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13 statistical considerations

This is a Phase I trial using a design including 4 cohorts of patients with varying degrees of hepatic dysfunction, including one group with normal hepatic function (see Section 5.1.1). The study incorporates a 3+3 design. The dose recommended for cohorts with greater liver dysfunction cannot be greater than the dose for cohorts of lesser dysfunction (see Section 5.1.5). Furthermore, the highest dose to be explored is no greater than the recommended dose for patients with normal liver function. These restrictions will compensate in part for patient  
heterogeneity and yield more accurate final recommended doses in liver dysfunction groups. Further rules for dose escalation and MTD determination are given in Sections 5.1 and 5.2. Patients in cohort 1 are included in this study to obtain PK data in the same manner as for the patients with liver dysfunction. This group will also be followed for toxicity. Occasionally a patient consented for a group with liver dysfunction will present with normal liver function tests on the day of treatment initiation. These patients may be entered into cohort 1 on a case-by-case basis. Toxicity will be graded according to the NCI CTCAE v4.0 and relationship to the study drug; results will be tabulated by liver dysfunction group. All patients who receive any amount of belinostat will be evaluable for toxicity, but patients who receive other than the prescribed dose and do not experience a DLT will be considered inevaluable for DLT. Patients who are not evaluable for DLT will be replaced. The PK variables described in Section 9.1 will be tabulated and descriptive statistics calculated for each function group. Geometric means and coefficients of variation will be presented for Cmax and AUCINF for each group.  
In addition, indirect bilirubin levels will be evaluated to see if there is a correlation between those results and toxicity or activity of belinostat.
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13.1 sample size/accrual rate

A minimum of 2 and a maximum of 6 patients will be accrued in each liver dysfunction cohort (2-4) at each dose level, and 12 patients will be entered at the recommended dose level in cohort 1. MTD will not be established for the normal cohort as that is already known. Patients in this cohort are being enrolled to obtain PK data in the same manner as for the patients with liver dysfunction. Three additional patients will be accrued to the MTD levels (following establishment of MTD for that cohort in the first 6 patients at that dose level) for each liver dysfunction cohort to allow additional information to be gained at these levels. Therefore, the minimum number of patients will be 24 patients. The maximum would include the 12 patients in cohort 1, 6 patients for all other non-MTD levels (up to 6 such), and 9 patients for the MTD levels (3 such), bringing the total to 75 patients. We do not expect all dose levels to have 6 patients and recognize that some patients may need to be replaced if they are not evaluable based on protocol guidelines. As long as < 33% of the patients treated at a given dose level experience a DLT, that dose level will be considered the MTD.  
The estimated monthly accrual is 4 patients/month, and the accrual ceiling for this trial is 80 patients.
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13.2 stratification factors

Patients will be stratified according to the level of hepatic dysfunction as described in Section 5.1.1. Dose escalation and MTD determination will be performed separately for each stratum.
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14 human subjects protections 14.1

This study will be open to all individuals regardless of gender, ethnicity, or race, provided that the aforementioned inclusion and exclusion criteria are met. Patients for this study will be recruited through internal referral, our physician referral base, and through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer). To date, there is no information that suggests that differences in drug metabolism or effect on tumor would be expected in one ethnic group compared to another. Efforts will be made to extend accrual to each representative population, but a balance must be struck between participant safety considerations and limitations on the number of individuals exposed to potentially ineffective treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to ethnic identity are noted, a follow-up study may be written to investigate those differences more fully. Due to lack of knowledge of the effects of belinostat on the fetus or infants, as well as the possibility of teratogenic effects, pregnant and nursing women will be excluded from this trial. Patients with unstable or serious medical conditions are excluded due to the possibility that belinostat may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events with respect to belinostat. HIV-positive patients on combination antiretroviral therapy are excluded from the study because of possible PK interactions with belinostat.
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14.2 participation of children

Children aged <18 years are excluded because of the lack of safety data of the compound in this population. Appropriate studies in the pediatric age group may be undertaken in the future.
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14.3 evaluation of benefits and

Patients will receive evaluation and treatment of their malignancy as a result of participating in this trial. All the medications, tests, hospitalizations, and physician services during this trial within the NIH will be free of charge to the participant. Imaging studies may help determine the extent of disease and or identify lesion not detected by conventional modalities. The trial will help investigators learn the effects of the study medication, but may or may not be helpful for a specific patient. The study treatment may offer temporary control of the disease, but is not 68 curative by this protocol. Benefit cannot be promised nor can the chance of benefit be accurately predicted. The risks and discomforts of the tumor biopsies will be slight pain, as well as the small possibility of bleeding or infection. Alternative approaches other than entering this trial, including supportive care only, if it is available, will also be discussed before the verbal and written consent regarding the risk and benefits and the treatment requirements of this trial.
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14.3.1 alternative approaches or treatments

There are no effective alternative therapies. Other investigational agents could be employed, or the patient may elect to be treated for symptomatic control alone or with agents of marginal or unknown clinical benefit.
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14.3.2 procedure for protecting against

All care will be taken to minimize side effects, but they can be unpredictable in nature and severity. This study may involve risks to patients, which are currently unforeseeable. All patients will be monitored for side effects from taking study medication and from undergoing research-related procedures. If patients suffer any physical injury as a result of the participation in this study, immediate medical treatment is available at the Clinical Center, National Cancer Institute, Bethesda, Maryland. Although no compensation is available, any injury will be evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations.
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14.4 risks/benefits analysis

There may or may not be any clinical benefit to a patient from participation in this trial. Their participation will benefit future cancer patients. Potential risks include the possible occurrence of any of a range of side effects that are listed in the consent document. Clinical and laboratory data gathered in this trial will be analyzed frequently. Any new or significant finding(s) found during the course of the research that may affect a patient's willingness to participate further will be shared and explained to each participant.
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14.5 consent process and documentation

An associate or principal investigator on the trial will inform patients of the purpose, alternatives, drug administration plan, research objectives and follow-up of this trial. The patient will be provided an IRB-approved consent for review and signature and his/her questions will be answered. After a decision is made to enroll into the study, a signature will be obtained from the patient. The original signed consent goes to Medical Records; a copy is placed in the research record. All patients must have a signed informed consent form and an on-study (confirmation of eligibility) form filled out and signed by a participating investigator before entering on study.  
For NCI only: adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation, all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team for evaluation. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who are (a)
decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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15 references

1. Finn P, Watkins C, Romero R, et al. Discovery and structure-activity relationships of novel classes of histone deacetylase inhibitors. Proc Am Assoc Cancer Res 2002;43:A3672. 2. Plumb JA, Finn PW, Williams RJ, et al. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 2003;2:721-8. 3. Gimsing P. Belinostat: a new broad acting antineoplastic histone deacetylase inhibitor. Expert Opinion on Investigational Drugs 2009;18:501-8. 4. Kalvinsh I, Loza E, Starchenkov I. Discovery and structure-activity relationships of a novel class of histone deacetylase inhibitors. Proc Am Assoc Cancer Res 2002:A3672. 5. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: Inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 2000;92:1210-6. 6. Finnin MS, Donigian JR, Cohen A, et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 1999;401:188-93. 7. IB. Belinostat Investigator's Brochure version 6.0 2009; 2009. 8. Kelly WK, Richon V, Troso-Sandoval T. Suberoylanilide hydroxamic acid (SAHA), a Histone Deacetylase inhibitor: Biologic activity without toxicity. Proc Am Soc Clin Oncol 2001;20:A344. 9. Richon VM, Emiliani S, Verdin E, et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci U S A 1998;95:3003-7. 10. Yoshida M, Kijima M, Akita M, Beppu T. Potent and specific inhibition of mammalian histone deacetylase both *in vivo* and *in vitro* by trichostatin A. J Biol Chem 1990;265:17174-9. 11. Johnstone RW. Histone-deacetylase inhibitors: Novel drugs for the treatment of cancer. Nat Rev Drug Discov 2002;1:287-99. 12. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002;3:415-28. 13. Glaser KB, Staver MJ, Waring JF, Stender J, Ulrich RG, Davidsen SK. Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2003;2:151-63. 14. Di Gennaro E, Bruzzese F, Romano G, et al. Antitumor effect of histone deacetylase inhibitor SAHA alone and combined with cytotoxic drugs in human colorectal cancer cells. Proc Am Assoc Cancer Res 2003;44:A3636. 15. Yu X, Guo ZS, Marcu MG, et al. Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst 2002;94:504-13. 16. Rahmani M, Yu C, Dai Y, et al. Coadministration of the heat shock protein 90 antagonist 17-allylamino- 17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells. Cancer Res 2003;63:8420-7. 17. Ma B, Sung F, Tao Q, et al. The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines. Investigational New Drugs;28:10714.  
18. Gimsing P, Hansen M, Knudsen L, M., et al. A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia. European Journal of Haematology 2008;81:170-6. 19. Steele NL, Plumb JA, Vidal L, et al. A Phase 1 Pharmacokinetic and Pharmacodynamic Study of the Histone Deacetylase Inhibitor Belinostat in Patients with Advanced Solid Tumors. Clinical Cancer Research 2008;14:804-10. 20. Mackay HJ, Hirte H, Colgan T, et al. Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours. European Journal of Cancer;46:1573-9. 21. Wang LZ, Goh BC, Lwin TW, Lee H, Chan SL. Phase I pharmacokinetics and metabolic pathway of belinostat in patients with hepatocellular carcinoma. J Clin Oncol 2010;28:. 22. Perera M, Innocenti F, Ratain M. Pharmacogenetic Testing for Uridine Diphosphate Glucuronosyltransferase 1A1 Polymorphisms: Are We There Yet? Pharmacotherapy 2008;28. 23. Hasegawa Y, Sarashina T, Ando M, et al. Rapid Detection of UGT1A1 Gene Polymorphisms by Newly Developed Invader Assay. Clin Chem 2004;50:1479-80. 24. Bosma PJ, Chowdhury JR, Bakker C, et al. The Genetic Basis of the Reduced Expression of Bilirubin UDP-Glucuronosyltransferase 1 in Gilbert's Syndrome. N Engl J Med 1995;333:1171-5. 25. Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2008;47:97-104. 26. FDA News Release: FDA Approves DNA Test to Measure Hepatitis B Virus Levels. September 4, 2008. (Accessed October 25, 2011, at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116940.htm.) 27. McGovern BH, Birch CE, Bowen MJ, et al. Improving the diagnosis of acute hepatitis C virus infection with expanded viral load criteria. Clin Infect Dis 2009;49:1051-60. 28. Alter M, Kuhnert W, Finelli L. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. Morbidity and Mortality Weekly Report 2003;52:1-16. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5203a1.htm.  
29. Sexually Transmitted Diseases Treatment Guidelines, 2010: Hepatitis C. Centers for Disease Control and Prevention, Last updated January 28, 2011. (Accessed October 25, 2011, at http://www.cdc.gov/std/treatment/2010/hepC.htm.) 30. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 2009;45:228-47. 31. Assouline S, Meyer RM, Infante-Rivard C, et al. Development of adapted RECIST criteria to assess response in lymphoma and their comparison to the International Workshop Criteria. Leukemia & Lymphoma 2007;48:513-20. 32. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-86. 33. Navari RM, Koeller JM. Electrocardiographic and cardiovascular effects of the 5hydroxytryptamine3 receptor antagonists. Ann Pharmacother 2003;37:1276-86.
appendix a gi50 mean graph
15 references

| Cell Panel             | Cell Line   | Log Gl   |
|------------------------|-------------|----------|
| Leukemia               | CRF-CEM     | -7.7     |
| HL-60(TB)              | -7:4        |          |
| K-562                  | -7.2        |          |
| MOLT-4                 | -7.6        |          |
| RPMI-8226              | -8.0        |          |
| SR                     | -7.8        |          |
| Non-Small Cell Lung    | A549/ATCC   | -7.1     |
| EKVX                   | -6.4        |          |
| HOP-62                 | -6.5        |          |
| HP-92                  | -7.1        |          |
| NCI-H226               | -6.2        |          |
| NCI-H23                | -7.0        |          |
| NCI H322M              | -7.1        |          |
| NCI-H460               | -6.9        |          |
| NCI-H522               | -7.2        |          |
| Colon                  | COLO 205    | -6.8     |
| HCC-2998
HCT-116                        | -6.6        |          |
| -7.4                   |             |          |
| HCT-15                 | -5.9        |          |
| HT29                   | -5.9        |          |
| KM12                   | -7.1        |          |
| SW-620                 | -7.5        |          |
| Central Nervous System | SF-268      | -6.5     |
| SF-295                 | -6.2        |          |
| SF-539                 | -6.9        |          |
| SNB-19                 | -6.1        |          |
| SNB-75                 | -5.2        |          |
| U251                   | -6.3        |          |
| Melanoma               | LOX IMVI    | -6.5     |
| MALME-3M               | -7.4        |          |
| M14                    | -6.4        |          |
| MDA-MB-435             | -6.7        |          |
| SK-MEL-2               | -5.2        |          |
| SK-MEL-28              | -5.8        |          |
| SK-MEL-5               | -7.5        |          |
| UACC-257               | -6.6        |          |
| UACC-62                | -7.4        |          |
| Ovarian                | IGROV1      | -6.9     |
| OVCAR-3                | -6.3        |          |
| OVCAR-4                | -6.0        |          |
| OVCAR-5                | -6.8        |          |
| OVCAR-8                | -7.5        |          |
| NCLADR-RES             | -7.5        |          |
| SK-OV-3                | -6.3        |          |
| Renal                  | 786-0       | -6.0     |
| A498                   | -6.5        |          |
| ACHN                   | -6.4        |          |
| CAKI-1                 | -6.3        |          |
| RXF 393                | -7.0        |          |
| SN12C                  | -6.6        |          |
| TK-10                  | -7.6        |          |
| UO-31                  | -6.9        |          |
| Prostate               | PC-3        | -6.8     |
| DU-145                 | -7.3        |          |
| Breast                 | MCF7        | -6.8     |
| MDA-MB-231/ATCC        | -6.7        |          |
| HS 578T                | -6.3        |          |
| BT-549                 | -5.7        |          |
| T-47D                  | -6.8        |          |  
  
Data from October 2009; average GI 50 over all cell lines is 1.78E-7.  
| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                   |                                                                    |             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|--------------------------------------------------------------------|-------------|
| Grade                                                                                                                                                                                      | Descriptions                                                  | Percent                                                            | Description |
| 100                                                                                                                                                                                        | Normal, no complaints, no  evidence of disease.               |                                                                    |             |
| Normal activity. Fully active, able                                                                                                                                                        |                                                               |                                                                    |             |
| 0                                                                                                                                                                                          | to carry on all pre-disease  performance without restriction. | Able to carry on normal activity;                                  |             |
| 90                                                                                                                                                                                         | minor signs or symptoms of  disease.                          |                                                                    |             |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). | 80                                                            | Normal activity with effort; some  signs or symptoms of disease.   |             |
| 1                                                                                                                                                                                          | Cares for self, unable to carry on                            |                                                                    |             |
| 70                                                                                                                                                                                         | normal activity or to do active  work.                        |                                                                    |             |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                             | Requires occasional assistance,                               |                                                                    |             |
| 60                                                                                                                                                                                         | but is able to care for most of  his/her needs.               |                                                                    |             |
| 2                                                                                                                                                                                          | 50                                                            | Requires considerable assistance  and frequent medical care.       |             |
| 40                                                                                                                                                                                         | Disabled, requires special care  and assistance.              |                                                                    |             |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                     |                                                               |                                                                    |             |
| 3                                                                                                                                                                                          | 30                                                            | Severely disabled, hospitalization  indicated. Death not imminent. |             |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   | 20                                                            | Very sick, hospitalization  indicated. Death not imminent.         |             |
| 4                                                                                                                                                                                          | 10                                                            | Moribund, fatal processes  progressing rapidly.                    |             |
| 5                                                                                                                                                                                          | Dead.                                                         | 0                                                                  | Dead.       |
appendix a gi50 mean graph
appendix b performance status criteria

It has been recognized for a number of years that certain prescription medications can prolong the QT/QTc interval and cause a form of acquired long QT syndrome, known as drug-induced LQTS. The drugs that prolong the QT interval and/or have a risk of inducing Torsades de Pointes (TdP) are listed below. We have divided these into two groups based on their known or perceived risk of causing TdP:  
| Drug (generic names)     | Drug class (clinical usage)                | Comments                          |
|--------------------------|--------------------------------------------|-----------------------------------|
| Albuterol (by parenteral | Bronchodilator (asthma)                    | Inhaled albuterol at normal doses |
| administration)          | acceptable                                 |                                   |
| Amiodarone               | Anti-arrhythmic (heart rhythm)             | F >M, TdP cases in literature     |
| Arsenic trioxide         | Anti-cancer (leukemia)                     | TdP cases in literature           |
| Bepridil                 | Anti-anginal (heart pain)                  | F >M                              |
| Chlorpromazine           | Anti-psychotic/anti-emetic                 | TdP cases in literature           |
| (schizophrenia/nausea)   |                                            |                                   |
| Chloroquine              | Anti-malaria (malaria infection)           |                                   |
| Disopyramide             | Anti-arrhythmic (heart rhythm)             | F >M                              |
| Dofetilide               | Anti-arrhythmic (heart rhythm)             |                                   |
| Droperidol               | Sedative/hypnotic (anaesthesia             | TdP cases in literature           |
| adjunct)                 |                                            |                                   |
| Erythromycin             | Antibiotic/GI stimulant                    | F >M                              |
| (infection/GI motility)  |                                            |                                   |
| Halofantrine             | Anti-malarial (malaria infection)          | F >M                              |
| Haloperidol              | Anti-psychotic (schizophrenia,  agitation) |                                   |
| Ibutilide                | Anti-arrhythmic (heart rhythm)             | F >M                              |
| Mesoridazine             | Anti-psychotic (schizophrenia)             |                                   |
| Methadone                | Opiate agonist (pain control/              | F >M                              |
| narcotic dependence)     |                                            |                                   |
| Pentamidine              | Anti-infective (pneumocystic               | F >M                              |
| pneumonia)               |                                            |                                   |
| Pimozide                 | Anti-psychotic (Tourette's tics)           | F >M, TdP cases in literature     |
| Procainamide             | Anti-arrhythmic (heart rhythm)             |                                   |
| Quinidine                | Anti-arrhythmic (abnormal heart            | F >M                              |
| rhythm)                  |                                            |                                   |
| Sotalol                  | Anti-arrhythmic (heart rhythm)             | F >M                              |
| Sparfloxacin             | Antibiotic (bacterial infection)           |                                   |
| Thioridazine             | Anti-psychotic (schizophrenia)75           |                                   |  
Table 1. Group 1 Drugs That are Generally Accepted by Authorities to Have a Risk of Causing TdP*  
*Concomitant use of these drugs is not allowed during the study or within 2 weeks of study entry.  
These drugs should also be avoided for up to 4 weeks following discontinuation of study treatment.  
| Drug (brand names)   | Drug class (clinical usage)              | Comments                               |
|----------------------|------------------------------------------|----------------------------------------|
| Amantadine           | Dopaminergic/anti-viral/antiinfective (Parkinson's disease)                                          |                                        |
| Amitriptyline        | Tricyclic anti-depressant  (depression)  |                                        |
| Amoxapine            | Tricyclic anti-depressant  (depression)  |                                        |
| Azithromycin         | Antibiotic (bacterial infection)         |                                        |
| Citalopram           | Anti-depressant (depression)             |                                        |
| Clarithromycin       | Antibiotic (bacterial infection)         | TdP cases in literature                |
| Clomipramine         | Tricyclic antidepressant  (depression)   |                                        |
| Chloral hydrate      | Sedative (sedation/insomnia)             |                                        |
| Clozapine            | Anti-psychotic (schizophrenia)           |                                        |
| Desipramine          | Tricyclic anti-depressant                | TdP cases in literature                |
| (depression)         |                                          |                                        |
| Dolasetron           | Anti-nausea (nausea and vomiting)        |                                        |
| Doxepin              | Anti-depressant (depression)             | TdP cases in literature                |
| Felbamate            | Anti-convulsant (seizures)               |                                        |
| Flecainide           | Anti-arrhythmic (heart rhythm)           | Association not clear                  |
| Fluconazole          | Anti-fungal (fungal infection)           |                                        |
| Fluoxetine           | Anti-depressant (depression)             | Association not clear                  |
| Foscarnet            | Antiviral (HIV infection)                |                                        |
| Fosphenytoin         | Anticonvulsant (seizures)                |                                        |
| Gatifloxacin         | Antibiotic (bacterial infection)         |                                        |
| Gemifloxacin         | Antibiotic (bacterial infection)         |                                        |
| Granisetron†         | Anti-nausea (nausea and vomiting)        |                                        |
| Imipramine           | Anti-depressant (depression, pain,       | TdP cases in literature                |
| other)               |                                          |                                        |
| Indapamide           | Diuretic (stimulates urine & salt        | TdP cases in literature, QT in animals |
| loss)                |                                          |                                        |
| Isradipine           | Anti-hypertensive (high blood  pressure) |                                        |
| Levofloxacin         | Antibiotic (bacterial infection)         | Association not clear                  |
| Lithium              | Anti-mania (bipolar disorder)            |                                        |  
Table 2. Group 2 Drugs That in Some Reports may be Associated With TdP but at This Time Lack Substantial Evidence of Causing It*  
| Drug (brand names)                                                                                                                                                                             | Drug class (clinical usage)                                       | Comments                |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|-------------------------|
| Mexiletine                                                                                                                                                                                     | Anti-arrhythmic (abnormal heart  rhythm)                          |                         |
| Moexipril/HCTZ                                                                                                                                                                                 | Anti-hypertensive (high blood  pressure)                          |                         |
| Moxifloxacin                                                                                                                                                                                   | Antibiotic (bacterial infection)                                  |                         |
| Nicardipine                                                                                                                                                                                    | Anti-hypertensive (high blood  pressure)                          |                         |
| Nortriptyline                                                                                                                                                                                  | Tricyclic antidepressant  (depression)                            |                         |
| Octreotide                                                                                                                                                                                     | Endocrine (acromegaly/ carcinoid  diarrhoea)                      |                         |
| Ofloxacin Ondansetron†                                                                                                                                                                         | Anti-emetic (nausea and vomiting)                                 |                         |
| Paroxetine                                                                                                                                                                                     | Anti-depressant (depression)                                      |                         |
| Protriptyline                                                                                                                                                                                  | Tricyclic antidepressant  (depression)                            |                         |
| Quetiapine                                                                                                                                                                                     | Anti-psychotic (schizophrenia)                                    |                         |
| Risperidone                                                                                                                                                                                    | Anti-psychotic (schizophrenia)                                    |                         |
| Salmeterol                                                                                                                                                                                     | Sympathomimetic (asthma, COPD)                                    |                         |
| Sertraline                                                                                                                                                                                     | Antidepressant (depression)                                       | Association not clear   |
| Solifenacin                                                                                                                                                                                    | Muscarinic receptor antagonist  (treatment of overactive bladder) |                         |
| Tacrolimus                                                                                                                                                                                     | Immune suppressant                                                | TdP cases in literature |
| Tamoxifen                                                                                                                                                                                      | Anti-cancer (breast cancer)                                       |                         |
| Telithromycin                                                                                                                                                                                  | Antibiotic (bacterial infection)                                  |                         |
| Tizanidine                                                                                                                                                                                     | Muscle relaxant                                                   |                         |
| Trimipramine                                                                                                                                                                                   | Tricyclic antidepressant  (depression)                            |                         |
| Vardenafil                                                                                                                                                                                     | Phosphodiesterase inhibitor  (vasodilator)                        |                         |
| Venlafaxine                                                                                                                                                                                    | Antidepressant (depression)                                       |                         |
| Voriconazole                                                                                                                                                                                   | Anti-fungal (fungal infection)                                    |                         |
| Ziprasidone                                                                                                                                                                                    | Anti-psychotic (schizophrenia)                                    |                         |
| *Concomitant use of these drugs will be allowed at the discretion of the PI. In such cases, the  patient must be closely monitored, including regular checks of QTc and electrolytes. Patients |                                                                   |                         |  
†Granisetron and ondansetron are acceptable antiemetics in this study. In clinical use, QT interval changes do not exceed 15 msec, and consequently, the potential for induction of arrhythmias is low.33
appendix d cyp450 interactions
appendix b performance status criteria

| CYP3A4 Substrates Albuterol Alfentanil Alprazolam Amiodarone Amlodipine Amprenavir Aprepitant Aripiprazole Atazanavir Atorvastatin Benzphetamine Bisoprolol Bortezomib Bosentan Bromazepam Bromocriptine Budesonide Buprenorphine Buspirone Busulfan Carbamazepine Cerivastatin Chlordiazepoxide Chloroquine Chlorpheniramine Cilostazol Cisapride Citalopram Clarithromycin Clobazam Clonazepam Clorazepate Cocaine Colchicine Conivaptan Cyclophosphamide Cyclosporine Dantrolene Dapsone Dasatinib (1) Delavirdine Diazepam Dihydroergotamine  Diltiazem  Disopyramide  Docetaxel Doxepin Doxorubicin Doxycycline Efavirenz Eletriptan Enalapril Eplerenone Ergoloid mesylates Ergonovine Ergotamine Erythromycin Escitalopram Estradiol Estrogens, conj.,  synthetic Estrogens, conj., equine Estrogens, conj.,  esterified Estrone Estropipate Ethinyl estradiol Ethosuximide Etoposide Exemestane Felbamate Felodipine Fentanyl Flurazepam Flutamide Fluticasone Fosamprenavir Gefitinib Haloperidol Ifosfamide Imatinib Indinavir Irinotecan Isosorbide Isosorbide dinitrate   | Isosorbide mononitrate  Isradipine  Itraconazole Ketamine  Ketoconazole Lansoprazole Letrozole Levonorgestrel Lidocaine Losartan Lovastatin Medroxyprogesterone  Mefloquine Mestranol Methadone Methylergonovine Methysergide Miconazole Midazolam Miglustat Mirtazapine Modafinil Montelukast Moricizine Nateglinide Nefazodone Nelfinavir Nevirapine Nicardipine Nifedipine Nimodipine Nisoldipine Norethindrone Norgestrel Ondansetron Paclitaxel Pergolide Phencyclidine Pimozide Pipotiazine Primaquine Progesterone Quetiapine   | Quinidine Rabeprazole  Ranolazine Repaglinide Rifabutin Ritonavir Salmeterol Saquinavir Sibutramine Sildenafil Simvastatin Sirolimus Spiramycin Sufentanil Sunitinib Tacrolimus Tamoxifen Tamsulosin Telithromycin Teniposide Tetracycline Theophylline Tiagabine Ticlopidine Tipranavir Tolterodine Toremifene Trazodone Triazolam Trimethoprim Trimipramine Troleandomycin Vardenafil Venlafaxine Verapamil Vinblastine Vincristine Vinorelbine Zolpidem Zonisamide Zopiclone   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
CTEP List of drugs that may have potential CYP3A4 interactions Additional information for drug interactions with cytochrome P450 isoenzymes can be found at http://medicine.iupui.edu/flockhart/.
appendix d cyp450 interactions
cyp2c8 substrates

Role for CYP2C8 Major role Amiodarone Amodiaquine Arachidonic acid (2C9, 2J2)
Cerivastatin (3A4 minor)
Chloroquine (3A4 minor) Paclitaxel (3A4)
Repaglinide (3A4 minor)
Retinoic acid (2C9)
Rosiglitazone (3A4 minor)
Tazarotenic acid Troglitazone (3A4 minor)
Intermediate role Diclofenac Fluvastatin (2C9, 3A4)
Ibuprofen (2C9)
Methadone (3A4, 2D6, 2B6)
Morphine (3A4)
Minor role Carbamazepine (3A4 major)
Cyclophosphamide (2A6, 2B6, 2C9, 2C19, 3A)
Dapsone (2C9 major)
Ifosfamide (2A6, 2B6, 2C9, 2C19, 3A4)
Torsemide (2C9 major) Verapamil (3A4 major)
Zopiclone (3A4 major)
Other CYPs that contribute to metabolism are given in parenthesis.
appendix d cyp450 interactions
cyp2c9 substrates

| diclofenac     | losartan      | fluoxetine      |
|----------------|---------------|-----------------|
| ibuprofen      | irbesartan    | fluvastatin     |
| lornoxicam     | glyburide     | glyburide       |
| meloxicam      | glibenclamide | nateglinide     |
| S-naproxen_Nor | glipizide     | phenytoin-4-OH2 |
| piroxicam      | glimepiride   | rosiglitazone   |
| suprofen       | tolbutamide   | tamoxifen       |
| tolbutamide    | amitriptyline | torsemide       |
| glipizide      | celecoxib     | S-warfarin      |  
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at http://medicine.iupui.edu/flockhart/.
appendix e ctep multicenter guidelines
cyp2c9 substrates

If an institution wishes to collaborate with other participating institutions in performing a CTEP sponsored research protocol, then the following guidelines must be followed.
appendix e ctep multicenter guidelines
responsibility of the protocol chair

The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office (PIO). The Protocol Chair is responsible for the coordination, development, submission, and approval of the protocol as well as its subsequent amendments. The protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use that document. The Protocol Chair is responsible for assuring that all participating institutions are using the correct version of the protocol.  
The Protocol Chair is responsible for the overall conduct of the study at all participating institutions and for monitoring its progress. All reporting requirements to CTEP are the responsibility of the Protocol Chair.  
The Protocol Chair is responsible for the timely review of adverse events to assure safety of the patients.  
The Protocol Chair will be responsible for the review of and timely submission of data for study analysis.
appendix e ctep multicenter guidelines
responsibilities of the coordinating center

Each participating institution will have an appropriate assurance on file with the Office for Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for assuring that each participating institution has an OHRP assurance and must maintain copies of IRB approvals from each participating site.  
Prior to the activation of the protocol at each participating institution, an OHRP form 310
(documentation of IRB approval) must be submitted to the CTEP PIO.  
The Coordinating Center is responsible for central patient registration. The Coordinating Center is responsible for assuring that IRB approval has been obtained at each participating site prior to the first patient registration from that site.  
The Coordinating Center is responsible for the preparation of all submitted data for review by the Protocol Chair.  
The Coordinating Center will maintain documentation of adverse event reports. There are two options for adverse event reporting: (1) participating institutions may report directly to CTEP with a copy to the Coordinating Center, or (2) participating institutions report to the Coordinating Center who in turn report to CTEP. The Coordinating Center will submit adverse event reports to the Protocol Chair for timely review.  
Audits may be accomplished in one of two ways: (1) source documents and research records for selected patients are brought from participating sites to the Coordinating Center for audit, or (2) selected patient records may be audited on-site at participating sites. If the NCI chooses to have an audit at the Coordinating Center, then the Coordinating Center is responsible for having all source documents, research records, all IRB approval documents, NCI Drug Accountability Record forms, patient registration lists, response assessments scans, x-rays, etc. available for the audit.
appendix e ctep multicenter guidelines
inclusion of multicenter guidelines in

The protocol must include the following minimum information:
The title page must include the name and address of each participating institution and the name, telephone number and e-mail address of the responsible investigator at each participating institution.  
The Coordinating Center must be designated on the title page.  
Central registration of patients is required. The procedures for registration must be stated in the protocol.  
Data collection forms should be of a common format. Sample forms should be submitted with the protocol. The frequency and timing of data submission forms to the Coordinating Center should be stated.  
Describe how adverse events will be reported from the participating institutions, either directly to CTEP or through the Coordinating Center.  
Describe how Safety Reports and Action Letters from CTEP will be distributed to participating institutions.
appendix e ctep multicenter guidelines
agent ordering

Except in very unusual circumstances, each participating institution will order DCTDsupplied investigational agents directly from CTEP. Investigational agents may be ordered by a participating site only after the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO.
appendix e ctep multicenter guidelines
appendix f pharmacokinetic sample acquisition

INSTRUCTIONS: This form should be completed as required per protocol. Information in the upper box must be completed for this form to be accepted. Do not leave any entries blank. Enter all times in 24-hour format. Enter - 1 to indicate that an answer is unknown, unobtainable, not applicable, or not done. Highlight or circle amended data. Include ORIGINAL form with sample shipment, retain a copy for your records.  
| Patient's Initials: ___________________________ Patient Accession Number: ___________________ Institution:   |
|--------------------------------------------------------------------------------------------------------------|  
DAY -7 **Date Belinostat administered: (mm/dd/yy)** ⊔⊔/⊔⊔/⊔⊔
DOSING INFORMATION
Belinostat Dose (mg/m2) ⊔⊔⊔ BSA (m2) ⊔.⊔⊔
Belinostat Dose (mg) ⊔⊔⊔
Time Belinostat Started: (hh:mm) ⊔⊔:⊔⊔
Each timed sample will be noted with corresponding number (1-14) for labeling purposes  
| BLOOD SAMPLES REQUIRED: Projected Time   | Actual Time                        | Problems?        |         |
|------------------------------------------|------------------------------------|------------------|---------|
| #                                        | Obtained (hh:mm)                   | Obtained (hh:mm) | Specify |
| 1                                        | Pre-Belinostat (B)                 | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 2                                        | 15 min into infusion of B          | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 3                                        | 25 min into infusion of B          | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 4                                        | 5 min after end of  infusion of B  | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 5                                        | 10 min after end of  infusion of B | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 6                                        | 15 min after end of  infusion of B | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 7                                        | 30 min after end of  infusion of B | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 8                                        | 1 h after end of infusion  of B    | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 83                                       |                                    |                  |         |  
| Projected Time   | Actual Time                       | Problems?        |         |
|------------------|-----------------------------------|------------------|---------|
| #                | Obtained (hh:mm)                  | Obtained (hh:mm) | Specify |
| 9                | 1.5 h after end of  infusion of B | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 10               | 2 h after end of infusion  of B   | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 11               | 4 h after end of infusion  of B   | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 12               | 6 h after end of infusion  of B   | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 13               | 8 h after end of infusion  of B   | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
| 14               | 24 h after end of infusion  of B  | ⊔⊔:⊔⊔            | ⊔⊔:⊔⊔   |
appendix e ctep multicenter guidelines
shipping information

SHIP TO: **Clinical Pharmacology Analytical Facility**
Attention of Dr. Jan H. Beumer UPCI Hillman Research Pavilion, G.28 5117 Centre Avenue Pittsburgh, PA 15213
*Prior to shipment of samples, please contact Clinical Pharmacology Analytical Facility by calling (412) 623-1213 or (412) 623-3248 or by sending a fax to Dr. Beumer **at (412) 623-** 1212.  
Condition of sample when shipped (1-frozen, 2-thawed) ⊔ Date sample shipped: (mm/dd/yy) ⊔⊔/⊔⊔/⊔⊔
Shipper's name: __________________________ E-mail address or phone no.: _____________
appendix g multicenter informed consent
shipping information

Phase I Pharmacokinetic Study of Belinostat for Solid Tumors and Lymphomas in Patients with Varying Degrees **of Hepatic Dysfunction**
appendix g multicenter informed consent
introduction

We invite you to take part in this research study. First, we want you to know that:
Taking part in this research study is entirely voluntary. You may choose not to take part, or you may withdraw from the study at any time. In either case, you will not lose any benefits to which you are otherwise entitled. You may receive no benefit from taking part. The research may give us knowledge that may help people in the future.  
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments they would want to receive (such as blood transfusions). If you have such beliefs, please discuss them with your doctors or research team before you agree to the study. Now we will describe this research study. Before you decide to take part, please take as much time as you need to ask any questions and discuss this study with family, friends or your personal physician or other health professional. You have been asked to take part in a clinical research study testing an experimental drug, called belinostat, because you have an advanced cancer and your liver may or may not be working properly, and the standard drugs to treat your disease are no longer effective, or it may be that no effective treatment is known for your disease.
appendix g multicenter informed consent
description of research study

The purpose of this study is to test the safety of belinostat at different dose levels in patients with cancer who have different degrees of liver function. Belinostat is an experimental drug that works by helping to turn on genes that control cell growth and survival that are switched off in cancer cells. This is the first study in which belinostat will be given systematically to patients with different degrees of liver function. We already know the safe dose for patients with normal liver function. Other purposes of this study are to find out what side effects occur when belinostat is given to patients with different degrees of liver function, how much belinostat is in your blood at specific times, and whether or not belinostat is effective in treating your cancer. We will compare how the patients with abnormal liver function do in comparison with patients with  
normal liver function. That is the reason that a group of patients with normal liver function will also be included on this trial.
appendix g multicenter informed consent
how many people will take

Up to 80 patients will take part in this study at multiple centers across the United States. Out of this, about ___ patients will take part in this study at ________________ *[name of center]*.
appendix g multicenter informed consent
has this drug been given

Belinostat has been given to about 500 patients with different types of cancer to measure its safety and how the body handles this drug. Belinostat has not been given in a formal trial to patients with cancer who have abnormal liver function to learn how these patients tolerate and respond to the drug.
appendix g multicenter informed consent
what will happen if i

You will need to have the following examinations, tests, or procedures to find out if you can be in the study. These examinations, tests, or procedures are part of your regular cancer care and should be done by your health care team even if you do not join the study. If you have had them recently, they may not need to be repeated. This will be up to your study doctor. If you decide that you would like to participate in this study, you will be asked to sign this consent form. You will then have the examinations, tests, and procedures listed below done to see if you can take part in the study (this is called the screening/baseline evaluation).
appendix g multicenter informed consent
during the study

After you are accepted for this study and you choose to take part, you will begin taking the study drug, belinostat. Belinostat is given through a vein for 30 minutes. Belinostat will be given in cycles. Except for cycle 1, all cycles are 3 weeks long. Cycle 1 is 4 weeks long. Now, we will describe what will happen during each cycle.
appendix g multicenter informed consent
complete medical history.

**Physical examination,** including height, weight, blood pressure, pulse, and temperature. **Standard blood tests** (requiring about 1 tablespoon of blood total), which include measurement of your white blood cells, red blood cells, platelets, blood sugar and electrolytes, how your liver and kidneys work, and how well your blood clots.  
**Urine tests:** Depending on the results of blood tests, you may be asked to give a collect your urine for 24 hours for further testing.  
**Pregnancy test:** A blood test will be done to check for pregnancy in women who are able to become pregnant.  
EKG to check your heart.  
**CT scans** of your chest, abdomen, and pelvis to measure your tumor(s). Other imaging tests may be done as needed.  
For cycle 1 only, you will receive one extra dose of belinostat 1 week before the regular treatment starts (Day -7). **In each cycle,** belinostat will be given once a day for 5 days (Day 1-5). For some study procedures we will need you to come to ________________ *[name of center]*. You will also have tests performed because you are in the study to see how the study drugs are affecting your body. This will include imaging studies (for example, CT scans) every 2 cycles (about every 6 weeks) to find out if your cancer has responded. Clinical Center Visits: We will ask that you come to ________________ *[name of center]* each day you receive belinostat (6 days in cycle 1 and 5 days in all other cycles) and on other days during cycle 1 when samples are collected for research (see Study Chart). While you are at
________________ *[name of center]*, we will also perform study tests and procedures to see how the study drugs are affecting your body. Standard procedures being done because you are in this study; these may be done more often **because you are in the study:**
**Clinic visit** to ask how you are feeling and to evaluate you with a physical examination at the beginning of each cycle.  
**Vital signs:** You will need to have your vital signs, including your temperature, heart rate, blood pressure, and respiratory rate, measured each time you are seen in the outpatient clinic.  
**Blood tests:** Measurement of your white blood cells, red blood cells and platelets, and measurements of your blood sugar and electrolytes and of how your liver and kidneys work will be done each time you are seen in the outpatient clinic. All of these blood tests combined will require 1-2 tablespoons (20-30 mL) of blood each time.  
**Urine test:** Depending on the results of blood tests, you may be asked to give a urine sample for testing or to collect your urine for 24 hours for further testing.  
EKG to check your heart on Day 5 of cycle 1, at the beginning of cycle 2, and more often if needed.  
**CT scans** or other imaging tests such as ultrasound (an examination using sound waves)
or MRI (an examination using magnetic field and radio waves) that detect your tumor will be done every 2 cycles (about every 6 weeks) while you are receiving treatment. This is done so that any benefit of the treatment can be determined, and so that if your cancer is not responding to the treatment, the study team can tell you and help you move to a different treatment program (discussed further below).
appendix g multicenter informed consent
tests and procedures that are

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

The chart below shows what will happen to you while you take part in this study. The left-hand column shows the day in the cycle, and the right-hand column tells you what will happen on that day.  
| Day             | What to do and what will happen to you  Get routine blood tests  Receive belinostat through a vein once a day for 30 minutes  EKG will be done on Day 1 of cycle 2 only to check your heart   |                                                                                                                         |
|-----------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------|
| Cycle 3 onwards |                                                                                                                                                                                                 | CT scans to determine how your tumor is responding to the treatment will be  done every 2 cycles (about every 6 weeks). |
appendix g multicenter informed consent
alternative approaches or treatments

What other choices do I have if I do not take part in this study? Talk to your doctor about your choices before you decide if you will take part in this study. Your other choices may include:
Getting treatment or care for your cancer without being in a study.  
Taking part in another study. However, if you have moderate or severe abnormal liver function, you may not be eligible for most other studies.  
Getting comfort care, also called palliative care. This kind of care helps reduce pain, tiredness, appetite problems, and other problems caused by cancer. It does not treat the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible.
appendix g multicenter informed consent
risks or discomforts of taking

If you choose to take part in this study, there is a risk that you may:
Lose time at work or home and spend more time in the hospital or doctor's office than usual Be asked sensitive or private questions which you normally do not discuss The agents used in this study may affect how different parts of your body work such as your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if changes occur that may affect your health. There is also a risk that you could have side effects from the study drug(s)/study approach. Here are important points about side effects:
The study doctors do not know who will or will not have side effects. Some side effects may go away soon, some may last a long time, or some may never go away.  
Some side effects may interfere with your ability to have children.  
Some side effects may be serious and may even result in death.  
Here are important points about how you and the study doctor can make side effects less of a problem:
Tell the study doctor if you notice or feel anything different so they can see if you are having a side effect.  
The study doctor may be able to treat some side effects.  
The study doctor may adjust the study drugs to try to reduce side effects.  
The tables below show the most common and the most serious side effects that researchers know about. There might be other side effects that researchers do not yet know about. If important new side effects are found, the study doctor will discuss these with you. It is important to remember that this is a dose-ranging study, meaning that the dose of belinostat will increase between groups of patients until notable side effects are seen. Because of this, some patients may have severe side effects as the study investigators find the highest dose of belinostat can be given safely to patients with different degrees of liver function. We already know the "safe dose" for patients with normal liver function and will not give you a dose bigger than this. If a dose has too many or certain unacceptable side effects, a lower dose may be recommended as the "safe dose" for future testing in patients with abnormal liver function. Risks and side effects observed with **belinostat** include:
appendix g multicenter informed consent
common some may be serious

In 100 people receiving belinostat, more than 20 and up to 100 may have:
Diarrhea, nausea, vomiting Tiredness  
| In 100 people receiving belinostat, from 4 to 20 may have:   |                                                              |
|--------------------------------------------------------------|--------------------------------------------------------------|
|                                                             | Anemia which may require blood transfusion                   |
|                                                             | Belly pain                                                   |
|                                                             | Constipation                                                 |
|                                                             | Dry mouth                                                    |
|                                                             | Swelling of arms, legs                                       |
|                                                             | Swelling and redness at the site of the medication injection |
|                                                             | Infection                                                    |
|                                                             | Change in the heart rhythm                                   |
|                                                             | Bruising, bleeding                                           |
|                                                             | Weight loss, loss of appetite                                |
|                                                             | Dehydration                                                  |
|                                                             | Dizziness, headache                                          |
|                                                             | Changes in taste                                             |
|                                                             | Shortness of breath                                          |
|                                                             | Flushing                                                     |
appendix g multicenter informed consent
side effects of blood draw

Infrequent (occurs in 1 to 10 out of 100 people): persistent pain and discomfort at the injection or needle insertion site as well as possible infection, bleeding, bruising, and soreness.
appendix g multicenter informed consent
birth control

If you are a woman who is breast feeding or pregnant, you may not take part in the study because we don't know how belinostat would affect your baby or your unborn child. If you are a woman who can become pregnant, or are the partner of a woman who can become pregnant, you will need to practice an effective form of birth control before starting study treatment and for the entire time you are in the study. If you think that you or your partner is pregnant, you should tell your study doctor or nurse at once.  
Effective forms of birth control include:
- abstinence intrauterine device (IUD) - hormonal (birth control pills, injections, or implants)
- tubal ligation
- vasectomy
appendix g multicenter informed consent
potential benefits of taking part

We hope that you will get personal medical benefit from taking part in this study, but we cannot be certain. These potential benefits could include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by the cancer. Because there is not much information about the drug's effect on your cancer, we do not know if you will benefit from taking part in this study, although the knowledge gained from this study may help others in the future who have cancer.
appendix g multicenter informed consent
research subject's rights what are

Taking part in this study is your choice. You may choose either to take part or not to take part in this study. If you decide to participate, you may leave the study at any time. No matter what decision you make, there will be no penalty to you, and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution if you are eligible and choose to participate in another trial. We will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study. In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form.
appendix g multicenter informed consent
what are the costs of

The National Cancer Institute will supply the Belinostat at no charge while you take part in this study. The NCI does not cover the cost for getting the Belinostat ready and giving it to you, so  
you or your insurance company may have to pay for this. Even though it probably won't happen, it is possible that the manufacturer may not continue to provide the Belinostat to the NCI for some reason. If this would occur, other possible options are:  
You may be able to get the Belinostat from the manufacturer or your pharmacy but you or your insurance company may have to pay for it.  
If there is no Belinostat available at all, no one will be able to get more and the study would close.
If a problem with getting Belinostat occurs, your study doctor will talk to you about these options.
appendix g multicenter informed consent
you will not be paid

For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.  
Stopping Therapy Your doctor may decide to stop your therapy for the following reasons:
if he/she believes that it is in your best interest if your disease gets worse during treatment if you have side effects from the treatment that your doctor thinks are too severe if new information shows that another treatment would be better for you if too many patients in the study experience severe side effects
In this case, you will be informed of the reason therapy is being stopped. You can stop taking part in the study at any time. However, if you decide to stop taking part in the study, we would like you to talk to the study doctor and your regular doctor first. If you decide at any time to withdraw your consent to participate in the trial, we will not collect any additional medical information about you. However, according to FDA guidelines, information collected on you up to that point may still be provided to the Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute (NCI) or designated representatives.  
If you withdraw your consent and leave the trial, any samples of yours that have been obtained for the study and stored at the NCI can be destroyed upon request. However, any samples and data generated from the samples that have already been distributed to other researchers or placed in the research databases cannot be recalled and destroyed.
appendix g multicenter informed consent
will my medical information be

We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used. Organizations that may look at and/or copy your medical records, including research records, for research, quality assurance, and data analysis include:  
The National Cancer Institute (NCI) and other government agencies, like the Food and Drug Administration (FDA), involved in keeping research safe for people.  
Qualified representatives from the drug company sponsor may also review the medical records.  
Designees from cancer centers participating in this study.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time. [Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation found at 21 CFR 50.25(c) and must be included verbatim in all informed consent documents. *The* text in this paragraph cannot be revised.] [Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed by the local institution. The regulations may or may not be included in the informed consent form depending on local institutional policy.]
appendix g multicenter informed consent
what happens if i am

It is important that you tell your study doctor, __________________ *[investigator's name(s)],* if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at __________________ *[telephone number].* You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health plan will be charged for this treatment. The study will not pay for medical treatment.
appendix g multicenter informed consent
who can answer my questions

You can talk to your study doctor about any questions or concerns you have about this study. Contact your study doctor __________________ *[name(s)]* at __________________ *[telephone* number]. For questions about your rights while taking part in this study, call the ________________________ *[name of center]* Institutional Review Board (a group of people who review the research to protect your rights) at __________________ (telephone number).  
[Note to Local Investigator: Contact information for patient representatives or other individuals in a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.]
appendix g multicenter informed consent
where can i get more

You may call the National Cancer Institute's Cancer Information Service at: 1-800-4-CANCER (1-800-422-6237). You may also visit the NCI Web site at http://cancer.gov/.  
For NCI's clinical trials information, go to: http://cancer.gov/clinicaltrials/
For NCI's general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form. If you want more information about this study, ask your study doctor.
appendix g multicenter informed consent
signature

I have been given a copy of all _____ *[insert total of number of pages]* pages of this form. I have read it or it has been read to me. I understand the information and have had my questions answered. I agree to take part in this study.
appendix g multicenter informed consent
participant date appendix h registration

A. Registrations for the Liver Dysfunction Trial must be made through the Coordinating Center, at the National Cancer Institute's Center for Cancer Research through the Developmental Therapeutics Clinic. Patients are registered Monday through Friday between the hours of 8:30am through 4:30pm, excluding Federal Holidays. Documentation of IRB approval of this protocol by collaborating institutions must be on file.  
B. Following registration, patients should begin protocol treatment within 3 business days. However, beginning therapy within 24 hours of registration is preferable in patients with organ dysfunction.  
C. Pre-study laboratory tests and scans must be completed prior to registration, within the time frame specified in the protocol. The eligibility form provided by the NCI, CCR (Appendix J) must be completed and signed by the treating physician. Patients must also sign an informed consent and HIPAA authorization form prior to registration.  
D. A patient failing to meet all protocol requirements cannot be registered. If you have any questions regarding eligibility, contact the DTC at (301) 435-4949
appendix g multicenter informed consent
ii. slot reservations

A. If a potential patient has been identified for the Liver Dysfunction trial, the data manager or research nurse must contact the DTC Research Nurse at (301) 4354949 to verify that a slot is available on a particular dose-level. Please provide the patient's initials, diagnosis, bilirubin, and AST at that time.  
1. If a dose level is open, the Research Nurse will reserve the "slot" for a maximum of 14 days (10 business days) to allow sufficient time to determine eligibility. If a patient does not start treatment within this time frame, the slot will be released. Slots will be released on a first come first served basis for all slots other than the normal cohort slots.  
a. The data manager or research nurse must follow up the NCI,
CCR within 14 days (10 business days) to complete the registration or cancel the reservation.  
2. If no dose-level is open (based on the criteria for dose expansion or escalation- as described in the protocol), then the NCI, CCR can indicate the anticipated date of reopening and the slot may be reserved for the patient.  
a. The data manager or research nurse must stay in touch with the NCI, CCR and must complete or cancel registration within 24 hours of the planned treatment date. It is preferred that the Coordinating Center is informed of the intended treatment date at least 48 hrs prior.  
3. No more than 3 patients may be held on the waiting list for a single liver dysfunction cohort.  
a. If a patient on the waiting list becomes ineligible, then the data manager or research nurse must call or email the Coordinating Center to remove the patient from the list.  
4. No slot reservation at the given dose level will be made prior to escalation or expansion until such time as the 3rd patient at that level has been evaluated for toxicity.
appendix g multicenter informed consent
iii. registration procedures

A. Once a patient is eligible, and all the pre-study requirements have been fulfilled, a data manager or research nurse must contact the Coordinating Center's Primary Research Nurse: Nancy Moore RN, phone (240) 760-6045, nancy.moore@nih.gov, fax (301) 451-5625.  
B. Fax a copy of the signed informed consent, HIPAA authorization form, eligibility screening worksheet, required pre-study tests (pathology and baseline laboratory reports), and the completed On-Study/Eligibility Form. NCI registration form to (301) 480-7281. Upon receipt of the documents, the Coordinating Center, will confirm completion of the registration process and verify eligibility.  
C. All eligible patients will be registered through the NCI Central Registration Office (CRO). The CRO is open from 8:30am to 5:00pm EST Monday through Friday, excluding Federal Holidays. The CRO will notify the Coordinating Center via encrypted e-mail that the protocol Eligibility Checklist has been received and registered.  
D. The Coordinating Center will contact the registering data manager or research nurse via email confirming registration. The email confirmation will be available and sent to the participating site within 1 business day. The confirmation of registration form includes patient name, cohort, dose level, NIH medical record number, unique identifier (7 digit number), and an assigned patient ID.
appendix g multicenter informed consent
iv. c3d database patient id

A. Upon registration, the CRO will assign a unique 7 digit patient/subject ID
number for each patient that will be used to enter data into the C3D database. The number is coded to identify the patient number according to the participating site. The number will appear as 1010001, the first three digits identify the site 101. Subsequent sites will be listed as 102, 103, 104, etc. The last three digits in the series will identify the sites patient number 001.  
B. This assigned unique identifier is to be used in the Patient ID field for the CTEPAERS submission and Theradex Data Reporting.  
C. Each site will be listed in the C3D database according to the CTEP assigned code. Each site is assigned a 5 character code composed of an alphabetical site abbreviation and numbers.
appendix g multicenter informed consent
v. assigned patient id

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

a. A master liver dysfunction slot reservation excel spreadsheet will be maintained and distributed biweekly to the participating site 24 hours prior to the conference call.  
b. Each participating site is required to have at least one representative participating in the conference call.  
c. Patients will be referenced using the assigned Patient ID. d. Sites are required to provide an update on each active patient.  
II. **Protocol Enrollment Log**
a. A patient enrollment log template word version will be distributed to each participating site.  
b. Data managers or research nurses should maintain and update the log c. The updated log should be sent via email to the Coordinating Center by 2pm EST
the Thursday prior to the Friday Conference Call.
appendix j forms eligibility/pre-registration worksheet
appendix i organ dysfunction conference

A Phase I Pharmacokinetic Study of Belinostat for Solid Tumors and Lymphomas in Patients with Varying Degrees of Hepatic Dysfunction Coordinating Center: NCI Principal Investigator: Bethesda, MD 20892 Naoko Takebe, MD, PhD Primary Contact: Nancy Moore, RN National Cancer Institute Tel: (240) 760-6045 Tel: (240) 781-3398 Fax: (301) 451-5625 takeben@mail.nih.gov nancy.moore@nih.gov  
| Patient's Name: (FML)                                                                                                                                                                                                     | Institution:                       |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|
| Medical Record Number:                                                                                                                                                                                                    | Investigator:                      |
| Patient's Date of Birth:                                                                                                                                                                                                  | Treating Physician:                |
| Sex: ______Male _____Female                                                                                                                                                                                               | Date Informed Consent Signed:      |
| IRB approval valid until (date) Race: _____ Black _____ Caucasian _____ Asian _____ American Indian _____ Native  Hawaiian/Pacific _____ Other: _________ Ethnicity: ____ Hispanic ____ Non-Hispanic ____ Other: ________ | Projected start date of treatment: |  
INCLUSION CRITERIA: A NO response will make the subject **INELIGIBLE**.  
| Yes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | No   | N/A   | INCLUSION CRITERIA   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|-------|----------------------|
| Does the patient (except those with hepatocellular carcinoma) have histologically or cytologically confirmed solid tumor or lymphoma that is  metastatic, unresectable, progressive, or recurrent, and for which standard  curative or palliative measures do not exist or are no longer effective?  Patients with hepatocellular carcinoma do not require biopsy confirmation.  If the patient has hepatocellular carcinoma, does the patient have a liver  mass with raised α-fetoprotein level (≥500 ng/mL), consistent radiographic  changes, and serology and viral DNA/RNA measurements consistent with  chronic hepatitis (see Section 3.1.9) AND have disease that has failed  standard therapy? Is it correct that the patent has had no radiation, major surgery,  chemotherapy or biologic therapy within 4 weeks prior to entering the study  (6 weeks for nitroureas or mitomycin C); ≥ 2weeks since any prior  administration of study drug in an exploratory IND/Phase 0 study. Has the  patient recovered to at least eligibility levels due to adverse events and/or  toxicity of prior chemotherapy or biologic therapy? Is the patient's age ≥ 18 years? Because no dosing or adverse event data are  currently available on the use of Belinostat in patients <18 years of age,  children are excluded from this study but will be eligible for future pediatric  Phase 1 single-agent trials. Is the patient's ECOG performance status ≤ 2 and Karnofsky ≥60%,  (Appendix B)? Status ______ Is the patient's life expectancy greater than 3 months? Does the patient have acceptable renal and marrow function as defined  below? Date: ____________ Leukocytes ≥ 3,000/mcL ____________ Absolute Neutrophil Count  (ANC) ≥ 1,5000/mcL ____________ Platelets ≥ 100,000/mcL ____________ Serum Creatinine ___________ ULN _______ (within normal institutional limits) OR  Creatinine Clearance ≥ 60 mL/min for patients with creatinine levels above institutional  normal, as determined by measured 24-hour creatinine clearance  Baseline evaluations should be conducted within 7 days of the treatment  start date. Patients with abnormal liver function will be eligible and will be grouped  according to the criteria described in Section 5.1. No distinction will be 100 |      |       |                      |  
| Yes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | No   | N/A   | INCLUSION CRITERIA   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|-------|----------------------|
| made between liver dysfunction due to metastases and liver dysfunction due  to other causes. Liver function tests should be repeated with 24 hours prior  to starting treatment on study Patients with biliary obstruction for which a stent has been placed are  eligible, provided the stent has been in place for at least 10 days prior to the  first dose of belinostat and the liver function has stabilized. Two  measurements at least 2 days apart that put the patient in the same hepatic  dysfunction stratum will be accepted as evidence of stable hepatic function.  There should be no evidence of biliary sepsis. Does the patient either not have a stent, or, if a stent is in place, has it been  in place for over 10 days, AND has the liver function shown stability  (placing patient into same cohort with measurements at least 2 days apart)? If patient has hepatitis B, are HepBsAg, HepBcAb, HepBsAb, and  HepBeAb consistent with chronic disease as measured within 3 months of  starting on study? If patient has hepatitis B, has COBAS TaqMan been checked within 1  month of starting on study? If patient has hepatitis C, has anti-HCV been checked within 3 months of  starting on study? If patient has hepatitis C, has HCV-RNA been checked within 1 month of  starting on study? Patient with gliomas or brain metastases who require corticosteroids or anticonvulsants must be on a stable dose of corticosteroids and seizure free  for 1 month prior to enrollment. Patients with known brain metastases  should have had brain irradiation (whole brain or gamma knife) more than 4  weeks before starting the protocol. Note that patients should have had their  steroids tapered to low dose (i.e., 1.5 mg of dexamethasone/day). Does the patient either not have gliomas or brain metastases, or if the  patient does, have they met the above criteria?  Is the patient able to understand and willing to sign a written informed consent document? The effects of belinostat on the developing human fetus are unknown. For  this reason and because HDAC inhibitors are known to be teratogenic,  women of child-bearing potential and men must agree to use adequate  contraception (hormonal or barrier method of birth control; abstinence)  prior to study entry and for the duration of study participation. Should a  woman become pregnant or suspect she is pregnant while participating in  this study, she should inform her treating physician immediately. Does the patient agree to use contraception for the duration of study  participation? |      |       |                      |  
EXCLUSION CRITERIA: A **YES** response will make the patient **INELIGIBLE** for the study.  
| Yes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | No   | N/A   | EXCLUSION CRITERIA   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|-------|----------------------|
| Is the patient receiving any other investigational agents? Has the patient previously been treated with Belinostat? Does the patient have a history of allergic reactions attributed to compounds  of similar chemical or biologic composition to belinostat, including  hydroxamate compounds or arginine? Has the patient taken valproic acid, another HDAC inhibitor, within 2 weeks  prior to enrollment? Does the patient have uncontrolled intercurrent illness including, but not  limited to ongoing or active infection, or psychiatric illness/social situations  that would limit compliance with study requirements? Is the patient pregnant or breastfeeding? Pregnant women are excluded from  this study because belinostat is an HDAC inhibitor with the potential for  teratogenic or abortifacient effects. Does the patient have active hemolysis? Patients with active hemolysis  should be excluded. Is the patient on antiretroviral therapy? HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK  interactions with belinostat. Appropriate studies will be undertaken in  patients receiving combination antiretroviral therapy when indicated. For patients with hepatitis B or C, does the patient require interferon  treatment or has the patient received interferon within the past 4 weeks?  Patients must be stable without having received interferon in at least 4 weeks. Does the patient have significant cardiovascular disease (New York Heart  Association Class III or IV cardiac disease), symptomatic congestive heart  failure, myocardial infarction within the past 6 months, unstable angina,  unstable arrhythmia or a need for anti-arrhythmic therapy (use of frequency  adjusting medication for atrial fibrillation is allowed, if stable medication for  at least last month prior to initiation of belinostat treatment and medication  not listed as causing Torsades de Points), evidence of acute ischemia or ECG,  marked baseline prolongation of QT/QTc interval, e.g., repeated  demonstration of a QTC interval > 450 msec*; Long QT Syndrome? Or does  the patient require a drug known to prolong the QT interval and/or cause  Torsades de Pointes (Table 1, Appendix C) or have taken such a drug within 2  weeks of study entry? (Note: Drugs that may be associated with Torsades de  Pointes but lack substantial evidence [Table 2, Appendix C] will be allowed  at the discretion of the PI, although it is preferable to substitute an alternate  medication.) |      |       |                      |
appendix j forms eligibility/pre-registration worksheet
pre-study evaluations

Laboratory evaluations are to be conducted within 1 week prior to the start of the protocol therapy unless otherwise indicated. Scans and x-rays must be performed within 28 days prior to the start of therapy.  
| Pre-Study Evaluations:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Completion Date   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|
| History and Physical Exam: (prior to study drug administration) (including height, weight, vital signs, and Performance Status) Baseline Imaging Studies: (CT Scan of the Chest/Abd/pelvis within 28 days prior to study drug  administration) Laboratory Evaluation: (within 1 week prior to study drug  administration) Hematological Profile: CBC with differential and Platelet Count Coagulation Studies: PT* /INR/aPTT* is required to be checked at  baseline Biochemical Profile: Electrolytes, BUN, creatinine, glucose, AST  (SGOT), ALT (SGPT), bilirubin, calcium, phosphorous, albumin,  magnesium, alkaline phosphatase. *=as clinically indicated Serum Pregnancy Test: (within 1 week prior to study drug  administration) Participants of childbearing age and anatomic ability. EKG (within 1 week prior to study drug administration) Child-Pugh Classification score (Appendix M). Please submit with  enrollment package. Histologic Confirmation:  A block or stained slides of primary tissue from the time of diagnosis  will be required from each participant to confirm diagnosis. Tissue  blocks from a known recurrence will be accepted if original tumor  samples are unavailable. |                   |  
Laboratory evaluation for patients with hepatocellular carcinoma secondary to hepatitis B or C:
For patients with hepatitis B
HepBsAg, HepBcAb, HepBsAb, and HepBeAb; results may be from within 3 months before starting on study. COBAS TaqMan; results must be from within 1 month before starting on study.  
For patients with hepatitis C
anti-HCV; results may be from within 3 months before starting on study. HCV-RNA; results must be from within 1 month before starting on study.
appendix j forms eligibility/pre-registration worksheet
descriptive factors

Primary: ________________________ Histology: ___________________ Height _______ cm Weight _____kg BSA ______ PRIOR THERAPY (Please specify date, procedure, agent, dose, and response)  
| Treatment Type                              | Agent   | Treatment  Start Date   | Treatment  End Date   | Response   |
|---------------------------------------------|---------|-------------------------|-----------------------|------------|
| Surgery/Biopsy: Chemotherapy: Radiotherapy: | 104     |                         |                       |            |  
| Hormonal Therapy: Immunotherapy:   |
|------------------------------------|
appendix j forms eligibility/pre-registration worksheet
liver dysfunction groups

Patients entering the study are stratified into four dysfunction groups [(Cohort 1) Normal, (Cohort 2) Mild, (Cohort 3) Moderate, (Cohort 4) Severe] according to their hepatic function as outlined in the following table:  
| Liver                |           |           |               |                 |
|----------------------|-----------|-----------|---------------|-----------------|
| Dysfunction  Cohorts | Cohort 1  | Cohort 2  | Cohort 3      | Cohort 4        |
| Normal               | Mild      | Moderate  | Severe        |                 |
| Total Bilirubin      | ≤ ULN     | >ULN but  | >1.5 X ULN to | > 3 X ULN but ≤ |
| ≤ 1.5 X ULN          | ≤ 3 X ULN | 10 X ULN  |               |                 |
| AST (SGOT)           | ≤ ULN     | AST > ULN | Any AST       | Any AST         |
appendix j forms eligibility/pre-registration worksheet
hepatic function total bilirubin

| Normal Cohort 1:   | ≤ ULN                    |
|--------------------|--------------------------|
| Mild Cohort 2:     | > ULN but ≤ 1.5 X ULN    |
| Moderate Cohort 3: | >1.5 X ULN to ≤ 3 X ULN  |
| Severe Cohort 4:   | > 3 X ULN but ≤ 10 X ULN |  
AST (SGOT):  
| Normal Cohort 1:   | ≤ ULN   |
|--------------------|---------|
| Mild Cohort 2:     | > ULN   |
| Moderate Cohort 3: | Any AST |
| Severe Cohort 4:   | Any AST |  
Date Measured _____________________ (Second Measurement - for patients with a biliary stent) Patients should have biliary stent placed at least 10 days prior to the start of treatment. Provide the placement date in the table, if placed within 10 days of treatment.  
| Biliary Stent   | Yes   | No               | Biliary Stent Placement   | Second Lab   |
|-----------------|-------|------------------|---------------------------|--------------|
| Present         | Date  | Measurement Date |                           |              |  
Liver Dysfunction Group Normal Cohort 1:  
| Mild Cohort 2: Moderate Cohort 3: Severe Cohort 4:   |
|------------------------------------------------------|  
Printed Name of Physician: ______________________ Date: ____________ Physician Signature: ______________________  
| Date Registered with NCI                                                                                                    | ____________________             |
|-----------------------------------------------------------------------------------------------------------------------------|----------------------------------|
| Spoke with:                                                                                                                 | ________________________________ |
| Study ID:                                                                                                                   | ________________________________ |
| Eligibility Completed Complete By: _____________________________ Assigned CRA/ Data Manager: ______________________________ |                                  |  
The NCI will send a confirmation of registration within 24 hours.  
Appendix K: **Off Study/Death Notification Form**
Complete form and e-mail to the Coordinating Center Research Nurse nancy.moore@nih.gov Patient Information:  
  
Registrar: Participating Site: __________________________________ Name: _______________________ Date: _____________  
Appendix L: Study Diary Phase I Belinostat for Solid Tumors and Lymphomas in Patients with Varying Degrees of Hepatic Dysfunction  
Patient Name: _________________________ Cycle ______ Week _______ Cohort: ______________________________  
| Date                                                                                               | Note any side effects   | List any medications taken and the  reason why (prescription & nonprescription)  **Do not list your daily meds**   |
|----------------------------------------------------------------------------------------------------|-------------------------|---|
| Monday Date: Tuesday Date: Wednesday Date: Thursday Date: Friday Date: Saturday Date: Sunday Date: |                         |   |
appendix j forms eligibility/pre-registration worksheet
appendix m child-pugh classification (cpc)

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