center, at the National Cancer Institute’s Center for Cancer 
Research through the Developmental Therapeutics Clinic.  Patients are 
registered Monday through Friday between the hours of 8:30am through 4:30pm, 
excluding Federal Holidays.  Documentation of IRB approval of this protocol by 
collaborating institutions must be on file. 
B. 
Following registration, patients should begin protocol treatment within 
3 business days.  However, beginning therapy within 24 hours of registration is 
preferable in patients with organ dysfunction.  
C. 
Pre-study laboratory tests and scans must be completed prior to registration, 
within the time frame specified in the protocol.  The eligibility form provided by 
the NCI, CCR (Appendix J) must be completed and signed by the treating 
physician.  Patients must also sign an informed consent and HIPAA 
authorization form prior to registration. 
D. 
A patient failing to meet all protocol requirements cannot be registered.  If you 
have any questions regarding eligibility, contact the DTC at (301) 435-4949  
II. 
Slot Reservations 
A. 
If a potential patient has been identified for the Liver Dysfunction trial, the data 
manager or research nurse must contact the DTC Research Nurse at (301) 435-
4949 to verify that a slot is available on a particular dose-level.  Please provide 
the patient’s initials, diagnosis, bilirubin, and AST at that time. 
1. If a dose level is open, the Research Nurse will reserve the “slot” for a 
maximum of 14 days (10 business days) to allow sufficient time to 
determine eligibility.  If a patient does not start treatment within this time 
frame, the slot will be released.  Slots will be released on a first come 
first served basis for all slots other than the normal cohort slots.   
a. The data manager or research nurse must follow up the NCI, 
CCR within 14 days (10 business days) to complete the 
registration or cancel the reservation. 
2. If no dose-level is open (based on the criteria for dose expansion or 
escalation- as described in the protocol), then the NCI, CCR can indicate 
the anticipated date of reopening and the slot may be reserved for the 
patient. 
a. The data manager or research nurse must stay in touch with 
the NCI, CCR and must complete or cancel registration 
within 24 hours of the planned treatment date.  It is 
preferred that the Coordinating Center is informed of the 
intended treatment date at least 48 hrs prior. 


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3. No more than 3 patients may be held on the waiting list for a single liver 
dysfunction cohort. 
a. If a patient on the waiting list becomes ineligible, then the 
data manager or research nurse must call or email the 
Coordinating Center to remove the patient from the list. 
4. No slot reservation at the given dose level will be made prior to 
escalation or expansion until such time as the 3rd patient at that level has 
been evaluated for toxicity. 
III. 
Registration Procedures 
A. Once a patient is eligible, and all the pre-study requirements have been fulfilled, a 
data manager or research nurse must contact the Coordinating Center’s Primary 
Research Nurse: Nancy Moore RN, phone (240) 760-6045, 
nancy.moore@nih.gov, fax (301) 451-5625. 
B. 
Fax a copy of the signed informed consent, HIPAA authorization form, 
eligibility screening worksheet, required pre-study tests (pathology and baseline 
laboratory reports), and the completed On-Study/Eligibility Form.  NCI 
registration form to (301) 480-7281.  Upon receipt of the documents, the 
Coordinating Center, will confirm completion of the registration process and 
verify eligibility.  
C. 
All eligible patients will be registered through the NCI Central Registration 
Office (CRO).  The CRO is open from 8:30am to 5:00pm EST Monday through 
Friday, excluding Federal Holidays.  The CRO will notify the Coordinating 
Center via encrypted e-mail that the protocol Eligibility Checklist has been 
received and registered.  
D. 
The Coordinating Center will contact the registering data manager or research 
nurse via email confirming registration.  The email confirmation will be 
available and sent to the participating site within 1 business day.  The 
confirmation of registration form includes patient name, cohort, dose level, NIH 
medical record number, unique identifier (7 digit number), and an assigned 
patient ID.          
IV. 
C3D Database Patient ID  
A. 
Upon registration, the CRO will assign a unique 7 digit patient/subject ID 
number for each patient that will be used to enter data into the C3D database.  
The number is coded to identify the patient number according to the participating 
site.  The number will appear as 1010001, the first three digits identify the site 
101.  Subsequent sites will be listed as 102, 103, 104, etc.  The last three digits 
in the series will identify the sites patient number 001.  
B. 
This assigned unique identifier is to be used in the Patient ID field for the CTEP-
AERS submission and Theradex Data Reporting.  


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C. 
Each site will be listed in the C3D database according to the CTEP assigned 
code.  Each site is assigned a 5 character code composed of an alphabetical site 
abbreviation and numbers.  
V. 
Assigned Patient ID 
A. 
The CTEP site abbreviation will be utilized along with the last three digits in the 
unique identifier to reference the patients during the biweekly Organ 
Dysfunction conference call. 
B. 
The assigned patient ID is an alpha numeric code that will be used to reference 
the participating site, patient number dysfunction cohort, and dose level. 
C. 
The alphabetical site abbreviation is combined with the last three digits of the 
unique identifier, cohort letter, and dose level to formulate the assigned Patient 
ID.  Each dysfunction cohort will be referenced alphabetically as Cohort A 
(Normal), Cohort B (Mild), Cohort C (Moderate), Cohort D (Severe).  The 
assigned ID will appear as NCI-001-A-1. 
D. 
The assigned ID will also be used as the Patient ID to code the pharmacokinetic 
samples. 
 
 
 


CTEP #8846 
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APPENDIX I: Organ Dysfunction Conference Call Policies 
 
 
I. 
Biweekly Conference Call Policies 
a. A master liver dysfunction slot reservation excel spreadsheet will be maintained 
and distributed biweekly to the participating site 24 hours prior to the conference 
call. 
b. Each participating site is required to have at least one representative participating 
in the conference call. 
c. Patients will be referenced using the assigned Patient ID. 
d. Sites are required to provide an update on each active patient. 
II. 
Protocol Enrollment Log 
a. A patient enrollment log template word version will be distributed to each 
participating site.  
b. Data managers or research nurses should maintain and update the log  
c. The updated log should be sent via email to the Coordinating Center by 2pm EST 
the Thursday prior to the Friday Conference Call. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX J: Forms 
 
 
Eligibility/Pre-Registration Worksheet 
CTEP #8846, NCI #11-C-0060 
 
A Phase I Pharmacokinetic Study of Belinostat for Solid Tumors and Lymphomas in 
Patients with Varying Degrees of Hepatic Dysfunction 
 
Coordinating Center: NCI 
 
 
 
Principal Investigator: 
Bethesda, MD  20892  
 
 
 
Naoko Takebe, MD, PhD 
Primary Contact: Nancy Moore, RN   
 
National Cancer Institute 
Tel: (240) 760-6045  
 
 
 
Tel:  (240) 781-3398 
Fax: (301) 451-5625  
 
 
 
takeben@mail.nih.gov 
nancy.moore@nih.gov 
 
 
 
Patient’s Name: (FML) 
 
 
Institution: 
Medical Record Number: 
 
Investigator: 
 
 
Patient’s Date of Birth: 
 
 
Treating Physician: 
Sex: ______Male  _____Female 
Date Informed Consent Signed: 
 
 
IRB approval valid until (date) 
 
 
 
Race: 
_____ Black 
_____ Caucasian 
_____ Asian 
_____ American Indian 
_____ Native   
Hawaiian/Pacific 
_____ Other: _________ 
Ethnicity: 
____ Hispanic 
____ Non-Hispanic 
____ Other: ________ 
Projected start date of treatment: 


CTEP #8846 
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INCLUSION CRITERIA:  A NO response will make the subject INELIGIBLE. 
 
Yes 
No 
N/A 
INCLUSION CRITERIA 
 
 
 
Does the patient (except those with hepatocellular carcinoma) have 
histologically or cytologically confirmed solid tumor or lymphoma that is 
metastatic, unresectable, progressive, or recurrent, and for which standard 
curative or palliative measures do not exist or are no longer effective?  
Patients with hepatocellular carcinoma do not require biopsy confirmation.  
If the patient has hepatocellular carcinoma, does the patient have a liver 
mass with raised α-fetoprotein level (≥500 ng/mL), consistent radiographic 
changes, and serology and viral DNA/RNA measurements consistent with 
chronic hepatitis (see Section 3.1.9) AND have disease that has failed 
standard therapy? 
 
 
 
Is it correct that the patent has had no radiation, major surgery, 
chemotherapy or biologic therapy within 4 weeks prior to entering the study 
(6 weeks for nitroureas or mitomycin C); ≥ 2weeks since any prior 
administration of study drug in an exploratory IND/Phase 0 study.  Has the 
patient recovered to at least eligibility levels due to adverse events and/or 
toxicity of prior chemotherapy or biologic therapy? 
 
 
 
Is the patient’s age ≥ 18 years?  Because no dosing or adverse event data are 
currently available on the use of Belinostat in patients <18 years of age, 
children are excluded from this study but will be eligible for future pediatric 
Phase 1 single-agent trials. 
 
 
 
Is the patient’s ECOG performance status ≤ 2 and Karnofsky ≥60%, 
(Appendix B)? 
Status ______ 
 
 
 
Is the patient’s life expectancy greater than 3 months? 
 
 
 
Does the patient have acceptable renal and marrow function as defined 
below?                                     Date: ____________ 
Leukocytes  ≥ 3,000/mcL       ____________ 
Absolute Neutrophil Count      
(ANC)  ≥ 1,5000/mcL             ____________ 
Platelets  ≥  100,000/mcL         ____________ 
Serum Creatinine                    ___________   ULN _______ 
(within normal institutional limits) 
OR  
Creatinine Clearance 
≥ 60 mL/min for patients with creatinine levels above institutional 
normal, as determined by measured 24-hour creatinine clearance  
 
Baseline evaluations should be conducted within 7 days of the treatment 
start date. 
Patients with abnormal liver function will be eligible and will be grouped 
according to the criteria described in Section 5.1.  No distinction will be 


CTEP #8846 
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Yes 
No 
N/A 
INCLUSION CRITERIA 
made between liver dysfunction due to metastases and liver dysfunction due 
to other causes.  Liver function tests should be repeated with 24 hours prior 
to starting treatment on study 
 
 
 
Patients with biliary obstruction for which a stent has been placed are 
eligible, provided the stent has been in place for at least 10 days prior to the 
first dose of belinostat and the liver function has stabilized.  Two 
measurements at least 2 days apart that put the patient in the same hepatic 
dysfunction stratum will be accepted as evidence of stable hepatic function. 
 There should be no evidence of biliary sepsis.  
Does the patient either not have a stent, or, if a stent is in place, has it been 
in place for over 10 days, AND has the liver function shown stability 
(placing patient into same cohort with measurements at least 2 days apart)? 
 
 
 
If patient has hepatitis B, are HepBsAg, HepBcAb, HepBsAb, and 
HepBeAb consistent with chronic disease as measured within 3 months of 
starting on study? 
 
 
 
If patient has hepatitis B, has COBAS TaqMan been checked within 1 
month of starting on study? 
 
 
 
If patient has hepatitis C, has anti-HCV been checked within 3 months of 
starting on study? 
 
 
 
If patient has hepatitis C, has HCV-RNA been checked within 1 month of 
starting on study? 
 
 
 
Patient with gliomas or brain metastases who require corticosteroids or 
anticonvulsants must be on a stable dose of corticosteroids and seizure free 
for 1 month prior to enrollment.  Patients with known brain metastases 
should have had brain irradiation (whole brain or gamma knife) more than 4 
weeks before starting the protocol.  Note that patients should have had their 
steroids tapered to low dose (i.e., 1.5 mg of dexamethasone/day). 
Does the patient either not have gliomas or brain metastases, or if the 
patient does, have they met the above criteria?   
 
 
 
Is the patient able to understand and willing to sign a written informed 
consent document? 
 
 
 
The effects of belinostat on the developing human fetus are unknown.  For 
this reason and because HDAC inhibitors are known to be teratogenic, 
women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for the duration of study participation.  Should a 
woman become pregnant or suspect she is pregnant while participating in 
this study, she should inform her treating physician immediately. 
Does the patient agree to use contraception for the duration of study 
participation? 
 
 
 


CTEP #8846 
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EXCLUSION CRITERIA:  A YES response will make the patient INELIGIBLE for the study. 
 
Yes 
No N/A 
EXCLUSION CRITERIA 
 
 
 
Is the patient receiving any other investigational agents? 
 
 
 
Has the patient previously been treated with Belinostat? 
 
 
 
Does the patient have a history of allergic reactions attributed to compounds 
of similar chemical or biologic composition to belinostat, including 
hydroxamate compounds or arginine? 
 
 
 
Has the patient taken valproic acid, another HDAC inhibitor, within 2 weeks 
prior to enrollment? 
 
 
 
Does the patient have uncontrolled intercurrent illness including, but not 
limited to ongoing or active infection, or psychiatric illness/social situations 
that would limit compliance with study requirements? 
 
 
 
Is the patient pregnant or breastfeeding?  Pregnant women are excluded from 
this study because belinostat is an HDAC inhibitor with the potential for 
teratogenic or abortifacient effects. 
 
 
 
Does the patient have active hemolysis?  Patients with active hemolysis 
should be excluded. 
 
 
 
Is the patient on antiretroviral therapy?  HIV-positive patients on combination 
antiretroviral therapy are ineligible because of the potential for PK 
interactions with belinostat.  Appropriate studies will be undertaken in 
patients receiving combination antiretroviral therapy when indicated. 
 
 
 
For patients with hepatitis B or C, does the patient require interferon 
treatment or has the patient received interferon within the past 4 weeks?  
Patients must be stable without having received interferon in at least 4 weeks. 
 
 
 
Does the patient have significant cardiovascular disease (New York Heart 
Association Class III or IV cardiac disease), symptomatic congestive heart 
failure, myocardial infarction within the past 6 months, unstable angina, 
unstable arrhythmia or a need for anti-arrhythmic therapy (use of frequency 
adjusting medication for atrial fibrillation is allowed, if stable medication for 
at least last month prior to initiation of belinostat treatment and medication 
not listed as causing Torsades de Points), evidence of acute ischemia or ECG, 
marked baseline prolongation of QT/QTc interval, e.g., repeated 
demonstration of a QTC interval > 450 msec*; Long QT Syndrome?  Or does 
the patient require a drug known to prolong the QT interval and/or cause 
Torsades de Pointes (Table 1, Appendix C) or have taken such a drug within 2 
weeks of study entry?  (Note: Drugs that may be associated with Torsades de 
Pointes but lack substantial evidence [Table 2, Appendix C] will be allowed 
at the discretion of the PI, although it is preferable to substitute an alternate 
medication.) 


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PRE-STUDY EVALUATIONS 
 
Laboratory evaluations are to be conducted within 1 week prior to the start of the protocol therapy 
unless otherwise indicated.  Scans and x-rays must be performed within 28 days prior to the start 
of therapy.  
 
Pre-Study Evaluations: 
Completion Date 
History and Physical Exam:  (prior to study drug administration) 
(including height, weight, vital signs,  and Performance Status) 
 
Baseline Imaging Studies: 
(CT Scan of the Chest/Abd/pelvis within 28 days prior to study drug 
administration) 
 
Laboratory Evaluation:  (within 1 week prior to study drug 
administration) 
Hematological Profile: CBC with differential and Platelet Count 
Coagulation Studies: PT*/INR/aPTT* is required to be checked at 
baseline 
Biochemical Profile: Electrolytes, BUN, creatinine, glucose, AST 
(SGOT), ALT (SGPT), bilirubin, calcium, phosphorous, albumin, 
magnesium, alkaline phosphatase. *=as clinically indicated 
 
Serum Pregnancy Test: (within 1 week prior to study drug 
administration) 
Participants of childbearing age and anatomic ability. 
 
EKG (within 1 week prior to study drug administration) 
 
 
Child-Pugh Classification score (Appendix M).  Please submit with 
enrollment package. 
 
Histologic Confirmation:  
A block or stained slides of primary tissue from the time of diagnosis 
will be required from each participant to confirm diagnosis.  Tissue 
blocks from a known recurrence will be accepted if original tumor 
samples are unavailable. 
 


CTEP #8846 
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Laboratory evaluation for patients with hepatocellular carcinoma 
secondary to hepatitis B or C: 
For patients with hepatitis B 
HepBsAg, HepBcAb, HepBsAb, and HepBeAb; results may be from 
within 3 months before starting on study. 
COBAS TaqMan; results must be from within 1 month before 
starting on study. 
For patients with hepatitis C 
anti-HCV; results may be from within 3 months before starting on 
study. 
HCV-RNA; results must be from within 1 month before starting on 
study. 
 
 
DESCRIPTIVE FACTORS: 
 
Primary: ________________________ 
Histology:  ___________________ 
 
Height _______ cm 
Weight _____kg 
BSA ______ 
 
PRIOR THERAPY (Please specify date, procedure, agent, dose, and response) 
 
Treatment Type 
Agent 
Treatment 
Start 
Date 
Treatment  
End 
Date 
Response 
Surgery/Biopsy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiotherapy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Hormonal Therapy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunotherapy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LIVER DYSFUNCTION GROUPS 
 
Patients entering the study are stratified into four dysfunction groups [(Cohort 1) Normal, (Cohort 
2) Mild, (Cohort 3) Moderate, (Cohort 4) Severe] according to their hepatic function as outlined 
in the following table: 
 
Liver 
Dysfunction 
Cohorts 
Cohort 1 
Normal 
 
Cohort 2 
Mild 
Cohort 3 
Moderate 
Cohort 4 
Severe 
Total Bilirubin 
 
≤ ULN 
>ULN but   
≤ 1.5 X ULN 
 
>1.5 X ULN to 
≤ 3 X ULN 
 
> 3 X ULN but ≤ 
10 X ULN      
 
AST (SGOT) 
 
≤ ULN 
AST > ULN 
Any AST 
Any AST 
 
HEPATIC FUNCTION 
Total Bilirubin: 
 
 
 
Normal Cohort 1: 
 
 ≤ ULN 
 
 
 
Mild Cohort 2: 
 
> ULN but ≤ 1.5 X ULN 
 
 
Moderate Cohort 3: 
 
>1.5 X ULN to ≤ 3 X ULN 
 
 
Severe Cohort 4: 
 
> 3 X ULN but ≤ 10 X ULN      
 
 


CTEP #8846 
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AST (SGOT): 
 
Normal Cohort 1: 
 
≤ ULN  
 
 
 
Mild Cohort 2: 
 
> ULN  
 
 
 
Moderate Cohort 3: 
 
Any AST 
 
 
 
 
Severe Cohort 4: 
 
Any AST 
 
 
 
 
Date Measured 
_____________________ 
 
(Second Measurement – for patients with a biliary stent) 
 
Patients should have biliary stent placed at least 10 days prior to the start of treatment.  Provide 
the placement date in the table, if placed within 10 days of treatment. 
 
Biliary Stent  
Present 
Yes 
No 
Biliary Stent Placement 
Date 
Second Lab 
Measurement Date 
 
 
 
 
 
 
Liver Dysfunction Group 
 
 
Normal Cohort 1: 
 
Mild Cohort 2: 
 
Moderate Cohort 3: 
 
Severe Cohort 4: 
 
 
Printed Name of Physician: ______________________ Date: ____________ 
Physician Signature:  
______________________  
 
Date Registered with NCI ____________________ 
Spoke with: ________________________________ 
Study ID: 
________________________________ 
Eligibility Completed Complete By: _____________________________ 
Assigned CRA/ Data Manager: 
______________________________ 
 
The NCI will send a confirmation of registration within 24 hours. 


CTEP #8846 
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107 
 
 
Appendix K: Off Study/Death Notification Form 
 
Complete form and e-mail to the Coordinating Center Research Nurse 
nancy.moore@nih.gov 
Patient Information: 
 
First Name: 
 
 
 
Middle Initial:  
 
 
 
Last Name: 
 
 
 
ID Number: 
 
 
Protocol # (CC# Preferred):  
 
Off Study Date: 
 
 
 
 
 
 
(MM/DD/YY) 
 
Death Date: 
 
 
 
 
 
 
 
(MM/DD/YY) 
 
Choose one of the following Off Study Reasons: 
 
C: 
Completed Study 
 
L: 
Lost to Follow Up 
 
R: 
Refused Further Treatment 
 
T: 
Toxicity 
 
D: 
Death 
 
P: 
Progressive Disease 
 
O: 
Other   
 
 
Registrar: 
  
Participating Site: __________________________________ 
Name: _______________________ Date: _____________ 
 
 
 


CTEP #8846 
Clinical Center #11-C-0060 
 
108 
 
Appendix L: Study Diary 
Phase I Belinostat for Solid Tumors and Lymphomas in Patients with Varying Degrees of Hepatic Dysfunction 
 
Patient Name: _________________________ 
 
Cycle ______ Week _______ 
Cohort: ______________________________ 
 
Patient Signature: ___________________________________ Date: _______________________
Date 
Note any side effects  
List any medications taken and the 
reason why (prescription & non-
prescription)  
**Do not list your daily meds** 
Monday 
Date: 
 
 
Tuesday 
Date: 
 
 
Wednesday 
Date: 
 
 
Thursday 
Date: 
 
 
Friday 
Date: 
 
 
Saturday 
Date: 
 
 
Sunday 
Date: 
 
 


CTEP #8846 
Clinical Center #11-C-0060 
 
109 
 
APPENDIX M: Child-Pugh Classification (CPC) of Liver Dysfunction 
 
CPC score is calculated from the sum of the points for each CPC criteria: 
CPC Classification 
Level of dysfunction 
Score 
A 
Mild 
5-6 
B 
Moderate 
7-9 
C 
Severe 
10 
 
 
 
 
Points 
CPC Criteria 
1 
2 
3 
Encephalopathy grade 
(see table below) 
0 
1 or 2 
3 or 4 
Ascites 
Absent 
Asymptomatic 
Requiring 
intervention 
Serum bilirubin, mg/dL 
<2 
2 to 3 
>3 
Serum albumin, g/dL 
>3.5 
2.8 to 3.5 
<2.8 
Prothrombin time, sec 
prolonged 
<4 
4 to 6 
>6 
 
 
 
Encephalopathy 
Grade 
Definition 
(EEG required for Gr. 2,3,4) 
0 
Normal consciousness, personality, neurological exam 
1 
Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting 
2 
Lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic 
waves on EEG 
3 
Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, 
slower waves on EEG 
4 
Unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps 
delta activity on EEG 
CPC should be calculated at baseline as part of the eligibility assessment. 
 
 

ICF_001.pdf: 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Cancer Institute 
 
 
STUDY NUMBER: 
11-C-0060 
PRINCIPAL INVESTIGATOR:  A. P. Chen, MD 
 
 
STUDY TITLE: 
Phase I Pharmacokinetic Study of Belinostat for Solid Tumors and Lymphomas in 
Patients with Varying Degrees of Hepatic Dysfunction 
 
 
Continuing Review Approved by the IRB on 01/09/17 
Amendment Approved by the IRB on 08/15/17 (U) 
 
 
      Date Posted to Web: 08/22/17 
Standard 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time.  In either 
case, you will not lose any benefits to which you are otherwise entitled.  However, to receive 
care at the NIH, you must be taking part in a study or be under evaluation for study 
participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that may 
help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical 
or research treatments they would want to receive (such as blood transfusions).  If you have such 
beliefs, please discuss them with your NIH doctors or research team before you agree to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much time 
as you need to ask any questions and discuss this study with anyone at NIH, or with family, friends 
or your personal physician or other health professional. 
 
Description of Research Study 
 
The purpose of this study is to test the safety of belinostat at different dose levels in patients with 
cancer who have different degrees of liver function.  Belinostat is an experimental drug that works 
by helping to turn on genes that control cell growth and survival that are switched off in cancer 
cells.  This is the first study in which belinostat will be given to patients with different degrees of 
liver function.  We already know the safe dose for patients with normal liver function.  Other 
purposes of this study are to find out what side effects occur when belinostat is given to patients 
with different degrees of liver function, how much belinostat is in your blood at specific times, and 
whether or not belinostat is effective in treating your cancer.  We will compare how the patients 


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  2  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
with abnormal liver function do in comparison with patients with normal liver function.  That is the 
reason that a group of patients with normal liver function will also be included on this trial.   
 
How many people will take part in this study?  
 
Up to 80 patients will take part in this study at multiple centers across the United States.   
 
Has this drug been given to other people?  
 
Belinostat has been given to about 500 patients with different types of cancer to measure its safety 
and how the body handles the drug.  Belinostat has not been given in a formal trial to patients with 
cancer who have abnormal liver function to learn how these patients tolerate and respond to the 
drug.    
 
What will happen if I take part in this study? 
 
Before you begin the study 
You will need to have the following examinations, tests, or procedures to find out if you can be in 
the study.  These examinations, tests, or procedures are part of your regular cancer care and should 
be done by your health care team even if you do not join the study.  If you have had them recently, 
they may not need to be repeated.  This will be up to your study doctor. 
 
If you decide that you would like to participate in this study, you will be asked to sign this consent 
form.  You will then have the examinations, tests, and procedures listed below done to see if you 
can take part in the study (this is called the screening/baseline evaluation).  
 
• Complete medical history. 
• Physical examination, including height, weight, blood pressure, pulse, and temperature. 
• Standard blood tests (requiring about 1 tablespoon of blood total), which include 
measurement of your white blood cells, red blood cells, platelets, blood sugar and 
electrolytes, how your liver and kidneys work, and how well your blood clots. 
• Urine tests: Depending on the results of blood tests, you may be asked to give a collect your 
urine for 24 hours for further testing. 
• Pregnancy test: A blood test will be done to check for pregnancy in women who are able to 
become pregnant.   
• EKG to check your heart. 
• CT scans of your chest, abdomen, and pelvis to measure your tumor(s).  Other imaging tests 
may be done as needed. 
 
During the study 
After you are accepted for this study and you choose to take part, you will begin taking the study 
drug, belinostat.  Belinostat is given through a vein for 30 minutes.  Belinostat will be given in 
cycles.  Except for cycle 1, all cycles are 3 weeks long.  Cycle 1 is 4 weeks long.  Now, we will 


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  3  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
describe what will happen during each cycle.   
 
For cycle 1 only, you will receive one extra dose of belinostat 1 week before the regular treatment 
starts (Day -7).  In each cycle, belinostat will be given once a day for 5 days (Day 1-5).  
 
For some study procedures we will need you to come to the Clinical Center.  You will also have 
tests performed because you are in the study to see how the study drugs are affecting your body.  
This will include imaging studies (for example, CT scans) every 2 cycles (about every 6 weeks) to 
find out if your cancer has responded.   
 
Clinical Center Visits: We will ask that you come to the Clinical Center each day you receive 
belinostat (6 days in cycle 1 and 5 days in all other cycles) (see Study Chart).  While you are at the 
Clinical Center, we will also perform study tests and procedures to see how the study drugs are 
affecting your body. 
 
Standard procedures being done because you are in this study; these may be done more 
often because you are in the study: 
 
• Clinic visit to ask how you are feeling and to evaluate you with a physical examination at the 
beginning of each cycle. 
• Vital signs: You will need to have your vital signs, including your temperature, heart rate, 
blood pressure, and respiratory rate, measured each time you are seen in the outpatient clinic. 
• Blood tests: Measurement of your white blood cells, red blood cells and platelets, and 
measurements of your blood sugar and electrolytes and of how your liver and kidneys work 
will be done each time you are seen in the outpatient clinic.  All of these blood tests combined 
will require 1-2 tablespoons (20-30 mL) of blood each time. 
• Urine test: Depending on the results of blood tests, you may be asked to give a urine sample 
for testing or to collect your urine for 24 hours for further testing. 
• EKG to check your heart on Day 5 of cycle 1, at the beginning of cycle 2, and more often if 
needed. 
• CT scans or other imaging tests such as ultrasound (an examination using sound waves) or 
MRI (an examination using magnetic field and radio waves) that detect your tumor will be 
done every 2 cycles (about every 6 weeks) while you are receiving treatment.  This is done so 
that any benefit of the treatment can be determined, and so that if your cancer is not responding 
to the treatment, the study team can tell you and help you move to a different treatment 
program (discussed further below). 
 
Tests and procedures that are either being tested in this study or being done to see how the 
study is affecting your body: 
 
• Measurements of the drug in your blood: We will collect blood samples to measure 
amounts of belinostat in your blood several times during cycle 1.  Because we will collect 
several blood draws, a thin, flexible plastic tube (called a “catheter”) will be placed in your 
arm, and all blood samples would be taken from this tube.  Using a catheter will reduce the 


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  4  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
number of times a needle would be placed in your vein.  The total amount of blood that we 
collect will be about 4 tablespoons (52 mL).  
 
Patients in this study will be divided into 4 groups.  You will be placed in one of these groups 
based on how your liver is functioning (determined from the results of the blood tests done to 
check your liver).  Up to 12 patients with normal liver function will be included in the study.  All 
of the patients with normal liver function will receive the same dose of belinostat.  For each group 
of patients with abnormal liver function, 3 patients will be enrolled and will begin with a low dose 
of belinostat.  If no serious side effects are reported, the next set of 3 patients enrolled in that 
group will receive a higher dose of belinostat.  This will continue as long as belinostat is well 
tolerated, or the dose reaches the level that caused side effects in patients with normal liver 
function.  The dose level of the study drug you receive will depend on when you enter the study, 
and whether patients enrolled before you had any serious side effects at their dose levels.  If 
serious side effects are seen, the dose of the study drug may be lowered or stopped depending on 
the severity of the side effects.  
 
Study Chart 
 
The chart below shows what will happen to you while you take part in this study.  The left-hand 
column shows the day in the cycle, and the right-hand column tells you what will happen on that 
day.   
 
Day 
What to do and what will happen to you 
Before 
starting 
study drug 
• Check in at Outpatient Clinic 
• Get routine blood tests 
• EKG will be done to check your heart 
• Pregnancy test 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider 
• CT scan will be done 
Cycle 1,  
Day -7 
• Check in at Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination 
• Get routine blood tests 
• Receive belinostat through a vein for 30 minutes 
• Have blood samples taken for research 
Cycle 1,  
Day -6 
• Have blood samples taken for research 
Cycle 1,  
Days 1-5 
• Check in at Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination  
• Receive belinostat through a vein once a day for 30 minutes 
• EKG will be done on Day 5 to check your heart 


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  5  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
Day 
What to do and what will happen to you 
• Get routine blood tests 
Cycle 1,  
Days 6-21 
• Get routine blood tests once a week 
Cycle 2 and 
onwards, 
Days 1-5 
• Check in at Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination  
• Get routine blood tests 
• Receive belinostat through a vein once a day for 30 minutes 
• EKG will be done on Day 1 of cycle 2 only to check your heart 
Cycle 3 
onwards 
• CT scans to determine how your tumor is responding to the treatment will be 
done every 2 cycles (about every 6 weeks). 
 
 
Risks or Discomforts of Taking Part 
What side effects or risks can I expect from being in this study?  
 
If you choose to take part in this study, there is a risk that you may: 
• Lose time at work or home and spend more time in the hospital or doctor’s office than 
usual 
• Be asked sensitive or private questions which you normally do not discuss 
 
The agents used in this study may affect how different parts of your body work such as your 
liver, kidneys, heart, and blood.  The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health.  There is also a risk that you could have side 
effects from the study drug(s)/study approach.  Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about.  There might be other side effects that researchers do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  6  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
It is important to remember that this is a dose-ranging study, meaning that the dose of belinostat 
will increase between groups of patients until notable side effects are seen.  Because of this, 
some patients may have severe side effects as the study investigators find the highest dose of 
belinostat can be given safely to patients with different degrees of liver function.  We already 
know the “safe dose” for patients with normal liver function and will not give you a dose bigger 
than this.  If a dose has too many or certain unacceptable side effects, a lower dose may be 
recommended as the “safe dose” for future testing in patients with abnormal liver function. 
 
Risks and side effects observed with belinostat include: 
 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving belinostat, more than 20 and up to 100 may have: 
• Diarrhea, nausea, vomiting 
• Tiredness 
 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving belinostat, from 4 to 20 may have: 
• Anemia which may require blood transfusion 
• Belly pain 
• Constipation 
• Dry mouth 
• Swelling of arms, legs 
• Fever 
• Swelling and redness at the site of the medication injection 
• Infection 
• Change in the heart rhythm 
• Bruising, bleeding 
• Weight loss, loss of appetite 
• Dehydration 
• Dizziness, headache 
• Changes in taste 
• Shortness of breath 
• Rash 
• Flushing 
 
 


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  7  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
Side Effects of Blood Draw: 
 
Infrequent (occurs in 1 to 10 out of 100 people): persistent pain and discomfort at the injection 
or needle insertion site as well as possible infection, bleeding, bruising, and soreness.  
 
Reproductive Risks: Because the effect of Belinostat on unborn babies is not known, you 
should not become pregnant or father a baby while on this study.   
 
Women of childbearing potential will be required to have a pregnancy test.  If you are a woman 
who is breast feeding or pregnant, you may not participate in the study because we don’t know 
how this medicine would affect your baby or your unborn child.  If you are a woman who can 
become pregnant, or are the partner of a woman who can become pregnant, you will need to 
practice an effective form of birth control before starting study treatment, during study treatment, 
and for 3 months after you finish study treatment.  If you think that you or your partner is 
pregnant, you should tell your study doctor or nurse at once.  Avoiding sexual activity is the only 
certain method to prevent pregnancy.  But, if you choose to be sexually active, you should use an 
appropriate “double barrier” method of birth control (such as female use of a diaphragm, 
intrauterine device (IUD), or contraceptive sponge, in addition to male use of a condom) or the 
female should be using prescribed “birth control” pills, injections, or implants.  Male participants 
must also use adequate contraception.   
 
If you choose to be sexually active during this study, you understand that even with use of these 
birth control measures, pregnancy could still result.  Some methods might not be approved for 
use in this study.  Ask about counseling and more information about preventing pregnancy.  
Belinostat may reduce a man’s ability to father a child or a woman’s ability to become pregnant, 
and in some cases this may be permanent.  Women should not breast feed during the study and 
for 30 days after finishing study treatment.  For more information about risks and side effects, 
ask your study team.   
 
Potential Benefits of Taking Part 
 
Are there benefits to taking part in this study?  
 
We do not know if you will receive personal, medical benefit from taking part in this study.  
These potential benefits could include shrinking of your tumor or lessening of your symptoms, 
such as pain, that are caused by the cancer.  Because there is not much information about the 
drug’s effect on your cancer, we do not know if you will benefit from taking part in this study, 
although the knowledge gained from this study may help others in the future who have cancer.   


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  8  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
Alternative Approaches or Treatments 
 
What other choices do I have if I do not take part in this study? 
 
Talk to your doctor about your choices before you decide if you will take part in this study.  Your 
other choices may include: 
 
• Getting treatment or care for your cancer without being in a study. 
• Taking part in another study.  However, if you have moderate or severe abnormal liver 
function, you may not be eligible for most other studies. 
• Getting comfort care, also called palliative care.  This kind of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by cancer.  It does not treat the 
cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible.  
 
 
Research Subject’s Rights 
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
this study.  If you decide to participate, you may leave the study at any time.  No matter what 
decision you make, there will be no penalty to you, and you will not lose any of your regular 
benefits.  Leaving the study will not affect your medical care.  You can still get your medical care 
from our institution if you are eligible and choose to participate in another trial.  We will tell you 
about new information or changes in the study that may affect your health or your willingness to 
continue in the study.  In the case of injury resulting from this study, you do not lose any of your 
legal rights to seek payment by signing this form. 
 
What are the costs of taking part in this study?  
 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
 
The National Cancer Institute will supply the Belinostat at no charge while you take part in this 
study.  The NCI does not cover the cost for getting the Belinostat ready and giving it to you, so 
you or your insurance company may have to pay for this.  Even though it probably won’t happen, 
it is possible that the manufacturer may not continue to provide the Belinostat to the NCI for 
some reason.  If this would occur, other possible options are: 
 
• You may be able to get the Belinostat from the manufacturer or your pharmacy but you or 
your insurance company may have to pay for it. 


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  9  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
• If there is no Belinostat available at all, no one will be able to get more and the study 
would close. 
If there is a problem with getting Belinostat, your study doctor will talk to you about these 
options. 
 
Stopping Therapy 
 
Your doctor may decide to stop your therapy for the following reasons: 
 
• if he/she believes that it is in your best interest 
• if your disease gets worse during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
• if too many patients in the study experience severe side effects 
 
In this case, you will be informed of the reason therapy is being stopped.  You can stop taking 
part in the study at any time.  However, if you decide to stop taking part in the study, we would 
like you to talk to the study doctor and your regular doctor first.  If you decide at any time to 
withdraw your consent to participate in the trial, we will not collect any additional medical 
information about you.  However, according to FDA guidelines, information collected on you up 
to that point may still be provided to the Cancer Therapy Evaluation Program (CTEP) at the 
National Cancer Institute (NCI) or designated representatives.  If you withdraw your consent and 
leave the trial, any samples of yours that have been obtained for the study and stored at the 
NCI can be destroyed upon request.  However, any samples and data generated from the samples 
that have already been distributed to other researchers or placed in the research databases cannot 
be recalled and destroyed. 


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  10  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
Will my medical information be kept private? 
 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. 
 
Organizations that may look at and/or copy your medical records, including research records, for 
research, quality assurance, and data analysis include:  
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
• Qualified representatives from the maker of belinostat. 
•  Member institutions of the NCI Organ Dysfunction Working Group and their associated 
scientific review and Institutional Review Boards 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
Research Subject’s Rights 
 
Taking part in this research study is voluntary, and you can withdraw at any time.  We encourage 
you to ask questions so you can make the most informed decisions while you take part in this 
study.  Refusal to take part will not result in penalty or loss of benefits to which you are 
otherwise entitled. 
 
It is important to stress that being in this study does not promise long-term medical care here at 
the NIH Clinical Center.  If there is no further research study that is suitable for you and your 
state of disease, or if you are not now on another research study, you will be returned to the care 
of your referring doctor or institution or other source of care closer to your home.  If you have 
any questions about your treatment at NIH, you can contact the Principal Investigator, Dr. Alice 
Chen (301-496-4291) or the patient care representative (301-496-2626). 
 
Where can I get more information? 
 
You may call the National Cancer Institute’s Cancer Information Service at: 1-800-4-CANCER 
(1-800-422-6237).  You may also visit the NCI Web site at http://cancer.gov/ 
 
• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
• For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  11  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor.  
 
Conflict of Interest 
 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
Use of Specimens and Data for Future Research 
We would like to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be identified by a number and not your name.  
Your specimens and data will be used for research purposes only and will not benefit you.  
Researchers use specimens and data stored in scientific databases to advance science and learn 
about health and disease.  It is also possible that the stored specimens and data may never be 
used.  Results of research done on your specimens and data will not be available to you or your 
doctor.  It might help people who have cancer and other diseases in the future.   
If you decide now that your specimens and data can be kept for research and shared, you can 
change your mind at any time. Just contact us and let us know that you do not want us to use your 
specimens and/or data.  Then any specimens that have not already been used or shared will be 
destroyed and your data will not be used for future research.  
Please read the sentence below and think about your choice. After reading the sentence, circle 
and initial the answer that is right for you.  No matter what you decide to do, it will not affect 
your care. 
My specimens and data may be kept and shared for use in research to learn about, prevent, or 
treat cancer or other health problems.  
 
Yes              No               Initials_________ 


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  12  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or 
at scientific meetings, the people who take part are not named and identified.  In most cases, the 
NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term 
medical care for any injury resulting from your participation in research here.  In general, no 
long-term medical care or financial compensation for research-related injuries will be provided 
by the National Institutes of Health, the Clinical Center, or the Federal Government.  However, 
you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
 
4. Problems or Questions.  If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Dr. Alice Chen, 31 Center Drive, Building 31, Room 3A44, (301) 496-4291.  If you 
have any questions about the use of your specimens for future research studies, you may also 
contact the Office of the Clinical Director, Telephone:  240-760-6070. 
 
You may also call the Clinical Center Patient Representative at 301-496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 


  
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0060 
CONTINUATION:  page  13  of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this 
study and have been given the 
opportunity to discuss it and to ask 
questions.  I hereby consent to take part 
in this study. 
I have read the explanation about this study and 
have been given the opportunity to discuss it and to 
ask questions.  I hereby give permission for my 
child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
 
 
 
 
 
 
 
Signature of Adult Patient/             Date 
Legal Representative 
 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
 
 
 
 
 
 
 
Signature of Parent(s)/Guardian        Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JANUARY 9, 2017 THROUGH JANUARY 8, 2018. 
 
 
 
  
 
______________________      ______ 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness                      Date 
 
 
Print Name