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phase i pharmacokinetic study of

| Abbreviated Title:                                                                                                                                                                       | PhI Belinostat ODWG                                                                                                                      |
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| 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; C*obtains 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
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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
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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 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 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  
| UCD                                                                                                                                                                                                       | 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                                                                                 |
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| 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                       | 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 |
| 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 NYC | PK Coordinator: Mohammed Ghalib mhghalib@montefiore.org Shipping Address: 1695 Eastchester Rd Oncology 1st FL/AECOM Bronx, NY 10461 Phone: 718-405-8515                                                                                                                               |
| 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  | 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                                              |  
| WSU FWA#:00002460                                                                                                                                                                                | Regulatory Coordinator: Rachelle Zeleny Karmanos Cancer Institute 87E. Canfield MM05P1 Detroit, MI 48201 Phone: 313-576-9811; Fax: 313-576-9684 zelenyr@karmanos.org                                                           |
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| 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             | 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 |
| 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 EMY                               | 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                                                          |
| 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 | 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                                        |
| 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                       | 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                      |  
| Statistician:          | Larry Rubinstein, PhDE Biometric Research Branch, NCI  9609 Medical Center Drive Rockville, MD 20850 Phone: (240) 276 6026  rubinsteinl@ctep.nci.nih.gov   |
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| 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                                                                                                                                           |
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precis 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/m2belinostat. 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.  
SCHEMA  
  
PK  
 sampling B = Belinostat, administered IV over 30 minutes. On Day -7 (Cycle 1 only), **all patients** will receive a single dose of 400 mg/m2belinostat.  
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
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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
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dose escalation scheme

| -1                    | 1          | 2          | 3    | 4    |     |
|-----------------------|------------|------------|------|------|-----|
| Cohorts: Normal       | 750        | 1000       | No   | No   | No  |
| escalation            | escalation | escalation |      |      |     |
| Mild  Dysfunction     | 500        | 750        | 1000 | No   | No  |
| escalation            | 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.  
| TABLE OF CONTENTS                                  |                                                                                                     |                      |
|----------------------------------------------------|-----------------------------------------------------------------------------------------------------|----------------------|
| PRÉCIS .                                           |                                                                                                     |                      |
| SCHEMA                                             |                                                                                                     |                      |
| OBJECTIVES                                         |                                                                                                     |                      |
| l                                                  | 1.1                                                                                                 | Primary Objectives . |
| 1.2                                                | Secondary Objectives .                                                                              |                      |
| 2                                                  | BACKGROUND .                                                                                        |                      |
| 2.1                                                | Belinostat                                                                                          |                      |
| 2.2                                                | RATIONALE                                                                                           |                      |
| 3                                                  | PATIENT SELECTION                                                                                   |                      |
| 3.1                                                | Eligibility Criteria                                                                                |                      |
| 3.2                                                | Exclusion Criteria                                                                                  |                      |
| 3.3                                                | Inclusion of Women and Minorities                                                                   |                      |
| 3.4                                                | Research Eligibility Evaluation                                                                     |                      |
| 4                                                  | REGISTRATION PROCEDURES                                                                             |                      |
| 4.1                                                | Registration Process .                                                                              |                      |
| s                                                  | TREATMENT PLAN                                                                                      |                      |
| 5.1                                                | Belinostat Administration                                                                           |                      |
| 5.2                                                | Definition of Dose-Limiting Toxicity .                                                              |                      |
| 5.3                                                | DESIGN                                                                                              |                      |
| Supportive Care Guidelines .                       |                                                                                                     |                      |
| 5.4                                                |                                                                                                     |                      |
| 5.5                                                | General Concomitant Medication .                                                                    |                      |
| 5.6                                                | D DURATION OF THERAPY                                                                               |                      |
| 5.7                                                | D DURATION OF FOLLOW UP                                                                             |                      |
| 5.8                                                | Criteria for Removal From Study.                                                                    |                      |
| 6                                                  | DOSING DELAYS/DOSE MODIFICATIONS                                                                    |                      |
| 6.1                                                | Intrapatient Dosing, Non-Hepatic Toxicities                                                         |                      |
| 6.2                                                | Intrapatient Dosing, Hepatic Toxicities                                                             |                      |
| ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS . |                                                                                                     |                      |
| 7                                                  | Comprehensive Adverse Events and Potential Risks List (CAEPR) .................................. 33 |                      |
| 7.1                                                |                                                                                                     |                      |
| 7.2                                                | Adverse Event Characteristics                                                                       |                      |
| 7.3                                                | Expedited Adverse Event Reporting                                                                   |                      |
| 7.4                                                | Routine Adverse Event Reporting.                                                                    |                      |
| 7.5                                                | Secondary AML/MDS                                                                                   |                      |
| 8                                                  | PHARMACEUTICAL INFORMATION                                                                          |                      |
| 9                                                  | CORRELATIVE/SPECIAL STUDIES                                                                         |                      |
| 8                                                  |                                                                                                     |                      |  
| Clinical Center #11-C-0060 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   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| 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   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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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.  
1.2.1 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.  
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 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 11 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
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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, 2and 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.  
12 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.
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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 13 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
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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 singleagent 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 Table 1: Doses and Schedules Used for Clinical Administration of Belinostat by IV Infusion  
| Belinostat                                                   | 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-                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
|--------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| monotherapy                                                  | 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.  
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/m2IV 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/m2IV) 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.  
  
A: Western blot showing histone H4 acetylation in PBMC extract for 2 patients treated with belinostat (150
Fig. 2 Changes in PBMC Protein Histone H4 Acetylation Before and After Belinostat Administration in Patients With Solid Tumors 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/m 2 (bottom) doses.  
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.
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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.
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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.
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3 patient selection 3.1 eligibility

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 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 subtherapeutic 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  
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.
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3.2 exclusion criteria

3.2.1 Prior therapy with belinostat. 3.2.2 Patients may not be receiving any other investigational agents.  
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

Both men and women and members of all races and ethnic groups are eligible for this trial.
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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.  
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.
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4 registration procedures 4.1 registration

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.
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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).
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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

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.
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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

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.
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5.1.1 stratification by hepatic dysfunction

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
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5.1.2 schedule

On Day -7 (Cycle 1 only), patients in all cohorts will receive belinostat 400 mg/m2and 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 cohortassigned dose (Cycle 1 Day 5) and again pre-Cycle 2 to evaluate for any elevation in QTc after cumulative exposure.
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5.1.3 dose escalation scheme

| -1                    | 1          | 2          | 3    | 4    |     |
|-----------------------|------------|------------|------|------|-----|
| Cohorts: Normal       | 750        | 1000       | No   | No   | No  |
| escalation            | escalation | escalation |      |      |     |
| Mild  Dysfunction     | 500        | 750        | 1000 | No   | No  |
| escalation            | 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.).
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5.1.4 definition of evaluable and

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.
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5.1.5 maintaining consistent dosing across

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 dysfunctiontoxicity 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 |                                                                                                                                                                                                      |
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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.  
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.
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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.
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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   | Escalation Decision Rule                                 |
|------------------------------------|----------------------------------------------------------|
| Given Dose Level 0 out of 3        | Enter 3 patients at the next dose level.                 |
| ≥ 2                                | Dose escalation will be stopped. This dose level will be |  
| declared the maximally administered dose (highest dose  administered). Three (3) additional patients will be  entered at the next lowest dose level if only 3 patients  were treated previously at that dose.   |                                                                                                                                                                                                                                                                                                                                                                                                              |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1 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.                                                                                                                                                                                                                                                                                       |
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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).
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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).
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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.  
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.
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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).
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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.
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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.
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5.8 criteria for removal from

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,
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.
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6 dosing delays/dose modifications 6.1

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 lifethreatening 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
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 reexposed, and the patient will come off study.
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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.
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7 adverse events list and

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.
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7.1 comprehensive adverse events and

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                                      |                                                              |                        |  
| 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:
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blood and lymphatic system disorders

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  
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.
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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.
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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 reestablishment 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 Days1of the Last Dose of the Investigational Agent on Phase 1 Trials  
| Grades                                                                                                                                                                                                                                                                                                              |             |            |          |          |          |      |          |      |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|------------|----------|----------|----------|------|----------|------|
| Grade 1                                                                                                                                                                                                                                                                                                             | Grade 2     | Grade 2    | Grade 3  | Grade 3  | 4 & 52   |      |          |      |
| Unexpected                                                                                                                                                                                                                                                                                                          | Expected    | Unexpected |          |          |          |      |          |      |
| with                                                                                                                                                                                                                                                                                                                | without     | with       | without  | and      |          |      |          |      |
| Hospitalization                                                                                                                                                                                                                                                                                                                     | Hospitalization             | Hospitalization            | Hospitalization          | Expected |          |      |          |      |
| Unexpected                                                                                                                                                                                                                                                                                                          |             |            |          |          |          |      |          |      |
| Unexpected                                                                                                                                                                                                                                                                                                          | Expected    |            |          |          |          |      |          |      |
| and Expected                                                                                                                                                                                                                                                                                                        | 10          | 10         | 24-Hour; |          |          |      |          |      |
| Unrelated                                                                                                                                                                                                                                                                                                           | Not         | Not        | Not      | Not      | Not      |      |          |      |
| Calendar                                                                                                                                                                                                                                                                                                            | Calendar    | 5 Calendar |          |          |          |      |          |      |
| Unlikely                                                                                                                                                                                                                                                                                                            | Required    | Required   | Required | Days     | Required | Days | Required | Days |
| Possible                                                                                                                                                                                                                                                                                                            | 24-Hour;    |            |          |          |          |      |          |      |
| Not                                                                                                                                                                                                                                                                                                                 | 10 Calendar | Not        |          |          |          |      |          |      |
| Probable                                                                                                                                                                                                                                                                                                            | 5 Calendar  |            |          |          |          |      |          |      |
| Required                                                                                                                                                                                                                                                                                                            | Days        | Required   |          |          |          |      |          |      |
| Definite                                                                                                                                                                                                                                                                                                            | Days        | 10         | 24-Hour; |          |          |      |          |      |
| Not                                                                                                                                                                                                                                                                                                                 |             |            |          |          |          |      |          |      |
| Calendar                                                                                                                                                                                                                                                                                                            | 5 Calendar  |            |          |          |          |      |          |      |
| Required                                                                                                                                                                                                                                                                                                            |             |            |          |          |          |      |          |      |
| Days                                                                                                                                                                                                                                                                                                                | 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: 24-Hour; 5 Calendar Days |             |            |          |          |          |      |          |      |  
10 Calendar Days Not Required 24-Hour; 5 Calendar Days  
  
Note: All deaths on study must be reported using expedited reporting regardless of causality. Attribution to treatment or other cause should be provided.  
Expedited AE reporting timelines defined:
"24 hours; 5 calendar days" - The investigator must initially report the AE
via CTEP-AERS within 24 hours of learning of the event followed by a complete CTEP-AERS report within 5 calendar days of the initial 24-hour report.  
"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 37 the "Description of Event" section of the CTEP-AERS report.
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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.
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7.3.4.2 fetal death 7.3.4.3 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.  
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.
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7.3.5 nci-irb expedited reporting of

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.
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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.
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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.
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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.
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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.
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disability

A substantial disruption of a person's ability to conduct normal life functions.
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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.
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protocol deviation (nih definition)

Any change, divergence, or departure from the IRB approved study procedures in a research protocol
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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.
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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 g*reater risk of harm*
(including physical, psychological, economic, or social harm) than was previously known or recognized.
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7.3.5.2 nci-irb and clinical director

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.  
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.
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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.
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adverse event reporting to nci

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.
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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 CTEPAERS must also **be reported in routine study data submissions.**
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7.4.1 nci-irb requirements for pi

Please use the following table for reporting adverse events at time of CR:  
| System Organ   | CTCAE   | Grade         | # of Events   | Total # of   | Attribution   | Serious?   | Unexpected?   |
|----------------|---------|---------------|---------------|--------------|---------------|------------|---------------|
| Class          | Term    | since last CR | Events        | to Research  |               |            |               |  
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.  
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.
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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.
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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 nonhistone 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.                                                                                                         |              |  
| 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.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| 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://eappsctep.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 45 |  
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.
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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).
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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.
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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.
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9.1.2 pharmacokinetic sampling schedule

On day -7 of cycle 1, belinostat will be administered at a dose of 400 mg/m2to 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  
*It may not always be feasible to obtain the 8 h sample for logistical reasons.
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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.  
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 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.
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9.2 analysis of pharmacokinetic data

Concentrations of belinostat and metabolites will be quantitated with a liquid chromatographyelectrospray 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.
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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.  
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.
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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.  
| PreStudy                                                                                                            | C1                                                                | C1                                                                      | C1   | C1   | C1   | C2 on   | C2 on   | C2 on  Off   |
|------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|-------------------------------------------------------------------------|------|------|------|---------|---------|--------------|
| D-7                                                                                                        | D-6                                                               | Wk 1                                                                    | Wk 2 | Wk 3 | Wk 1 | Wk 2    | Wk 3    | Treatment    |
| Belinostata                                                                                                | X                                                                 | X                                                                       | X    |      |      |         |         |              |
| Informed consent                                                                                           | X                                                                 |                                                                         |      |      |      |         |         |              |
| Demographics                                                                                               | X                                                                 |                                                                         |      |      |      |         |         |              |
| Medical history                                                                                            | X                                                                 |                                                                         |      |      |      |         |         |              |
| Child-Pugh  classification (CPC)                                                                           | X                                                                 |                                                                         |      |      |      |         |         |              |
| Concurrent medsm                                                                                           | X m                                                               | X m ----------------------------------------------------------------X m |      |      |      |         |         |              |
| 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    |      |         |         |              |
| d                                                                                                          | X d                                                               | X d                                                                     | X d  | X    | X    |         |         |              |
| CBC w/diff, plts                                                                                           | X                                                                 | X                                                                       |      |      |      |         |         |              |
| Serum chemistryb                                                                                           | X                                                                 | X d                                                                     | X d  | X d  | X d  | X       | X       |              |
| EKGe                                                                                                       | X                                                                 | X                                                                       | X    |      |      |         |         |              |
| AE evaluation                                                                                              | X---------------------------------------------------------------X | X                                                                       |      |      |      |         |         |              |
| Tumor measurements                                                                                         | Tumor measurements are repeated every 2 cycles (about every       |                                                                         |      |      |      |         |         |              |
| X                                                                                                          | 6 weeks). Documentation (radiologic) must be provided for         | X                                                                       |      |      |      |         |         |              |
| patients removed from study for progressive disease.                                                       |                                                                   |                                                                         |      |      |      |         |         |              |
| Serum Magnesiumf                                                                                           | X f                                                               | X f                                                                     |      |      |      |         |         |              |
| B-HCG                                                                                                      | X c                                                               |                                                                         |      |      |      |         |         |              |
| 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. |                                                                   |                                                                         |      |      |      |         |         |              |  
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/m2administered 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.  
* = 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).
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11 measurement of effect 11.1

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
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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  
will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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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 nonmeasurable) 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 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.
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11.1.3 methods for evaluation of

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 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 breathhold 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 55 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 diseasespecific 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.
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11.1.4 response criteria 11.1.4.1 evaluation

| Complete Response (CR):   | Disappearance of all target lesions. Any  pathological lymph nodes (whether target or nontarget) 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.                                                                                                                         |  
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).
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11.1.4.3 evaluation of best overall

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.  
| Target                                                                                                                                                                                                            | Non-Target                                                                         | New       | Overall   | Best Overall Response                             |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|-----------|-----------|---------------------------------------------------|
| Lesions                                                                                                                                                                                                           | Lesions                                                                            | Lesions   | Response  | when Confirmation is  Required*                   |
| CR                                                                                                                                                                                                                | CR                                                                                 | No        | CR        | ≥4 wks. Confirmation**                            |
| CR                                                                                                                                                                                                                | Non-CR/NonPD                                                                                    | No        | PR        | ≥4 wks. Confirmation**                            |
| CR                                                                                                                                                                                                                | Not evaluated                                                                      | No        | PR        |                                                   |
| PR                                                                                                                                                                                                                | Non-CR/NonPD/not  evaluated                                                                                    | No        | PR        |                                                   |
| SD                                                                                                                                                                                                                | Non-CR/NonPD/not  evaluated                                                                                    | No        | SD        | documented at least once ≥4  wks. from baseline** |
| PD                                                                                                                                                                                                                | Any                                                                                | Yes or No | PD        |                                                   |
| Any                                                                                                                                                                                                               | PD***                                                                              | Yes or No | PD        | no prior SD, PR or CR                             |
| 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 |                                                                                    |           |           |                                                   |  
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.  
| 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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for patients with non-measurable disease

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
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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.
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11.2 antitumor effect - lymphomas

Response and progression will be evaluated in this study using the International Working Group recommendations.  
32
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11.2.1 ct criteria of nodal

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.
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11.2.2 complete remission (cr)

1. Complete disappearance of all detectable clinical evidence of disease and diseaserelated 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.)
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.
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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.
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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  
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.
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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.
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11.2.6 relapsed disease (after cr)/progressive

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.  
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.
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12 data reporting / regulatory

Adverse event lists, guidelines, and instructions for adverse event reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements).
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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 CoInvestigators, 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.
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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.
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12.2 data monitoring and safety

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.
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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.
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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.  
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.
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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.
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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.
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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.
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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.
Except in very unusual circumstances, each participating institution will order DCTDsupplied 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).
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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.  
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.