Clinical trial NCT00667615
Conditions: Hodgkin's Disease Lymphoma
Keywords: vorinostat rituximab cyclophosphamide etoposide prednisone Quality of life 08-045
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2008-04-01; Completion date: 2017-02-01
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to replace a drug with many side effects, procarbazine, with a new novel drug, vorinostat, in a drug combination for the treatment of patients with diffuse large B-cell lymphoma. Vorinostat is the first of a new type of chemotherapy drug, known as a histone deacetylase inhibitor, to be approved by the Food and Drug Administration. It is approved for the treatment of certain lymphomas of the skin. It alters the cancer cell pathway by preventing cancer cells from reproducing. Vorinostat will be added to a combination of four other effective chemotherapy drugs that have been used for many years for the treatment of diffuse large B-cell lymphoma: rituximab, cyclophosphamide, etoposide and prednisone. The doses of vorinostat will be increased or decreased depending on the side effects that occur in each of the first few patients in the trial to find the safest dose with the least side effects. This is termed the phase I part of the clinical trial. Once the best dose of vorinostat is found, the rest of the patients in the clinical trial will be treated with this dose. This is termed the phase II part of the trial. The object of the trial is to find out what effects, good and/or bad, the combination of vorinostat, rituximab, cyclophosphamide, etoposide and prednisone will have on you and your lymphoma.

Detailed description:

Arms: arm 1: vorinostat in combination with cyclophosphamide, etoposide,prednisone and rituximab,peg-filgrastim or filgrastim
Interventions: intervention 1: rituximab, cyclophosphamide, etoposide, prednisone, vorinostat and QOL questionnaire, peg-filgrastim or filgrastim
Intervention descriptions: intervention 1: Patients will be treated with 6 cycles of rituximab, cyclophosphamide, etoposide, prednisone and vorinostat every 4 weeks. Quality of life determinations will be obtained at the beginning of each cycle of chemotherapy and at each visit during the first year of followup.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 08-045A(6) 
 
Amended: 12/13/11 
- 1 - 
A Multi-Center Phase I/II Trial Of Vorinostat In Combination With Cyclophosphamide, 
Etoposide, Prednisone And Rituximab For Elderly Patients With Relapsed Diffuse Large 
B-Cell Lymphoma (DLBCL) 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal Investigator/Department: David J. Straus, M.D 
Medicine 
 
 
Co-Principal 
Investigator(s)/Department: 
Paul A. Hamlin, M.D. 
Medicine 
 
 


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Investigator(s)/Department: 
John F. Gerecitano, M.D.,Ph.D 
Craig H. Moskowitz, M.D. 
Alison Moskowitz, M.D. 
Ariela Noy, M.D. 
M. Lia Palomba, M.D. 
Carol S. Portlock, M.D. 
Andrew D. Zelenetz, M.D.,Ph.D. 
Matthew Matasar, M.D 
Steven Horwitz, M.D. 
 
Ephraim Casper, MD 
Deena Atieh Graham, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD        
Magi Khalil, MD 
Shilen Patel, MD                            
Han Xiao, MD 
Stefan Berger, MD 
Julie Fasano, MD 
John Fiore, MD                              
Stuart Lichtman, MD  
Philip Schulman, MD 
Marni Sheren-Manoff, MD 
Steven Sugarman, MD 
Frank Y. Tsai, MD 
Arlyn Apollo, MD  
Pamela Drullinsky,  MD 
Zoe Goldberg,  MD 
Kenneth Ng,  MD 
Tiffany Troso-Sandoval, MD 
Michelle Boyar, MD 
Philip Caron, MD, PhD 
Nancy Mills, MD 
Stephanie Smith-Marrone, MD  
Carolyn Wasserheit-Lieblich, 
MD 
                                                        
Alexia Iasonos, Ph.D.  
 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 
Medicine - Basking Ridge 
Medicine - Basking Ridge 
Medicine - Basking Ridge 
Medicine - Basking Ridge 
Medicine - Basking Ridge 
Medicine - Basking Ridge 
Medicine - Basking Ridge 
Medicine - Basking Ridge 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine – Rockville Centre 
Medicine - Rockville Centre 
Medicine - Rockville Centre 
Medicine - Rockville Centre 
Medicine - Rockville Centre 
Medicine – Sleepy Hollow 
Medicine - Sleepy Hollow 
Medicine – Sleepy Hollow 
Medicine – Sleepy Hollow 
 
 
Epidemiology and Biostatistics 
 
Otilia-Liana Dumitrescu, M.D. 
Radiology 
 
 
 


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Consenting  
Professional(s)/Department: 
 
 
 
 
 
 
 
 
David J. Straus, M.D 
Paul A. Hamlin 
John F. Gerecitano, M.D.,Ph.D 
Alison Moskowitz, M.D. 
Craig H. Moskowitz, M.D. 
Ariela Noy, M.D. 
M. Lia Palomba, M.D. 
Carol S. Portlock, M.D. 
Andrew D. Zelenetz, M.D., Ph.D. 
Matthew Matasar, M.D 
Steven Horwitz, M.D. 
 
Ephraim Casper, MD 
Deena Atieh Graham, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD        
Magi Khalil, MD                                 
Shilen Patel, MD 
Han Xiao, MD 
Julie Fasano, MD 
Stefan Berger, MD 
John Fiore, MD                                    
Stuart Lichtman, MD  
Frank Y. Tsai, MD 
Philip Schulman, MD 
Marni Sheren-Manoff, MD 
Steven Sugarman, MD 
Arlyn Apollo, MD  
Pamela Drullinsky,  MD 
Zoe Goldberg,  MD 
Kenneth Ng,  MD 
Tiffany Troso-Sandoval, MD 
Michelle Boyar, MD 
Philip Caron, MD, PhD 
Nancy Mills, MD 
 
 
 
 
 
 
 
 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 
Medicine – Basking Ridge 
Medicine - Basking Ridge 
 
Medicine - Basking Ridge 
Medicine - Basking Ridge 
Medicine - Basking Ridge 
Medicine - Basking Ridge 
Medicine - Basking Ridge 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine - Commack 
Medicine – Rockville Centre 
Medicine – Rockville Centre 
Medicine – Rockville Centre 
Medicine – Rockville Centre 
Medicine – Rockville Centre 
Medicine – Sleepy Hollow 
Medicine – Sleepy Hollow 


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Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
Carolyn Wasserheit-Lieblich, MD 
Stephanie Smith-Marrone, MD 
 
 
Medicine – Sleepy Hollow 
Medicine – Sleepy Hollow 
Medicine – Sleepy Hollow 
 
 
 
 
 
Medicine – Sleepy Hollow 
Medicine – Sleepy Hollow 
Medicine – Sleepy Hollow 
 
 
 
 
 
 
 
 
Collaborating Institution: 
PI's Name  
Site's Role  
Northwestern University Medical 
School 
Evanston Northwestern Healthcare 
 
David Cella, Ph.D.                       Data Analysis:  
Appendix V global rating of 
change scale  
 Weill Cornell Medical College 
520 East 70th Street, Starr Pavilion 
New York, NY 10021 
Phone: 212-746-2063 
Fax: 212-746-3844 
Email: ree2001@med.cornell.edu 
Rebecca Elstrom, M.D.    
 Data Collection 
  


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Table of Contents 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL ...................................................................... 1 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ........................................................................ 7 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 8 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 8 
 
3.1  VORINOSTAT 
 
3.1.1  HISTONE DEACETYLASES AND HDAC INHIBITORS 
 
3.1.2  MECHANISM OF ACTION OF VORINOSTAT 
 
3.1.3  NON CLINICAL PHARMACOLOGY OF VORINOSTAT 
 
3.1.4  NON CLINICAL TOXICOLOGY OF VORINOSTAT 
 
3.1.5  CLINICAL PHARMACOKINETICS OF VORINOSTAT  
 
3.1.6  SUMMARY OF CLINICAL EXPERIENCE WITH VORINOSTAT  
 
3.1.7  SAFETY OF VORINOSTAT   
 
3.1.8  EFFICACY OF VORINOSTAT (SEE APPENDIX VI) 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .......................................................... 13 
4.1  DESIGN ............................................................................................................................. 13 
4.2  INTERVENTION .............................................................................................................. 14 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 14 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................. 18 
6.1  SUBJECT INCLUSION CRITERIA ................................................................................. 18 
6.2  SUBJECT EXCLUSION CRITERIA................................................................................ 19 
7.0 
RECRUITMENT PLAN ........................................................................................................... 17 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 18 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 18 
 
9.1  CONCOMITANT AND PROHIBITED MEDICATIONS/TREATMENTS 
 
9.2  DIET 
 
9.3  SUPPORTIVE CARE GUIDELINES  
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ................................................ 25 
11.0     TOXICITIES/SIDE EFFECTS ................................................................................................. 25 
 
11.1  VORINOSTAT 
 
11.2  CYCLOPHOSPHAMIDE 
 
11.3  ETOPOSIDE 
 
11.4  RITUXIMAB 
 
11.5  PREDNISONE 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT....................... 28 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................ 29 
14.0 
BIOSTATISTICS ..................................................................................................................... 29 
 
14.1  QUALITY OF LIFE AS MEASURED BY THE FACT-LYM INSTRUMENT. 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION    
PROCEDURES..................................................................................................................................... 33 
15.1   RESEARCH PARTICIPANT REGISTRATION .......................................................... 33 


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15.1.1  FOR PARTICIPATING SITES 
16.0 
DATA  MANAGEMENT ISSUES .......................................................................................... 34 
16.1QUALITY ASSURANCE ................................................................................................. 37 
16.2DATA AND SAFETY MONITORING ............................................................................ 38 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................... 41 
17.1PRIVACY .......................................................................................................................... 41 
17.2 SERIOUS ADVERSE EVENT (SAE) REPORTING ...................................................... 41 
17.3  REGULATORY AND REPORTING REQUIREMENTS  ............................................ 42 
18.0 
INFORMED CONSENT PROCEDURES ............................................................................... 45 
18.1    RESEARCH AUTHORIZATION ................................................................................. 46 
19.0 
REFERENCE(S) ....................................................................................................................... 37 
20.0 
APPENDICES .......................................................................................................................... 40 
 
 
 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA       
Study Title: A multicenter phase I/II trial of vorinostat in combination with cyclophosphamide, 
etoposide, prednisone and rituximab for elderly patients with relapsed diffuse large B-cell 
lymphoma (DLBCL) 
 
Patient Population: 
Relapsed/refractory DLBCL patients ≥60 years of age and not candidates for autologous stem 
cell transplantation 
 
Design: This is a phase I/II, open-label, single arm trial. The goals are to determine the optimal 
dose of vorinostat when given in combination to rituximab, cyclophosphamide, etoposide and 
prednisone. In addition, we hypothesize that this regimen will  increase the response rate and one 
-year progression free survival for elderly patients with relapsed or refractory DLBCL who are 
not candidates for autologous stem cell transplantation with the addition of a new 
chemotherapeutic agent, vorinostat, to rituximab, cyclophosphamide, etoposide and prednisone. 
As this is a palliative regimen, quality of life measurements will be another important endpoint. 
 
Rituximab 375 mg/m2  intravenously day one. Cyclophosphamide 600 mg/m2 intravenously days 
1 and 8, etoposide 70 mg/m2 day 1 intravenously, then 140 mg/m2 days 2 and 3 orally, vorinostat 
orally days 1-10 (see below), prednisone 60 mg/m2 days 1-10. The regimen will be repeated 
every 4 weeks for 6 cycles unless there is disease progression or intolerance of the regimen due 
to toxicity. 
 
The starting dose of vorinostat will be 300 mg orally days 1-10. All other agents will be held 
constant at the above doses. Three patients will be enrolled at this dose. If 0/3 experience DLT 
then the dose will be increased to 400 mg orally days 1-10. If 1/3 patient experiences a DLT then 
3 more patients will be added at the 300 mg dose. If ≥2 patients experience DLT at 300 mg, the 
trial will be discontinued because of excessive toxicity. If ≤1 out of 6 patients experience a DLT 
at 300 mg then we will escalate to 400 mg and follow the same scheme. If 2 or more experience 
a DLT at 400 mg and only 3 patients were treated at 300 mg, then we will de-escalate to 300 mg 
and 3 additional patients will be added. If ≤1 out of 6 patients experience a DLT at 400 mg, then 
400 mg will be the MTD for the Phase II part of the study. DLT is defined as any grade 3 or 4 
non-hematological toxicity or grade 4 thrombocytopenia seen in the first cycle of treatment.  
 
FACT-Lym will be administered at baseline, on first day of each treatment cycle and at all 
followup visits in first year of followup. 
 
 
 
 


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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Phase I: 
1. To determine the maximum tolerated  dose (MTD)  of vorinostat given orally for 10 
days in combination with cyclophosphamide, etoposide, prednisone and rituximab for 
elderly patients with relapsed diffuse large B-cell lymphoma 
Phase II: 
1. To determine the complete response rate to rituximab and a combination of vorinostat 
with cyclophosphamide, etoposide, and prednisone in elderly patients with relapsed 
diffuse large B-cell lymphoma who are not candidates for autologous stem cell 
transplantation. 
2. To determine the overall response rate (complete and partial).  
3. To estimate the one-year progression-free and overall survival  
4. To estimate the quality of life for these patients at baseline, during and at completion of 
treatment.  
 
3.0 
BACKGROUND AND RATIONALE 
Diffuse large B-cell lymphoma comprises 30-40% of non-Hodgkin lymphomas in adults. The 
median age is in the seventh decade. Approximately 50% of newly-diagnosed patients ages 60 
years and older will achieve durable un-maintained remissions following treatment with 
rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone (R-CHOP)1. The standard 
treatment for relapsed and refractory patients is salvage chemotherapy and high-dose 
chemotherapy with peripheral stem cell support. This results in durable remissions in 
approximately 30-40% of patients2. Some patients in their 60s and most patients above age 70 
are not candidates for this type of program. These patients are treated for palliation and not with 
the goal of durable remissions or cures. There are few clinical trials that have addressed the 
treatment of this population of patients for whom tolerance of treatment and quality of life during 
treatment are as important issues as tumor response. Effective treatment of this population can 
thus be considered an unmet need and an opportunity for clinical research. 
 
A combination of cyclophosphamide, etoposide, procarbazine and prednisone (CEPP) is used by 
many clinicians for palliative treatment of relapsed DLBCL, although there is little published 
literature on its efficacy. An overall response rate of 77% (17/22) and CR rate of 36 % (8/22) 
was reported with CEPP in a small number of patients with recurrent diffuse large cell 
lymphoma3.  
 
Remission durations with salvage chemotherapy alone without consolidation autologous stem 
cell transplantation for relapsed and refractory aggressive lymphomas have been short. The 
median time to progression following CEPP was 7 months3. The median duration of response in 
a phase II trial in a similar patient population with a combination of pixantrone with 
cyclophosphamide, vincristine and prednisone was 10.3 months4. The one-year progression-free 
survival of patients with relapsed/refractory DLBCL treated with gemcitabine, cisplatin and 


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methylprednisolone (GEM-P) was 27%. The addition of rituximab to combination chemotherapy 
may increase remission duration. The one-year progression-free survival of patients treated with 
GEM-P with rituximab was 51%.Only a minority of these patients received consolidation 
autologous stem cell transplants5. 
  
Vorinostat or suberorylanilide hydroxamic acid (SAHA) was synthesized in the laboratory of Dr. 
Ronald Breslow at Columbia University and developed in the laboratory of Dr. Paul Marks at 
Memorial Sloan-Kettering Cancer Center. Vorinostat was approved by the US Food and Drug 
Administration (FDA) on 6-Oct-2006 for the treatment of cutaneous manifestations in patients 
with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease 
on or following two systemic therapies. Phase I studies demonstrated a signal of activity of the 
drug in patients with relapsed/refractory non-Hodgkin lymphomas. The proto-oncogene BCL-6, 
which is constitutively expressed in many B-cell lymphomas, suppresses genes involved in the 
control of lymphocyte activation, differentiation and apoptosis. Promotion of acetylation of 
BCL-6 by vorinostat could result in inactivation of this suppressive effect and reactivation of 
genes involved with these desirable cellular activities in the tumor cells6,7. A preclinical study 
demonstrated enhanced cell death with combination of vorinostat and etoposide in the MCF-7 
breast cancer cell line8.  
Convenience of drug dosing, tolerance of treatment and overall quality of life are important 
issues in the treatment of elderly patients with relapsed DLBCL. The Functional Assessment of 
Cancer Therapy-Lymphoma (FACT-Lym) is an instrument that has been recently developed for 
assessment of quality of life in patients receiving chemotherapy for lymphoma and is now 
available for clinical chemotherapy trials9. 
 
In this study, vorinostat, the novel oral histone deacetylase inhibitor, will be substituted for 
procarbazine in the CEPP regimen. Procarbazine is associated with significant toxicity including 
carcinogenesis in animal and in humans in the MOPP combination, nausea and vomiting, 
pancytopenia, neurologic symptoms including neuropathy and confusion, hypersensitivity 
reactions and stomatitis. The toxicity of vorinostat is described in Section 11.1. Rituximab, an 
important agent with little toxicity will also be added. Its toxicity is described in Section 11.3. 
 
Quality of Life Component 
 
Quality of life is an important consideration in the treatment of these patients with the most 
likely expectation of palliation rather than cure. With this goal, it is important that this regimen 
will be associated with reasonably mild side effects that will not severely affect comfort or 
ability to function. To measure quality of life in this study we will use the Functional Assessment 
of Cancer Therapy – Lymphoma (FACT-Lym) questionnaire. The FACT-Lym was developed as 
part of the FACIT Measurement System to meet the growing need for a disease-specific quality 
of life (QOL) questionnaire for patients with non-Hodgkin’s lymphoma10 (www.facit.org). .  The 
15-item Lymphoma subscale was constructed to complement the existing subscales of the 
FACT-G questionnaire11 . The FACT-Lym (FACT-G + lymphoma subscale) is formatted for 


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self-administration and utilizes a 5-point Likert rating scales (0= Not at all; 1= A little bit; 2= 
Somewhat; 3= Quite a bit; 4= Very Much). Subscale scores are calculated by reversing 
negatively stated items and then summing individual item scores. A total score is derived by 
summing subscale scores. A Trial Outcome Index (TOI) can be calculated by summing the 
PWB, FWB, and Lymphoma subscale scores. The TOI is an efficient summary index of 
physical/functional outcomes and a common endpoint used in clinical trials because it is 
responsive to change in physical/functional outcomes, sometimes more than a total (overall) 
multidimensional aggregated score that includes social and emotional well-being. 
 
The FACT-Lymphoma was developed with input from experts and the literature. An extensive 
item-generation and scale construction process generated 176 candidate items from interviews 
and item ratings on frequency and relevancy from 17 expert healthcare providers and the 
published literature describing quality of life in NHL. Data summaries, including median NHL 
symptom relevancy ratings ≥ 2, disease-specificity, and clinical relevance were used to support 
retention of 22 items for testing. Cognitive debriefing with 75 NHL patients ensured content 
validity of the final scale 9,12. 
 
The 22-item subscale was validated on a sample of 84 NHL patients. Patients completed the 
FACT-Lym and other measures at baseline (T1), 3-7 days (T2), and 8-12 weeks (T3).   Item 
correlations, expert relevancy ratings, and patient input on content helped shorten the lymphoma 
subscale from 22 to 15 items. Patient interviews confirmed item relevance and 
comprehensiveness. The validation sample included 44% male, 60% with indolent disease, and 
85% currently receiving treatment. Internal consistency coefficients (alpha) for the 15-item 
subscale (.79, .85, .84) and test-retest stability (.84) indicate good reliability at each assessment. 
Correlations between the subscale and the SF-36 physical (r=.62) and mental (r=.48) summary 
scores reflect concurrent validity. Responsiveness to ECOG performance status rating and 
treatment status (on vs. off) equaled or exceeded that of the more established FACT subscale 
scores. From T1 to T3, subscale scores declined (-6.8, effect size= -0.87) in 14 patients who 
reported themselves as worsened, increased (4.5, effect size= 0.58) in 35 patients who reported 
themselves as improved, and did not change (-0.1, effect size= -0.01) in 21 patients who reported 
themselves as unchanged9,12. These results support the validity of the lymphoma subscale and 
suggest that it will be a useful targeted endpoint in trials where lymphoma-specific concerns are 
paramount. 
 
Global Rating of Change Scale (adapted from Jaeschke et al, 1989):   
The global rating of change scale (GRC) is a patient-reported measure used as the criterion 
against which actual change scores could be compared and calibrated.  To align GRC ratings to 
the subscales of the FACT-Lym, each FACT dimension (PWB, SWB, EWB, FWB, the 
“additional concerns”, and total HRQL) was briefly summarized, and then patients rated whether 
they experienced no change, a worsening, or an improvement in that area.  If they experienced a 
worsening or improvement, they rated the degree of change on a 7 point scale ranging from –3 (a 
great deal worse) through 0 (no change) to +3 (a great deal better).  Patients will complete this at 
every first year visit other than baseline. 


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3.1 
VORINOSTAT 
3.1.1 Histone deacetylases and HDAC Inhibitors 
 
Histone deacetylases (HDAC) are enzymes that catalyze the removal of acetyl groups from the 
lysine residues of proteins, including histones and transcription factors.  HDAC inhibitors can 
induce tumor cell growth arrest, differentiation, or apoptosis in vitro and inhibit tumor growth in 
animals13,14.  The transcription of genes is regulated at least in part by acetylation of nucleosomal 
histones15.  The core nucleosomal histones are the most widely studied of the proteins that 
become acetylated following inhibition of HDAC activity15.  In some cancer cells, there is an 
over expression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription 
factors causing hypo acetylation of core nucleosomal histones.  Hypo acetylation of histones is 
associated with a condensed chromatin structure and repression of gene transcription.  Inhibition 
of HDAC activity allows for the accumulation of acetyl groups on the histone lysine residues 
resulting in an open chromatin structure and transcriptional activation. 
3.1.2  Mechanism of Action of Vorinostat 
Vorinostat is a potent inhibitor of HDAC activity and binds directly to the catalytic pocket of 
HDAC enzymes.  Vorinostat, at low nanomolar concentrations, inhibits the enzymatic activity of 
HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II)14,16,17. Concentrations of 
vorinostat that cause the accumulation of acetylated histones also induces cell cycle arrest, 
differentiation or apoptosis of transformed cells16. 
Vorinostat induces apoptosis in a wide variety of transformed cells in culture, including 
cutaneous T-cell lymphoma (CTCL) cell lines, circulating atypical T-cells derived from patients 
with CTCL, human lymphoma cell lines and murine erythroleukemia (MEL) cells.  Vorinostat 
also inhibits proliferation of cultured transformed human cells derived from leukemias, non-
small cell lung carcinomas, colon carcinomas, central nervous system tumors, melanomas, 
ovarian carcinomas, renal cell carcinomas, prostate and breast cancers.   In cultured human 
transformed cell lines, vorinostat has synergistic or additive activity in combination with other 
cancer therapies, including radiation, kinase inhibitors, cytotoxic agents and differentiating 
agents16,18-24 . 
In vivo, vorinostat demonstrates anti-neoplastic activity in a variety of rodent tumor models 
including xenograft models of human prostate, breast and colon carcinoma. 
While it has been assumed that the effects of vorinostat on histone acetylation underpin its 
biological activities, a number of other proteins are regulated by histone acetyltransferases 
(HATs) and HDACs and may be targeted by vorinostat25. Several non-histone proteins, (e.g., 
tubulin, Hsp90 and p53) are known to be reversibly acetylated on lysine residues and undergo 
hyper acetylation following exposure to vorinostat26-28. Acetylation of these proteins may also 
contribute to the antitumor activity of vorinostat. 


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Please refer to the vorinostat Confidential Investigator’s Brochure (CIB) for detailed 
information. 
3.1.3 Non Clinical Pharmacology of Vorinostat 
 
Vorinostat is approximately 71% bound to human plasma proteins over the range of 
concentrations of 0.5 to 50 µg/mL. 
Vorinostat has a low propensity to cause or be affected by drug-drug interactions.  In animal 
models and in vitro human systems, the major pathways of metabolism of vorinostat involve 
glucuronidation and hydrolysis followed by β-oxidation.  Additionally, the glucuronidation of 
vorinostat is mediated by multiple uridine diphosphate glucuronosyltransferase isozymes 
(UGTs), making it less susceptible to drug interactions through modulation of UGTs. Vorinostat 
is not recovered intact in urine to any appreciable extent.  Therefore, compounds known to affect 
renal elimination are not expected to affect the pharmacokinetics of vorinostat. 
Vorinostat is not an inhibitor of CYP drug metabolizing enzymes in human liver microsomes at 
steady state Cmax of the 400 mg dose (Cmax of 1.2 µM vs. IC50 of  >75 µM). Gene expression 
studies in human hepatocytes detected some potential for suppression of CYP2C9 and CYP3A4 
activities by vorinostat at concentrations higher (≥ 10 µM) than pharmacologically relevant. 
Thus, vorinostat is not expected to affect the pharmacokinetics of other agents metabolized by 
CYP enzymes. As vorinostat is not eliminated via the CYP pathways, it is anticipated that 
vorinostat will not be subject to drug-drug interactions when co-administered with drugs that are 
known CYP inhibitors or inducers. However, no formal clinical studies have been conducted to 
evaluate drug interactions with vorinostat.  
Please refer to the vorinostat CIB for detailed information. 
3.1.4  Non Clinical Toxicology of Vorinostat 
 
Vorinostat has been investigated in non-clinical acute and oral repeated-dose toxicity studies, 
reproductive, developmental toxicity studies, and genetic toxicity studies to support oral 
administration of this compound to humans.  
The main toxicities observed in animal models were weight loss and inappetence, apparent 
hemolytic anemia (rats only at 3.8 times the equivalent 400 mg human dose), leukopenia (rats 
only at 1.3 times the equivalent 400 mg human dose), thrombocytopenia (male rats only, 
statistically significant change at 0.5 times the equivalent 400 mg clinically effective human 
dose, but within normal range at all doses), and gastrointestinal tract irritation (dogs only, at 8.5 
times the equivalent 400 mg human dose). Although statistically significant and dose-dependent, 
many of the clinical pathology findings were within normal historical ranges indicating that they 
should not have major toxicological consequences. The toxicities appeared to be rapidly 
reversible within 12 to 14 days. There has been no evidence of cardiac toxicity based on 


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electrocardiogram (ECG, dogs only), blood pressure (dogs only), heart rate (dogs only), 
creatinine kinase, organ weight, gross pathology, or histopathology assessments in studies up to 
one month duration. No serious, irreversible damage to any vital organ has been observed. 
Importantly, toxicities in rats and dogs were predictive of adverse effects in humans (anorexia, 
weight loss, fatigue). Toxicities present in animals would be manageable in the clinic, and the 
onset of serious toxicity is readily forecast by prodromal symptoms. The non clinical toxicity 
profile of vorinostat is acceptable for an oncology drug. 
Vorinostat rapidly crossed the placenta in both the rat and rabbit, following administration of a 
dose of 15 mg/kg/day and 150 mg/kg/day, respectively (<1 times the human exposure based on 
AUC0-24) and reached transplacental equilibrium within 30 minutes post-dose. 
Vorinostat was evaluated in a panel of genetic toxicity assays; in vivo and in vitro assays were 
found to be positive. No human safety data for the use of vorinostat during pregnancy are 
available.  
Please refer to the vorinostat CIB for detailed information. 
3.1.5. Clinical Pharmacokinetics of Vorinostat  
 
The pharmacokinetics of vorinostat following 400-mg single-dose in a fasted state; and 400 mg 
single- and multiple-doses in a fed (high-fat meal) state were evaluated in 23 patients in a Phase I 
study with relapsed or refractory advanced cancer using a validated assay. See Table A. 


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Table A 
PK Parameters of vorinostat following oral administration of single or multiple 
doses of 400 mg 
 
400 mg single-dose 
Fasted 
400 mg single-dose 
fed 
400 mg q.d. 
multiple-dose fed 
AUC0-∞, uM·hr‡ 
3.87 
5.33 
6.46 
Cmax, uM‡ 
1.12 
1.02 
1.13 
T max, hr#  
1.50 
4.00 
4.21 
Apparent t1/2, hr†† 
1.74 
1.44 
1.34 
‡ Geometric mean 
#Median 
†† Harmonic mean 
 
Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose 
recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the 
elimination of vorinostat. Recovery of two pharmacologically inactive metabolites, 
O-glucuronide of vorinostat (OG-V) and 4-anilino-4-oxobutanoic acid (4A4OA), in urine was 
more substantial.  
Please refer to the vorinostat CIB for detailed information. 
3.1.6 Summary of Clinical Experience with Vorinostat  
Vorinostat has been studied in Merck Research Labs (MRL) sponsored studies, Investigator 
Initiated Study Protocols (IISP) and National Cancer Institute (NCI) sponsored studies.  
Vorinostat has been orally administered in Phase I, Phase II and Phase III clinical studies in 
patients with advanced solid tumors and hematologic malignancies. Vorinostat has been studied 
both alone and in combination with other chemotherapy agents.   
Please refer to the vorinostat CIB for detailed information 
3.1.7 Safety of Vorinostat   
The types of adverse experiences observed in clinical trials of vorinostat were those usually 
associated with chemotherapy.  The most common drug-related adverse experiences in patients 
treated with vorinostat could be classified into four symptom complexes: gastrointestinal 
symptoms (diarrhea, nausea, anorexia, weight decrease, vomiting, and constipation), 
constitutional symptoms (fatigue, chills), hematologic abnormalities (thrombocytopenia, anemia) 
and taste disorders (dysgeusia, dry mouth). Most of the adverse experiences were manageable. In 
fact, most of the very common adverse experiences were reversible and could be managed using 
conventional supportive care for chemotherapy. Overall, treatment with oral vorinostat was well 
tolerated. 


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Adverse experiences considered by the Investigators to be at least possibly related to vorinostat 
in ≥10 % of patients across all Merck & Co., Inc. sponsored vorinostat clinical studies include 
(in descending frequency): fatigue, nausea, diarrhea, anorexia, vomiting, blood creatinine 
increased, hyperglycemia, weight decreased, thrombocytopenia, dysgeusia, constipation, 
dehydration, hemoglobin decreased, platelet count decreased, anemia, hypocalcemia, alanine 
aminotransferase increased, white blood cell count decreased, dyspnea, hyponatremia, aspartate 
aminotransferase increased, hypokalemia, dry mouth, alopecia, and muscle spasms. 
The tolerability of vorinostat appears to be determined by total daily dose, frequency and the 
number of consecutive days of dosing.  The results of an initial Phase I study of vorinostat in 
patients with advanced solid tumors and hematologic malignancies determined that the 
maximum tolerated dose (MTD) for continuous daily dosing without a rest period is 400 mg 
daily (q.d.) or 200 mg twice daily (b.i.d.). The MTD for intermittent dosing has been established 
as 300 mg b.i.d. x 3 consecutive days per week, or 250 mg 3 times daily (t.i.d.) x 14 consecutive 
days followed by a 7-day rest period29.  Therefore, the maximum tolerable total daily dose may 
range as high as 750 mg (250 mg P.O. t.i.d.) x 14 consecutive days followed by a 7-day rest 
period rather than 400 mg (given as q.d. or 200 mg b.i.d.) with continuous daily dosing or 600 
mg when given as 300 mg b.i.d. for 3 consecutive days each week followed by a 4-day rest 
period. In a Phase I study in Japanese patients with solid tumors, MTD was established as 200 
mg b.i.d. and 500 mg q.d. for 14 consecutive days followed by a 7-day rest. 
Dose-limiting toxicities (DLTs) have been mainly non-hematologic.  The majority of these DLTs 
occurred within the first month on vorinostat.  At continuous daily dosing of 600 mg q.d., 300 
mg b.i.d., and 400 mg b.i.d., doses that exceeded the established MTD, the pattern and severity 
of DLTs were similar.  The DLTs were manageable because these toxicities resolved quickly 
after drug administration was interrupted. Hematologic events were primarily anemia, 
leukopenia, and thrombocytopenia. Generally, these events were rapidly reversible after study 
drug interruption. 
Serious clinical adverse experiences (SAEs) regardless of causality have been reported in 
approximately 39% of the first 350 patients treated with vorinostat in Merck & Co., Inc. 
sponsored studies.  This overall high incidence may reflect the underlying conditions of patients 
in this group.  Of the patients who had a serious adverse experience, approximately 16% were 
considered by the Investigator to be related to study medication.  Serious laboratory adverse 
experiences were uncommon, occurring in 3% or fewer of patients in the various populations. By 
contrast, to patients with solid tumors, the incidence of serious adverse experiences was higher in 
patients with hematologic malignancies.  
Pulmonary embolism and deep vein thrombosis have been reported.   
QT prolongation has been observed.   
 
Please refer to the vorinostat CIB and ZOLINZA™ (vorinostat) package insert in Attachments 
for additional information. 


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3.1.8. Efficacy of Vorinostat (See Appendix VI) 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a phase I/II, open-label, single arm trial. The goals are to determine the optimal dose of 
vorinostat when given in combination to rituximab, cyclophosphamide, etoposide and 
prednisone. In addition, we hypothesize that this regimen will  increase the response rate and one 
-year progression free survival for elderly patients with relapsed or refractory DLBCL who are 
not candidates for autologous stem cell transplantation with the addition of a new 
chemotherapeutic agent, vorinostat, to rituximab, cyclophosphamide, etoposide and prednisone. 
As this is a palliative regimen, quality of life measurements will be another important endpoint. 
 
Rituximab 375 mg/m2  intravenously day one. Cyclophosphamide 600 mg/m2 intravenously days 
1 and 8, etoposide 70 mg/m2 day 1 intravenously, then 140 mg/m2 days 2 and 3 orally, vorinostat 
orally days 1-10 (see below), prednisone 60 mg/m2 days 1-10. The regimen will be repeated 
every 4 weeks for 6 cycles unless there is disease progression or intolerance of the regimen due 
to toxicity. 
 
Drug 
Day 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Ritux. 
(IV) 
375 
mg/m2 
 
 
 
 
 
 
 
 
 
CTX 
(IV) 
600 
mg/m2 
 
 
 
 
 
 
600 
mg/m2 
 
 
Vorin. 
(PO) 
See 
below 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pred. 
(PO) 
60 
mg/m2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etop. 
70 
mg/m2 
(IV) 
140 
mg/m2 
(PO) 
140 
mg/m2 
(PO) 
 
 
 
 
 
 
 
 
 
The starting dose of vorinostat will be 300 mg orally days 1-10. All other agents will be held 
constant at the above doses. Three patients will be enrolled at this dose. If 0/3 experience DLT 
then the dose will be increased to 400 mg orally days 1-10. If 1/3 patient experiences a DLT then 
3 more patients will be added at the 300 mg dose. If ≥2 patients experience DLT at 300 mg, the 
trial will be discontinued because of excessive toxicity. If ≤1 out of 6 patients experience a DLT 
at 300 mg then we will escalate to 400 mg and follow the same scheme. If 2 or more experience 
a DLT at 400 mg and only 3 patients were treated at 300 mg, then we will de-escalate to 300 mg 


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and 3 additional patients will be added. If ≤1 out of 6 patients experience a DLT at 400 mg, then 
400 mg will be the MTD for the Phase II part of the study. DLT is defined as any grade 3 or 4 
non-hematological toxicity or grade 4 thrombocytopenia seen in the first cycle of treatment.  
Once the patient has been assigned a dose level, that dose will not change for that patient’s 
treatment on protocol. If another cohort is opened, new patients may be accrued to a new dose 
level. However, previous patients will remain at their assigned dose level. 
 
Growth factor support will start on day 11 (+/- 2 days) with either peg-filgrastim or filgrastim for 
at least 5 days. On day 1 of each cycle, drugs will be held for at least 1 week if absolute 
neutrophil count <1000 /mm, platelet count < 50000/mm or for any other non-hematological 
grade 3 or 4 toxicity. On day 8 of each cycle, vorinostat will be discontinued and the 
cyclophosphamide dose held for 1 week if absolute neutrophil count <1000 /mm, platelet count < 
50000/mm or for any other non-hematological grade 3 or 4 toxicity. The subsequent cycle will 
begin 3 weeks after the second cyclophosphamide dose. In the phase II portion, the following 
dose modifications will be permitted if patients require admission for fever and with or without 
documented infection in the previous cycle of chemotherapy: reduction of cyclophosphamide 
dose by 25% on days 1 and 8 and omission of oral etoposide in subsequent cycles.If delays 
greater than 1 week are required, the Principal Investigator should be notified. 
 
FACT-Lym will be administered at baseline, on first day of each treatment cycle and at all 
followup visits in first year of followup. 
 
Estimated duration of accrual: 
Three years 
4.2 
Intervention 
Patients will be treated with 6 cycles of rituximab, cyclophosphamide, etopside, prednisone and 
vorinostat every 4 weeks. Quality of life determinations will be obtained at the beginning of each 
cycle of chemotherapy and at each visit during the first year of followup. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
All agents are FDA approved. Vorinostat is approved for treatment of cutaneous T-cell 
lymphoma. Vorinostat will be supplied by the manufacturer for this trial at no cost to the 
patients. 
 
Product Description of Vorinostat 
Vorinostat (N-hydroxy-N’-phenyl-octane-1, 8-diotic acid diamide, N hydroxy-N’-phenyl (9CI) 
octane diamide, suberoylanilide hydroxamic acid, also known as SAHA, or MK-0683), is an 
orally available HDAC inhibitor.  The physical and chemical properties of vorinostat are listed in 
Table 4. 


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Table B 
 
Properties of Vorinostat 
 
Molecular Formula 
C14H20N2O3 
Molecular Weight 
264.32 
Physical Appearance 
White to light orange powder 
Solubility 
Water (pH = 11.2) ≤5 mg/mL 
Moisture (Karl Fischer) 
≤1% 
Melting Point 
159.5 to 160.5oC 
pKa 
8.5 and 11.1 
Hygroscopicity 
None 
Hydrates 
None 
Chirality 
None 
 
The oral formulation of vorinostat is available as a 100-mg capsule.  Earlier studies of vorinostat 
were performed with formulation strengths of 50 mg and 200 mg.  Currently no additional dose 
images other that the 100 mg strength is manufactured.  Each 100 mg vorinostat capsule for oral 
administration contains 100 mg vorinostat and the following inactive ingredients: 
microcrystalline cellulose, sodium croscarmellose and magnesium stearate. The capsule shell 
excipients are titanium dioxide, gelatin and may contain sodium lauryl sulfate. 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
1. MSKCC or Weill Cornell biopsy confirmation of relapsed/refractory diffuse large B-cell 
lymphoma. Patients with large cell transformation of a low-grade B-cell lymphoma will 
be eligible.  
 
2. One or two prior chemotherapy regimens not including autologous stem cell 
transplantation. 
 
3. Age ≥ 60 years. 
 
4. Not a candidate for autologous stem cell transplantation. 
 
5. Patient must have performance status of ≤2 on the ECOG Performance Scale. 
 
6. Measurable disease (see Section 12). 
 
 
 


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7. Adequate organ and bone marrow function: ANC ≥ 1000/mm3, platelet count ≥ 
50,000/mm3, total bilirubin ≤ 1.5 ULN (with exception of Gilbert’s disease), AST/ALT 
≤ 2.5 ULN, creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 ml/min, potassium and 
magnesium within normal limits. 
 
8. Male patients agree to use an adequate method of contraception for the duration of the 
study.  
9. Patient is available for periodic blood sampling, study related assessments, and 
management at the treating institution for the duration of the study. 
 
6.2 
Subject Exclusion Criteria 
1. Patient who has had chemotherapy, radiotherapy, or biological therapy [including growth 
factors],  within 30 days (42 days for nitrosoureas or mitomycin C) prior to initial dosing 
with study drug(s) or who has not recovered from adverse events due to agents 
administered more than 30 days earlier. Patients on a stable dose of steroids for at least 4 
weeks prior to onset of study therapy may be included. 
2. Patient is currently participating or has participated in a study with an investigational 
compound or device within 30 days of initial dosing with study drug(s). 
3. Patient had prior treatment with an HDAC inhibitor (e.g., romidespin (Depsipeptide), 
NSC-630176, MS 275, LAQ-824, belinostat (PXD-101), LBH589, MGCD0103, 
CRA024781, etc).  Patients who have received compounds with HDAC inhibitor-like 
activity, such as valproic acid, as anti-tumor therapy should not enroll in this study.  
Patients who have received such compounds for other indications, e.g. valproic acid for 
epilepsy, may enroll after a 30-day washout period. 
4. Patients with active CNS lymphoma and/or lymphomatous meningitis are excluded.  
However, patients with a history of CNS lymphoma and/or lymphomatous meningitis 
who have been stable without evidence of CNS and/or leptomeningeal recurrence would 
be eligible. They must be off steroids or on a stable dose of steroids. 
   
5. Patient with a primary central nervous system lymphoma.  
6. Patient has known hypersensitivity to the components of study drug or its analogs. 
7. Patient has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.   
8. Patient is, at the time of signing informed consent, a regular user (including “recreational 
use”) of any illicit drugs, substance abuse or had a recent history (within the last year) of 
drug or alcohol abuse. 


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9. Patient is expecting to father children within the projected duration of the study. 
10. Patient has uncontrolled intercurrent illness or circumstances that could limit compliance 
with the study, including, but not limited to the following: active infection, acute or 
chronic graft versus host disease, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric conditions. 
11. Patient has a history or current evidence of any condition, therapy, or lab abnormality that 
might confound the results of the study, interfere with the patient's participation for the 
full duration of the study or is not in the best interest of the patient to participate. 
12. Patient has a history of a gastrointestinal surgery or other procedures that might, in the 
opinion of the investigator, interfere with the absorption or swallowing of the study 
drugs. 
13. Patient with a "currently active" second malignancy, other than non-melanoma skin 
cancer and carcinoma in situ of the cervix, should not be enrolled. Patients are not 
considered to have a "currently active" malignancy if they have completed therapy for a 
prior malignancy, are disease free from prior malignancies for >5 years or are considered 
by their physician to be at less than 30% risk of relapse. 
14. Patient is HIV +. 
15. Patient has active hepatitis B or C. 
 
7.0 
RECRUITMENT PLAN 
The trial will require 59 patients to meet study endpoints.  5 patients will be enrolled at Weill 
Cornell Medical College and 54 at Memorial Sloan-Kettering Cancer Center (MSKCC).  With 
the targeted monthly accrual of 1-2 patients, this study will require about 3 years to complete 
accrual.  
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or the research team at Memorial Sloan-Kettering Cancer Center 
(MSKCC) or Weill Cornell Medical College.  If the investigator is a member of the treatment 
team, s/he will screen their patient’s medical records for suitable research study participants and 
discuss the study and their potential for enrolling in the research study.  Potential subjects 
contacted by their treating physician will be referred to the investigator/research staff of the 
study. 
 


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8.0 
PRETREATMENT EVALUATION  (APPENDIX 1) 
1. History and physical exam including tumor measurements at the time of each visit (days 1 
and 8 of every 28 day cycle). 
2. CT scan of chest, abdomen and pelvis with oral and IV contrast unless there are allergic 
contraindications to IV contrast. CT scan with oral contrast only will then be permitted. 
Study should be performed within 6 weeks prior to study entry 
3. PET scan. Study should be performed within 6 weeks prior to study entry 
4. Bone marrow biopsy (unilateral permitted). 
5. CBC, WBC differential count, platelet count, creatinine, BUN, AST/ALT, calcium, 
electrolytes, uric acid, LDH, total bilirubin, alkaline phosphatase within 7 days prior to study 
entry, HIV I/II antibodies, Hep B surface antigen profile, Hep B core AB profile, Hep B 
surface antibody, Hep C antibody profile 
6. Urinanalysis within 7 days prior to study entry. 
7. FACT-Lym questionnaire within 7 days prior to study entry. 
8. Electrocardiogram (EKG) within 7 days prior to study entry.  
9. Serum pregnancy test (β-hCG) within 72 hours prior to receiving the first dose of vorinostat 
 
9.0 
TREATMENT/INTERVENTION PLAN 
Rituximab 375 mg/m2  intravenously day 1. Cyclophosphamide 600 mg/m2 intravenously days 1 
and 8, etoposide 70 mg/m2 day 1 intravenously, then 140 mg/m2 days 2 and 3 orally, vorinostat 
orally days 1-10 (see below), prednisone 60 mg/m2 days 1-10. The regimen will be repeated 
every 4 weeks for 6 cycles unless there is disease progression or intolerance of the regimen due 
to toxicity. 
 
Phase I: 
The starting dose of vorinostat will be 300 mg orally days 1-10. All other agents will be held 
constant at the above doses. Three patients will be enrolled at this dose. If 0/3 experience DLT 
then the dose will be increased to 400 mg orally days 1-10. If 1/3 patient experiences a DLT then 
3 more patients will be added at the 300 mg dose. If ≥ 2 patients experience DLT at 300 mg, the 
trial will be discontinued because of excessive toxicity. If ≤ 1 out of 6 patients experience a DLT 
at 300 mg then we will escalate to 400 mg and follow the same scheme. If 2 or more experience 
a DLT at 400 mg and only 3 patients were treated at 300 mg, then we will de-escalate to 300 mg 
and 3 additional patients will be added. If ≤1 out of 6 patients experience a DLT at 400 mg, then 
400 mg will be the MTD for the Phase II part of the study. DLT is defined as any grade 3 or 4 
non-hematological toxicity or grade 4 thrombocytopenia seen in the first cycle of treatment.  
 
Phase II: 
Chemotherapy will be administered in the doses and schedule above with the MTD for vorinostat 
that is determined in the Phase I portion of the trial.  
 


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Growth factor support will start on day 11 (+/- 2 days) with either peg-filgrastim or filgrastim for 
at least 5 days. On day 1 of each cycle, drugs will be held for at least 1 week if absolute 
neutrophil count <1000 /mm, platelet count < 50000/mm or for any other non-hematological 
grade 3 or 4 toxicity. On day 8 of each cycle, vorinostat will be discontinued and the 
cyclophosphamide dose held for 1 week if absolute neutrophil count <1000 /mm, platelet count < 
50000/mm or for any other non-hematological grade 3 or 4 toxicity. The subsequent cycle will 
begin 3 weeks after the second cyclophosphamide dose. In the phase II portion, the following 
dose modifications will be permitted if patients require admission for fever and with or without 
documented infection in the previous cycle of chemotherapy: reduction of cyclophosphamide 
dose by 25% on days 1 and 8 and omission of oral etoposide in subsequent cycles.  If delays 
greater than 1 week are required, the Principal Investigator should be notified. 
 
FACT-Lym will be administered at baseline and on first day of each treatment cycle and at all 
followup visits in first year of followup. The Patient Global Rating of Change will be 
administered at all assessments other than baseline, anchoring patient ratings to the previous visit 
in that first year. 
 
Adverse experiences will be graded and recorded throughout the study according to NCI-
CTCAE, version 3.0.  Toxicities will be characterized in terms including duration, intensity, and 
time to onset. 
9.1 Concomitant and Prohibited Medications/Treatments 
The major pathway(s) for metabolism of vorinostat involves glucuronidation and 
hydrolysis followed by β-oxidation. Therefore, it is anticipated that vorinostat will not be 
subject to drug-drug interactions when co-administered with drugs that are known to be 
CYP enzyme inhibitors.  Formal drug-drug interaction studies have not been performed 
with vorinostat.  All concomitant medications received within 14 days before the first 
dose of study medication and 30 days after the last dose of study medication must be 
recorded in the source document and on the case report form. 
The concomitant use of other medications/therapies is allowed unless specifically 
prohibited in the protocol.  Patients should be stabilized prior to study entry on all 
medications.   
• Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) have 
been observed in patients receiving vorinostat concomitantly with coumarin-derivative 
anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently 
administered vorinostat and coumarin derivatives.  
• Patients may not receive chemotherapy, radiotherapy, biological therapy or 
investigational anticancer therapy during the study. Patients who require these therapies 
should be considered to have progressive disease and be withdrawn from the study.   


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• Vorinostat should not be administered concomitantly with other HDAC inhibitors (e.g., 
valproic acid) as class-specific adverse reactions may be additive.   
9.2 Diet 
Vorinostat should be taken approximately 30 minutes after a meal whenever possible. 
Altered taste and decreased food and liquid intake are associated with vorinostat 
administration.  These toxicities can be actively managed with fluid management and 
nutritional consult.   
During the period of vorinostat administration, patients should consume at least 2 liters of 
fluid orally, daily, to prevent dehydration.  Patient may require electrolyte replacement.  
If  patients are experiencing dysgeusia, popsicles or Gatorade may be successful in 
maintaining oral intake.  Early use of anti-emetics should be encouraged. 
 
 
9.3 Supportive Care Guidelines  
 
Supportive treatment may include anti-emetics, antidiarrheal medications, anti-pyretics, 
anti-histamines, analgesics, antibiotics, and others, such as blood products.  Patients who 
experience indigestion or gastroesophageal reflux symptoms on vorinostat may be treated 
with Proton Pump Inhibitors (PPIs) as well as H2 blockers as clinically indicated. 
Growth factor support will start on day 11 with either peg-filgrastim or filgrastim for at 
least 5 days. On day 1 or 8 of each cycle, drugs will be held for at least 1 week if absolute 
neutrophil count <1000 /mm, platelet count < 50000/mm or for any grade 3 or 4 toxicity. 
Patients will be permitted to receive appropriate supportive care measures as deemed 
necessary by the treating physician including but not limited to the items outlined below:   
• Diarrhea: Diarrhea should be treated promptly with appropriate supportive care, 
including loperamide.  Loperamide should not be taken prophylactically. Patients should 
be instructed to begin taking loperamide at the first sign of: 1) poorly formed or loose 
stool, 2) occurrence of more bowel movements than usual in one day or 3) unusually high 
volume of stool.  Loperamide should be taken in the following manner: 4 mg at first 
onset of diarrhea, then 2 mg after each unformed stool.  The daily dose of loperamide 
should not exceed 16 mg/day.  Loperamide should be deferred if blood or mucus is 
present in the stool or if diarrhea is accompanied by fever. In this setting, appropriate 
diagnostic microbiologic specimens should be obtained to exclude an infectious etiology. 
Patients should also be advised to drink liberal quantities of clear fluids as detailed in 
Section [3.2.X] to help prevent dehydration.   
 
 


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• Nausea/vomiting:  Nausea and vomiting should be treated aggressively, and strong 
consideration should be given to the administration of prophylactic antiemetic therapy 
according to standard institutional practice. In particular, the use of antiemetics including 
5HT3 antagonists and/or a prepatent plus dexamethasone is encouraged. Patients should 
be strongly encouraged to maintain liberal oral fluid intake (as detailed in Section 
[3.2.X]) during therapy, especially during the initial 14 days of each treatment cycle. 
• Anemia: Treatment with vorinostat can cause dose-related anemia. If appropriate, the 
dose of vorinostat may be modified or therapy discontinued.  (see Section 9 for dose 
modification guidelines). Transfusions [and/or erythropoietin if not AML/MDS] may be 
utilized as clinically indicated for the treatment of anemia, but should be clearly noted as 
concurrent medications. 
• Thrombocytopenia: 
Treatment 
with 
vorinostat 
can 
cause 
dose-related 
thrombocytopenia. If platelet counts are reduced during treatment with vorinostat, the 
vorinostat dose may be modified or therapy discontinued.  Transfusion of platelets may 
be used if clinically indicated.  
• Neutropenia: Prophylactic use of colony-stimulating factors including G-CSF, pegylated 
G-CSF or GM-CSF should not be utilized during the first cycle of therapy. These factors 
may be utilized if clinically indicated in subsequent cycles as outlined in the guidelines 
for dose modification (see Section 9). 
• Hyperglycemia has been observed in patients receiving vorinostat.  Serum glucose 
should be monitored.  Adjustment of diet and/or anti-hyperglycemic therapy may be 
necessary.  
• Hypokalemia or hypomagnesemia should be corrected prior to administration of 
vorinostat, and consideration should be given to monitoring potassium and magnesium in 
symptomatic patients (e.g. patients with nausea, vomiting, diarrhea, fluid imbalance or 
cardiac symptoms.) 
• Pulmonary embolism and deep vein thrombosis have been reported.  Investigators 
should be alert to the signs and symptoms of these events.  Physicians should be alert to 
the signs and symptoms of these events, particularly in patients with a prior history of 
thromboembolic events. If a pulmonary embolism is documented, subsequent vorinostat 
doses should not be administered, and the Principal Investigator should be notified. 
• QTc prolongation has been observed.  Baseline and periodic ECGs should be performed 
during treatment.  Vorinostat should be administered with particular caution in patients 
with congenital long QT syndrome and patients taking anti-arrhythmic medicines or other 
medicinal products that lead to QT prolongation.  If significant new QTc prolongation is 


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observed, subsequent vorinostat doses should not be administered, and the Principal 
Investigator should be notified. 
For information regarding vorinostat use, please refer to the vorinostat label.  
10.0 EVALUATION DURING TREATMENT/INTERVENTION (APPENDIX 1) 
1. History and physical examination including tumor measurements every 4 weeks. 
2. Toxicity and FACT-Lym assessment every 4 weeks. Adverse experiences will be 
evaluated according to criteria outlined in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 3.0.    
3. CBC and platelet count on days 1 and 8 of every 28-day cycle. 
4. Creatinine, BUN, AST/ALT, calcium, electrolytes, uric acid, LDH, total bilirubin, 
alkaline phosphatase on day 1 of every 28-day cycle. 
5. CT scan of chest abdomen and pelvis at the end of cycle 4 and cycle 6.  
6. PET scan at the end of cycle 6. 
7. End of Cycle 6 (+/- 1 week): History and physical examination including tumor 
measurements, Toxicity,  FACT-Lym assessment, Global rating of Change assessment, 
CBC, Creatinine, BUN, AST/ALT, calcium, electrolytes, uric acid, LDH, total bilirubin, 
alkaline phosphatase.  Bone marrow biopsy (if bone marrow involved prior to treatment) 
at completion of treatment.. 
8. FACT-Lym will be administered at baseline, on first day of each treatment cycle and at 
all followup visits in first year of follow up. The Global rating of Change will be 
administered at all first year visits other than baseline, and each rating will be anchored to 
the previous assessment. 
9. Patients will be followed for five years after completing treatment or until relapse. 
Followup visits will include CBC, chemistry studies including serum LDH, and CT scans 
of the chest, abdomen and pelvis. FACT-Lym will be administered during followup visits 
during the first year. Starting from the End of Cycle 6 visit, the frequency of visits will be 
every 3 months (year 1), every 4 months (years 2 and 3) and every 6 months (years 5). 
Annual telephone calls will be made to patients who are not continuing in followup with 
the treating physician after 5 years to check on their health status. 
11.0 TOXICITIES/SIDE EFFECTS 
Toxicity will be described according the NCI Common Toxicity Criteria (Version 3.0). Doses of 
vorinostat will be either 300 mg or 400 mg daily according to a dose escalation/de-escalation 
scheme described in Section 9.0. Dose and schedule adjustments for the other agents will also be 
made according to the scheme described in Section 9.0. 
 
11.1 
Vorinostat 
 
Adverse experiences (Section 9.3) considered by the Investigators to be at least possibly related 
to vorinostat in ≥10 % of patients across all Merck & Co., Inc. sponsored vorinostat clinical 
studies include (in descending frequency): fatigue, nausea, diarrhea, anorexia, vomiting, blood 


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creatinine increased, hyperglycemia, weight decreased, thrombocytopenia, dysgeusia, 
constipation, dehydration, hemoglobin decreased, platelet count decreased, anemia, 
hypocalcemia, alanine aminotransferase increased, white blood cell count decreased, dyspnea, 
hyponatremia, aspartate aminotransferase increased, hypokalemia, dry mouth, alopecia, and 
muscle spasms. 
Pregnancy and Contraception 
Vorinostat can cause fetal harm when administered to a pregnant woman. There are no adequate 
and well-controlled studies of vorinostat in pregnant women.   
Results of animal studies indicate that vorinostat crosses the placenta and is found in fetal 
plasma. Doses up to 50 and 150 mg/kg/day were tested in rats and rabbits,   respectively (~0.5 
times the human exposure based on AUC0-24). Treatment-related developmental effects including 
decreased mean live fetal weights, incomplete ossifications of the skull, thoracic vertebra, 
sternebra, metacarpals and skeletal variations (cervical ribs, supernumerary ribs, vertebral count 
and sacral arch variations) in rats and rabbits at the highest doses of vorinostat tested. The no 
observed effect level (NOEL) for these effects was 15 and 50 mg/kg/day (<0.1 times the human 
exposure based on AUC) in rats and rabbits. If the drug is used during pregnancy, or if the 
patient becomes pregnant while taking this drug, the patient should be apprised of the potential 
hazard to the fetus.  
Women of childbearing potential should be advised to avoid becoming pregnant while receiving 
treatment with vorinostat. Female patients enrolled in this study should either be post 
menopausal, free from menses for > 2 years, surgically sterilized or willing to use 2 adequate 
barrier methods of contraception to prevent pregnancy or agree to abstain from heterosexual 
activity throughout the study, starting with visit 1.  Female patients of childbearing potential 
must have a negative serum pregnancy test (β-hCG) within 72 hours prior to receiving the first 
dose of vorinostat. Male patients enrolled in this study should also agree to use an adequate 
method of contraception for the duration of the study. Patients should be advised to discuss 
adequate birth control options with their physician. 
If a patient or their partner inadvertently becomes pregnant while on treatment with vorinostat, 
the patient will immediately be removed from the study.  The site will contact the patient at least 
monthly and document the patient’s status until the pregnancy has been completed or terminated.  
The outcome of the pregnancy will be reported to the SPONSOR without delay and within 24 
hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, 
or other disabling or life-threatening complication to the mother or newborn).  If a male patient’s 
partner becomes pregnant on study the pregnancy must be reported to the SPONSOR.  The study 
investigator will make every effort to obtain permission to follow the outcome of the pregnancy 
and report the condition of the fetus or newborn to the SPONSOR.  
Should a patient become pregnant refer to Safety Section for reporting instructions. 


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Use in nursing women 
It is unknown whether vorinostat is excreted in human milk. Because many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in nursing infants from 
vorinostat, breast feeding must be discontinued for the duration of therapy with vorinostat and 
the concomitantly used chemotherapy, if applicable. 
11.2 Cyclophosphamide 
Bone marrow suppression with neutropenia and thrombocytopenia. Less commonly, 
cardiotoxicity, hemorrhagic cystitis, and secondary malignancies. 
11.3 Etoposide 
Myelosuppression, alopecia, nausea vomiting headache, fever, hypotension, anorexia, and 
allergic reactions 
11.4 Rituximab 
Fever, chills, rigors, nausea, vomiting, urticaria, fatigue, headache, dizziness, pruritus, 
Bronchospasm, dyspnea, angioedema, rhinitis, hypotension, flushing, pain at disease sites, 
leukopenia, thrombocytopenia, anemia, tumor lysis syndrome, progressive multifocal 
leukoencephalopathy (PML), activation of or worsening of hepatitis B 
11.5 Prednisone 
Nausea, vomiting, dyspepsia, appetite change, edema, headache, dizziness, mood swings, 
insomnia, hypokalemia, hypertension, hyperglycemia, Cushingoid features (log-term use), 
ecchymoses, acne, skin atrophy (long-term use), impaired skin healing (long-term use) 
 
 
 
 
 
 
 
 


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12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Responses for primary and secondary endpoints will be determined according to the Revised 
Response Criteria for Malignant Lymphoma34 as described in the Table. 
 
 
Overall survival is defined as the period from the date of study entry to the date of death due to 
any cause. Progression-free survival is defined as the period from the date of study entry to the 
date of disease progression or death due to any cause. 
 
To compare results with those in the older literature, a secondary assessment of responses will be 
made according to the older “Report of an International Workshop to Standardize Response 
Criteria for Non-Hodgkin’s Lymphomas” as described in the table35. These criteria did not 
include results of PET scanning. 
 
 
 
Response Definitions for Clinical Trials 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of 
all evidence of 
disease 
(a) FDG-avid or PET positive prior to 
therapy; mass of any size permitted if 
PET negative 
(b) Variability FDG-avid or PET 
negative; regression to normal size on 
CT 
 
Not palpable, nodules 
disappeared 
Infiltrate cleared on repeat 
biopsy; if indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
≥ 50% decrease in SPD of up to 6 largest 
dominant masses; no increase in size 
of other nodes 
(a) FDG-avid or PET positive prior to 
therapy; one or more PET positive at 
previously involved site 
(b) Variably FDG-avid or PET negative; 
regression on CT 
≥ 50% decrease in 
SPD of nodules 
(for single nodule 
in greatest 
transverse 
diameter); no 
increase in size of 
liver or spleen 
 
Irrelevant if positive prior to 
therapy; cell type should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
( a) FDG-avid or Pet positive prior to 
therapy; PET positive at prior sites of 
disease and no new sites on CT or PET 
( b) Variably FDG-avid or PET negative; 
no change in size of previous lesions 
on CT 
 
 
 
Relapsed 
disease or 
PD 
Any new lesion or 
increase by ≥ 
50% of 
previously 
involved sites 
from Nadir 
Appearance of a new lesion(s) > 1.5 cm 
in any axis, ≥ 50% increase in SPD of 
more than one node.  , or ≥ 50% 
increase in longest diameter of a 
previously identified node > 1 cm in 
short axis. 
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior to 
therapy. 
 
>50% increase from 
nadir in the SPD of 
any previous 
lesions 
New or recurrent involvement 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, position emission tomography; CT, computed 
tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease. 


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Response Criteria for Non-Hodgkin’s Lymphoma 
Response Category 
Physical 
Examination 
Lymph Nodes 
Lymph Node 
Masses 
Bone marrow 
CR 
Normal 
Normal 
Normal 
Normal 
CRu 
Normal 
Normal 
Normal 
Indeterminate 
 
Normal 
Normal 
> 75% 
decrease 
Normal or 
indeterminate 
PR 
Normal 
Normal 
Normal 
Positive 
 
Normal 
≥ 50% 
decrease 
≥ 50% 
decrease 
Irrelevant 
 
Decrease in 
liver/spleen 
≥ 50% 
decrease 
≥ 50% 
decrease 
Irrelevant 
Relapse/progression Enlarging 
liver/spleen; 
new sites 
New or 
increased 
New of 
Increased 
Reappearance 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
If at anytime the patient develops progressive disease he/she will be taken off study and referred 
for alternative therapy. 
 
If at anytime the patient develops unacceptable toxicity he/she will be removed from study. 
 
If at anytime the patient is found to be ineligible for the protocol as designated in the section on 
Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), the patient will be removed 
from the study. 
 
14.0 
BIOSTATISTICS 
This is a phase I/II, open-label, multicenter, single arm trial. The goals are to determine the 
optimal dose of vorinostat when given in combination to rituximab, cyclophosphamide, 
etoposide and prednisone for elderly patients with relapsed or refractory DLBCL who are not 
candidates for autologous stem cell transplantation. The primary efficacy endpoint is complete 
response rate. Secondary efficacy endpoints include overall response rate (CR+PR) and one -
year progression free and overall survivals. Quality of life endpoints are described in Section 
14.1. Criteria of response are defined in section 12.0. The maximum number of assessable 
patients entered into the phase I and phase II components is 53 as described below. 
 
 
 
 


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Phase I: 
The starting dose of vorinostat will be 300 mg orally days 1-10. All other agents will be as 
described in Section 4.1. Three patients will be enrolled at this dose. If 0/3 experience DLT then 
the dose will be increased to 400 mg orally days 1-10. If 1/3 patient experiences a DLT then 3 
more patients will be added at the 300 mg dose. If ≥2 patients experience DLT at 300 mg, the 
trial will be discontinued because of excessive toxicity. If ≤ 1 out of 6 patients experience a DLT 
at 300 mg then we will escalate to 400 mg and follow the same scheme. If two or more 
experience a DLT at 400 mg and only three patients were treated at 300 mg, then we will de-
escalate to 300 mg and 3 additional pts will be added. If ≤1 out of 6 patients experience a DLT at 
400 mg, then 400 mg will be the MTD for the Phase II part of the study. DLT is defined as any 
grade 3 or 4 non-hematological toxicity or grade 4 thrombocytopenia as evaluated in the first 
cycle of treatment. The Phase I part of the study will accrue a maximum of 12. The six patients 
treated at the MTD will be included in the Phase II part of the study. 
 
Phase II statistical design:  
With type I and type II errors of 0.1, based on a Simon two-stage design, the sample size needed 
to show a clinically significant improvement in complete response rate (CR) from 35% to 55% is 
47 patients. If at least 8 patients out of 20 patients respond at the first stage, then the study will 
accrue 27 more patients at the second stage. If 7 or less patients respond at the first stage then the 
study will stop and conclude that this regimen has a CR lower or equal that 35%.  If at least 21 
patients respond at the end of the trial then this study will conclude that this regimen is 
promising in this patient population.  
 
For the secondary endpoint of progression-free survival (PFS) it will be assumed that 47 patients 
will be followed up for at least one year as for the primary endpoint.  
 
The overall response rate (CR+PR) and its 90% confidence interval will be estimated via 
binomial proportions. 
 
Frequency of toxicity will be tabulated according to the NCI common toxicity criteria. 
 
Assuming accrual rate of 1-2 patients per month, this trial will take approximately 26-53 months 
to complete. We expect to complete accrual within 3 years 
 
14.1 Quality of life as measured by the FACT-Lym instrument. 
 
FACT-Lym, the Functional Assessment of Cancer Therapy-Lymphoma, a validated QOL tool to 
evaluate quality of life in lymphoma clinical research, adds to the 27-item FACT-G a list of 15 
lymphoma-specific questions9 (www.facit.org). 
 
FACT-Lym will be administered at baseline, on first day of each treatment cycle and at all 
follow-up visits in the first year of follow-up which will be every 3 months for the first year. The 


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FACT-Lym questionnaire will be administered to patients registered on the phase I and phase II 
portions of the trial. 
The following FACT-Lym endpoints will be evaluated: Physical Well-being scale (raw scores), 
Functional Well-being scale (raw scores), Social/family Well-being scale (raw scores), 
Emotional Well-being scale (raw scores), Lymphoma scale (raw scores), Total score composed 
of all five scales (raw scores), Trial Outcome Index (TOI) composed of the physical well-being 
scale, functional well-being scale and the lymphoma specific scales (raw scores). Scoring of the 
FACT-Lym (version 4) will be done in accordance with the FACT-Lym as described in the 
Functional Assessment of Chronic Illness Therapy (FACIT) manual36 . For each endpoint, 
summary raw scores will be summarized using means and medians at each assessment point 
along with standard deviations and interquartile ranges.  
The aim is to evaluate whether FACT-Lym scores improve across time, especially among 
responding patients. A general class of models for the analysis of longitudinal data is that of 
mixed models37.  For this study, a mixed-effects longitudinal model to evaluate selected FACT-
Lym endpoints over time will be implemented.  Each patient will be scheduled to complete up to 
fourteen assessments: Week 0 (Baseline), 4, 8, 12, 16, 20, 24, and then every 3 months for the 
first year of followup. For each post-Baseline assessment, we will use the date of questionnaire 
completion to compute the amount of time in months from baseline.  The time variable will be 
set to zero for all Baseline questionnaires. An unstructured covariance pattern will be used to 
account for the correlations within patients, unless an alternative covariance structure better fits 
the data.  The unstructured covariance pattern provides maximum flexibility and allows the 
variance of the endpoint to be different at each visit, and the covariance of each pair of visits to 
be different.  We will attempt to use an unstructured covariance pattern to account for the 
correlations within patients. The unstructured covariance pattern, when viable, provides 
maximum flexibility and allows the variance of the endpoint to be different at each visit, and the 
covariance of each pair of visits to be different. Due to small sample size and potentially missing 
data, it is anticipated that less flexible covariance structures may need to be investigated. The 
basic analytical model will include fixed effects (time) and random effects (patient, 
patient*time).  A quadratic effect (time2) may be included to evaluate the possibility of nonlinear 
change over time.  Piece wise linear regression models may also be used to separately model the 
changes during the first month and the changes during subsequent months.  Patient age and 
gender will be added to the basic model to determine if these variables have any independent 
effect on the FACT-Lym scores.  A likelihood ratio test will be used to assess the contributions 
of these variables. The model parameter estimates, standard errors and p-values will be 
summarized. (Table 1). The effect of baseline characteristics on QOL will be evaluated in 
exploratory analyses.   
A potential problem in QOL studies is that missing data are often not missing at random, e.g., 
patients who experience increased toxicity, disease progression or death are more likely to miss 
one or more assessments.  If the probability of missingness depends on the unobserved QOL 
scores, then missing data are considered non ignorable, or missing not at random38 (MNAR ; 
Little & Rubin, 1987).  Formally distinguishing between missing at random (MAR) and MNAR 
is not trivial and relies on assumptions that are themselves untestable38,39.  Therefore, a pattern-


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mixture model to assist in the analysis of potentially non ignorable missing data will be 
implemented40 .  For this method, patients will be stratified into groups defined as “dropouts” 
and “completers”, the cut-off time mark of assessment completion will depend on the 
missingness pattern at each assessment. Mixed-effects repeated measures models will be created 
within each stratum and parameter estimates for each stratum will then be combined into a 
weighted average for the entire study population.  Estimated means at each time point will be 
calculated using the parameter estimates and standard errors from the final models. The 
parameters estimates from the pattern-mixture model will be compared to those from the naïve 
mixed-effects model.  
On the other hand, an exploratory method of analysis, a joint model of FACT-Lym scores and 
time-to-progression will be also fit. This model is based on an extension of the two-stage linear 
random effects model, where each subjects’ random intercept and slope are allowed to be 
associated with the underlying time to event41,42 . The joint distribution of the continuous 
responses and the time-to-event variable are then estimated via maximum likelihood using the 
EM algorithm. The parameters estimates from the joint model of longitudinal measures and time-
to-progression will be also compared to those from the naïve mixed-effects model.  
 
SAS v9.1 will be used for all analyses. As these health-related quality of life analyses are 
considered exploratory, there is no need to adjust the significance level for multiple comparisons.   
 
Table 1 
Parameter estimates from mixed-effects longitudinal model 
QOL Parameter    PWB 
EWB 
SWB 
FWB 
FACT-
Lym 
TOTAL 
TOI 
Mean change per 
month (slope) 
 
 
 
 
 
 
 
Parameter 
estimate 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
Standard error 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
p-value to test 
slope differ from 
zero 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
 
Anchoring interpretation of change to a subjective global rating from the patient. As this is an 
uncontrolled Phase I/II study, with FACT-Lymphoma measures periodically on the phase II 
portion, interpretation of any detected change will be aided by also asking patients to provide an 
estimate of the degree to which they have changed (improved or worsened), if at all, since 
baseline. We will use a 7-point patient global rating of change, adapted from Jaeschke et al 
(1989), to classify patients into those who have improved, worsened or not changed. These three 
distinct groups will then be compared on the FACT-Lymphoma subscales to provide some 
interpretation as to the meaningfulness of the noted change in terms of FACT-Lymphoma scores. We 
will evaluate general linear models using each patient's change score.  Changes in patient- and provider-
rated performance status, as well as patient-rated perceptions of QOL change, will be used to form three 
independent groups (better, no change, worse).  We will look for confirmation that the FACT-Lymphoma 


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measures provide clinically meaningful estimates of change.  No imputation of missing data will be done 
for patients who fail to participate after baseline evaluation; however, we will prospectively monitor the 
reasons for missing data (e.g., refusal, disease progression, death) and will compare characteristics of 
patients who do and do not participate in the longitudinal study.  
 
Jaeschke, R., Singer, J. & Guyatt, G.  Measurement of health status: Ascertaining the  
minimally clinically important difference.  Controlled Clinical Trials, Vol. 10, pp. 407-415, 1989. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.1   Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center.  PPR is available Monday through Friday from 
8:30am - 5:30pm at (646) 735-8000. The PPR fax numbers are (646) 735-0008 and (646) 735-
0003.  Registrations can be phoned in or faxed.  The completed signature page of the written 
consent/verbal script, and a completed Eligibility Checklist must be faxed to PPR. 
 
15.1.1 For Participating Sites: 
Central registration for this study will take place at Memorial Sloan Kettering Cancer Center 
(MSKCC). 
 
To complete registration and enroll a participant from another institution, the study staff at that 
site must contact the designated research staff at MSKCC to notify him/her of the participant 
registration. The site staff then needs to fax registration/eligibility documents to the Clinical 
Trials Office (Lymphoma Department) at MSKCC Fax: 646-227-2427.   
 
The following documents must be sent for each enrollment within 24 hours of the informed 
consent form being signed: 
• The completed or partially completed MSKCC eligibility checklist 
• The signed informed consent and signed HIPAA Authorization form (Research 
Authorization) 


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• Supporting source documentation for eligibility questions (laboratory results, 
pathology report, radiology reports, MD notes, physical exam sheets, medical history, 
prior treatment records, and EKG report).   
 
Upon receipt, the research staff at Memorial Sloan Kettering Cancer Center will conduct an 
interim review of all documents.   If the eligibility checklist is not complete, the patient will be 
registered PENDING and the site is responsible for sending a completed form within 30 days of 
the consent.  
 
 
If the eligibility checklist is complete, participant meets all criteria, all source documentation is 
received, the participating site IRB has granted approval for the protocol, and the site is in good 
standing with MSKCC, the MSKCC research staff will send the completed registration 
documents to the MSKCC Protocol Participant Registration (PPR) Office to be enrolled as stated 
in section 15.1.  The participant will be registered. 
 
Once eligibility has been established and the participant is registered, the participant will be 
assigned an MSKCC Clinical Research Database (CRDB) number (protocol participant number).  
This number is unique to the participant and must be written on all data and correspondence for 
the participant.  This protocol participant number will be relayed back to study staff at the 
registering site via e-mail and will serve as the enrollment confirmation.   
 
16.0 
DATA  MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study.  The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol 
study team. 
 
The data collected for this study will be entered into a secured database (Clinical Research 
Database, CRDB) at Memorial Sloan-Kettering Cancer Center. 
   
16.0.1  Data and Source Documentation for Participating Sites  
Data 
 
Standardized Case Report Forms (CRFs), directions for use and sign off requirements have been 
generated for this study. Blank case report forms will be sent to the study staff at each 
participating site for use. The participating Site PI is responsible for ensuring these forms are 
completed accurately, legibly and in a timely manner.  
 
 
 
 


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Source Documentation 
Source documentation refers to original records of observations, clinical findings and evaluations 
that are subsequently recorded as data. Source documentation should be consistent with data 
entered into CRFs. Relevant source documentation to be submitted throughout the study 
includes:  
o Baseline measures to assess pre–protocol disease status (ex. CT, PSA, bone 
marrow) 
o Treatment records  
o Grade 3-5 toxicities/adverse events not previously submitted with SAE Reports 
o Response designation 
 
16.0.2 Data and Source Documentation Submission for Participating Sites 
 
Participating sites should fax or e-mail CRFs and source documentation to MSKCC to the 
contact provided below. Submissions should include a cover page listing all CRFs enclosed per 
participant. 
 
FAX: [646-227-2427] to the attention of [Protocol:  08-045:  (Brett Wegner)] OR EMAIL:  
WegnerB@mskcc.org 
 
16.0.3 Data and Source Documentation Submission Timelines for Participating 
Sites 
 
Data and source documentation to support data should be transmitted to MSKCC according to 
chart: Data and Source Submission Requirements and Timelines for Therapeutic Studies 


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Baseline 
Cycle  
1-6 
Post- 
Tx-
Follow-
up 
visits 
SAE 
Off Study 
SUBMISSION SCHEDULE 
Source Documentation 
Within 24 hours     
(see section 
15.1.1) 
within 14 days of 
end of cycle 
Within 3 days of 
event (see section 
17.2.1); updates to 
be submitted as 
available 
Within 14 
days of 
visit 
CRFs 
Within 7 days of 
visit 
Required Forms 
Demographics Form 
X 
 
 
 
 
Medical History Form 
X 
 
 
 
 
Concomitant 
Medications  
Form 
X 
X 
X 
 
X 
Physical Exam Form 
X 
X 
X 
 
X 
Treatment Form 
 
X 
X 
 
X 
Laboratory Form 
X 
X 
X 
 
X 
Lesion/EOD Form 
 
 
X1 
 
X 
Adverse Event Form 
 
X 
X 
X 
X 
Serious Adverse Event 
Form 
 
 
 
X 
 
Off Study Form 
 
 
 
 
X 
(FACT-Lym) QOL 
X 
X 
X 
 
 
Global Rating of 
Change Questionnaire 
 
X 
X 
 
 


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16.0.4 Data Review and Queries for Participating Site Data 
 
Research staff at MSKCC will review data and source documentation as it is submitted. Data 
will be monitored against source documentation and discrepancies will be sent as queries to the 
participating sites. Queries will be sent by MSKCC Research staff twice a month. 
 
Participating sites should respond to data queries within 14 days of receipt. 
  
16.1 
Quality Assurance 
Registration reports will be generated to monitor patient’s accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study and potential problems will be brought to the 
attention of the study team for discussion and action. 
  
Random-Sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of once a year or more frequently if indicated. 
 
16.1.1 Quality Assurance for Participating Sites 
Each site participating in the accrual of participants to this protocol will be audited by the staff of 
the MSKCC study team for protocol and regulatory compliance, data verification and source 
documentation.  Audits may be accomplished in one of two ways: (1) selected participant 
records can be audited on-site at participating sites or (2) source documents for selected 
participants will be sent to MSKCC for audit. Audits will usually be determined by participant 
accrual numbers and rate of accrual, but can also be prompted by reported SAEs or request of 
MSKCC PI.  
 
Audits will be conducted at least once shortly after initiation of participant recruitment at a site, 
annually during the study (or more frequently if indicated), and at the end or closeout of the trial. 
The number of participants audited will be determined by available time and the complexity of 
the protocol.   
 
The audit will include a review of source documentation to evaluate compliance for: 
 
• Informed consent documents and procedures 
• Adherence to eligibility criteria 
• Protocol defined treatment 
• Required baseline, on study and follow-up protocol testing 
• IRB documents (submitted amendments, annual continuing review reports, SAEs) 
• Required specimen submission 


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• Case Report Form submissions to MSKCC: timelines and accuracy 
 
A wrap-up session will be conducted at the participating site and preliminary findings will be 
discussed with the participating site PI and research team. The preliminary results will be sent to 
the MSKCC PI.   
 
Each audit will be summarized and a final report will be sent to the PI at the audited participating 
site within 30 days of the audit. The report will include a summary of findings, participant by 
participant case review, specific recommendations on any performance and/or shortcomings and 
request for corrective action, when necessary. When corrective action is required, the 
participating site must reply within 45 days of receipt of audit report with their corrective action 
plan.   
 
A copy of the audit report and corrective action plan (if applicable) submitted by the 
participating site must be sent to the MSKCC IRB/PB, CRQA and maintained in the 
department’s protocol regulatory binder.    
 
16.1.2 Response Review 
 
 Since therapeutic efficacy is a stated primary objective, all sites participant’s responses are 
subject to review by MSKCC’s Therapeutic Response Review Committee (TRRC).  Radiology, 
additional lab reports and possibly bone marrow biopsies and/or aspirates will need to be 
obtained from the participating sites for MSKCC TRRC review and confirmation of response 
assessment. These materials must be sent to MSKCC promptly upon request.           
 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001.  The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for 
Data and Safety Monitoring of Clinical Trials” which can be found at  
http://cancertrials.nci.nih.gov/researchers/dsm/index.html.   The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research.  The MSKCC Data and Safety 
Monitoring Plans can be found on the MSKCC Intranet at: 
http://inside2/clinresearch/Documents/MSKCC Data and Safety Monitoring Plan.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality.  There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education on 
clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs.  The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 


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clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional Review Board.   
 
During the protocol development and review process, each protocol will be assessed for its level 
of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) Will be addressed and the 
monitoring procedures will be established at the time of protocol activation 
 
16.3 
Regulatory Documentation 
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSKCC Institutional Review Board/Privacy Board (IRB/PB). Prior to implementing this 
protocol at the participating sites, approval for the MSKCC IRB/PB approved protocol must be 
obtained from the participating site’s IRB.   
The following documents must be provided to MSKCC before the participating site can be 
initiated and begin enrolling participants:  
• Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 
• Participating Site IRB approved consent form 
• Participating Site IRB membership list 
• Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 
• Curriculum vitae and medical license for each investigator and consenting professional 
• Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site 
• Participating site laboratory certifications and normals 
 
Upon receipt of the required documents, MSKCC will formally contact the site and grant 
permission to proceed with enrollment.  
 
 
16.3.1 Amendments 
 
Each change to the protocol document must be organized and documented by MSKCC and first 
approved by the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, MSKCC will 
immediately distribute all non expedited amendments to the participating sites, for submission to 
their local IRBs. 
 
Participating sites must obtain approval for amendments from their IRB within 90 calendar days 
of MSKCC IRB/PB approval. If the amendment is the result of a safety issue or makes eligibility 
criteria more restrictive, sites will not be permitted to continuing enrolling new participants until 
the participating site IRB approval has been granted. 
 


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The following documents must be provided to MSKCC for each amendment within the 
stated timelines:  
 
• Participating Site IRB approval  
• Participating Site IRB approved informed consent form and HIPAA  authorization 
 
16.3.2 Additional IRB Correspondence 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form should be submitted to MSKCC within 7 days of 
expiration. Failure to submit the re-approval in the stated timeline will result in suspension of 
study activities. 
 
Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant who does 
not meet all the eligibility criteria, pretreatment evaluation, or who requires alteration in their 
study plan. If a deviation from this protocol is proposed for a potential or existing participant at 
MSKCC or a participating site, approval from the MSKCC IRB/PB is required prior to the 
action. Participating sites should contact the MSKCC PI who will in turn seek approval from the 
MSKCC IRB/PB. 
 
A protocol violation is anything that occurs with a participant, which deviated from the 
protocol without prior approval from the MSKCC IRB/PB. For protocol violations that are 
identified after they occur, the participating site should report to MSKCC as soon as possible. 
The MSKCC PI will in turn report the violation to the MSKCC IRB/PB.  
 
Participating sites should report deviations and violations to their institution’s IRBs as soon as 
possible per that site’s institutional guidelines. Approvals/acknowledgments from the 
participating site IRB for protocol deviations and violations should be submitted to MSKCC as 
received.  
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB according to 
local guidelines, and submit copies of that correspondence to MSKCC. 
 
16.3.3 Document maintenance 
 
The MSKCC PI and the Participating Site PI will maintain adequate and accurate records to 
enable the implementation of the protocol to be fully documented and the data to be 
subsequently verified. 
 


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The participating sites will ensure that all participating site IRB correspondence (IRB approval 
letters referencing protocol version date and amendment number, IRB approved protocol, 
appendices, informed consent forms, deviations, violations, and approval of continuing reviews) 
is maintained in the regulatory binder on site and sent to MSKCC. 
 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be paper or 
electronic. 
 
After study closure, the participating site will maintain all source documents, study related 
documents and CRFs for 3 years 
 
16.4 
Noncompliance  
 
If a participating site is noncompliant with the data and regulatory requirements set forth in 
section 16.0-16.3, accrual privileges may be suspended and/or contract payments maybe 
withheld (if applicable), until the outstanding issues have been resolved.   
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
Inclusion of Children in Research 
 
This protocol/project does not include children because the number of children is limited and 
because the majority are already accessed by a nationwide pediatric cancer research network.  
This statement is based on exclusion 4b of the NIH Policy and Guidelines on the Inclusion of 
Children as Participants in Research Involving Human Subjects. 
 
17.1 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form.  The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form.  A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 Serious Adverse Event (SAE) Reporting 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be 
submitted electronically to the SAE Office at sae@mskcc.org.  The report should contain 
the following information: 
Fields populated from CRDB: 


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• Subject’s name (generate the report with only initials if it will be sent outside of     
      MSKCC) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
 
 
 17.3 Regulatory And Reporting Requirements  
 
 
 17.3.1 Recording Adverse Experiences 
An adverse experience is defined as any unfavorable and unintended change in the structure, 
function, or chemistry of the body temporally associated with the use of the SPONSOR’s 
product, whether or not considered related to the use of the product. Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting condition 
which is temporally associated with the use of the SPONSOR’s product, is also an adverse 
experience. 
Changes resulting from normal growth and development which do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse experiences. 
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children, and onset of menses or menopause occurring at a physiologically appropriate time. 
Adverse experiences may occur in the course of the use of a Merck product in clinical studies or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse, and from withdrawal. 
Adverse experiences may also occur in screened subjects/patients during any pre allocation 
baseline period as a result of a protocol-specified intervention including washout or 
discontinuation of usual therapy, diet, placebo treatment, or a procedure. 


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17.3.2 Adverse Experiences* 
PI and participating investigators need to provide Merck & Co., Inc. (Attn: Worldwide Product 
Safety; FAX 215-993-1220) with copies of all serious and/or unexpected adverse experiences, 
within two working days.  PI and participating investigators also agree to establish and maintain 
records and make reports to the FDA with copies, as described above, to Merck for the following 
Adverse Experiences: (1) all serious, unexpected, adverse events, (2) any significant increase in 
the frequency of serious expected adverse events, and (3) any significant increase in the 
frequency of therapeutic failures.  Additionally, PI and participating investigators must  report 
any pregnancy occurring in association with use of a Merck Product to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-993-1220).  For any serious thromboembolic Adverse 
Experiences, PI and participating investigators must fax, at the same time as the submission to 
Merck of the original report, the additional information set forth on the Zolinza Thromboembolic 
Event Questionnaire  In addition, if the PI or participating investigator becomes aware of any 
new information regarding any Adverse Experience, he/she must submit that new information to 
Worldwide Product Safety within two working days. 
 
17.3.3   Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) the characteristics of the adverse event 
including the grade (severity), the relationship to the study therapy (attribution), and the prior 
experience (expectedness) of the adverse event; 3) the phase (1, 2, or 3) of the trial; and 4) 
whether or not hospitalization or prolongation of hospitalization was associated with the event. 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND) (vorinostat, bevacizumab). In some instances, the investigational agent may 
be available commercially, but is actually being tested for indications not included in the 
approved package label. Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source (paclitaxel, trastuzumab).  
 
When a study arm includes both investigational and commercial agents, the following rules 
apply: 
 
Concurrent administration: When an investigational agent(s) is used in combination with a 
commercial agent(s), the combination is considered to be investigational and expedited reporting 
of adverse events would follow the guidelines for investigational agents. 
 
Sequential administration: When a study includes an investigational agent(s) and a commercial 
agent(s) on the same study arm, but the commercial agent(s) is given for a period of time prior to 
starting the investigational agent(s), expedited reporting of adverse events which occur prior to 
starting the investigational agent(s) would follow the guidelines for commercial agents. Once 
therapy with the investigational agent(s) is initiated, all expedited reporting of adverse events 
should follow the investigational guidelines. 
 


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17.3.4 Steps to determine if an adverse event is to be reported in an expedited 
manner: 
 
Step 1: Identify the type of event using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 3.0. The CTCAE provides descriptive terminology and a grading scale 
for each adverse event listed. A copy of the CTCAE can be downloaded from the CTEP home 
page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCl has an Index to the 
CTCAE that provides help for classifying and locating terms. All appropriate treatment locations 
should have access to a copy of the CTCAE. 
 
Step 2: Grade the event using the NCI CTCAE. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy (investigational or 
commercial). Attribution categories are as follows: Unrelated, Unlikely, Possible, Probable, and 
Definite. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those that have 
been previously identified as resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when either the type of event or 
the severity of the event is NOT listed in the current NCI Agent-Specific Adverse Event List for 
the investigational agent. 
 
Step 5: Review the Additional instructions, requirements, and exceptions for this protocol 
specific requirements for expedited reporting of specific adverse events that require special 
monitoring. 
 
Step 6: Determine if the protocol treatment given prior to the adverse event included 
investigational agent(s), a commercial agent(s), or a combination of investigational and 
commercial agents. 
 
NOTE: If the patient received at least one dose of investigational agent, follow the guidelines for 
investigation agents. If no investigational agent was administered, follow the guidelines for non-
investigational agents.  
            
17.4 Serious Adverse Event (SAE) Reporting for Participating Sites 
Responsibility of Participating Sites 
• Participating sites are responsible for reporting all SAEs to the MSKCC PI via fax or e-mail 
within 3 calendar days of learning of the event.   
• Participating sites should notify the MSKCC PI of any grade 5 event immediately.  
• Participating sites should use the SAE Report Template (appendix 7) to report SAEs to 
MSKCC 


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SAE contact information for the Coordinating Center is listed below:  
 
Brett Wegner: 
 
- FAX: [646-227-2427] to the attention of [SAE - Protocol:  08-045:  (Brett Wegner)] 
- EMAIL:  WegnerB@mskcc.org 
 
David Straus, M.D. – Principal Investigator 
- EMAIL:  StrausD@mskcc.org  
 
Responsibility of MSKCC 
 
• The MSKCC Research Staff is responsible for submitting all SAEs to the MSKCC 
IRB/PB as specified in 17.2 and 17.3.2 
• The MSKCC PI is responsible for informing all participating sites about unexpected 
SAEs within 30 days of receiving the stamped SAE from the MSKCC IRB/PB.  
• Any report pertaining to a grade 5 event will be distributed to the participating sites as 
soon as possible. 
 
17.5 Safety Reports  
 
• MSKCC will distribute outside safety reports to the participating sites immediately upon 
receipt.  
• MSKCC must submit safety reports to the MSKCC IRB/PB according to institutional 
guidelines. 
• Participating sites must submit safety reports to their institution’s IRBs within 30 days of 
receipt from MSKCC or per participating site guidelines.  
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following:  
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 


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3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
18.1   For Participating Sites 
 
 
The investigators listed on the protocol cover page and their qualified designees at each 
participating site may obtain informed consent and care for the participants according to good 
clinical practice and protocol guidelines. 
 
Signed copies of the informed consent should be distributed as follows: One copy will be given 
to the participant to be retained for their personal records. One copy will be maintained on file at 
the MSKCC. The third copy will be confidentially maintained by the participating institution. 
 
A note will be placed in the medical record documenting that informed consent was obtained for 
this study, and that the participant acknowledges the risk of participation. 
 
19.0 
Reference(s) 
 
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Amended: 12/13/11 
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Sirohi B, Cunningham D, Norman A, et al. Gemcitabine, cisplatin and 
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Webster K, Odom L, Peterman A, Lent L, Cella D. The Functional Assessment of 
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Webster K, Cashy J, Cella D, et al. Measuring quality of life (QOL) in patients with non-
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Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 
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Richon VM, Emiliani S, Verdin E, et al. A class of hybrid polar inducers of transformed 
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Secrist JP, Zhou X, Richon VM. HDAC inhibitors for the treatment of cancer. Curr Opin 
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Munster PN, Troso-Sandoval T, Rosen N, Rifkind R, Marks PA, Richon VM. The 
histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human 
breast cancer cells. Cancer Res. 2001;61:8492-8497. 
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He LZ, Tolentino T, Grayson P, et al. Histone deacetylase inhibitors induce remission in 
transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest. 
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Ruefli AA, Ausserlechner MJ, Bernhard D, et al. The histone deacetylase inhibitor and 
chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway 
characterized by cleavage of Bid and production of reactive oxygen species. Proc Natl Acad Sci 
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21. 
Huang L, Pardee AB. Suberoylanilide hydroxamic acid as a potential therapeutic agent 
for human breast cancer treatment. Mol Med. 2000;6:849-866. 
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Butler LM, Agus DB, Scher HI, et al. Suberoylanilide hydroxamic acid, an inhibitor of 
histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer 
Res. 2000;60:5165-5170. 
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Vrana JA, Decker RH, Johnson CR, et al. Induction of apoptosis in U937 human 
leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are 
regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53. Oncogene. 
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Mitsiades N, Mitsiades CS, Richardson PG, et al. Molecular sequelae of histone 
deacetylase inhibition in human malignant B cells. Blood. 2003;101:4055-4062. 
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Lindemann RK, Gabrielli B, Johnstone RW. Histone-deacetylase inhibitors for the 
treatment of cancer. Cell Cycle. 2004;3:e77-e86. 
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Warrener R, Beamish H, Burgess A, et al. Tumor cell-selective cytotoxicity by targeting 
cell cycle checkpoints. Faseb J. 2003;17:1550-1552. 
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Glaser KB, Li J, Pease LJ, et al. Differential protein acetylation induced by novel histone 
deacetylase inhibitors. Biochem Biophys Res Commun. 2004;325:683-690. 
28. 
Bali P, Pranpat M, Swaby R, et al. Activity of suberoylanilide hydroxamic Acid against 
human breast cancer cells with amplification of her-2. Clin Cancer Res. 2005;11:6382-6389. 
29. 
Kelly WK, O'Connor OA, Krug LM, et al. Phase I study of an oral histone deacetylase 
inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol. 
2005;23:3923-3931. 
30. 
Olsen E, Kim YH, Kuzel T, al. e. Vorinostat (suberoylanilide hydroxamic acid, SAHA) is 
clinically active in advanced cutaneous T-cell lymphoma (abs. 7500). J Clin Oncol. 2006;24 
(2006 ASCO Annual Meeting Proceedings, Part 1, 18S). 
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Duvic M, Talpur R, Zhang C, al. e. A phase II trial of oral suberoylanilide hydroxamic 
acid (SAHA) in advanced cutaneous T-cell lymphoma (CTCL) unresponsive to conventional 
therapy (abs. 6571) 
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32. 
Garcia-Manero G, Yang H, Sanchez-Gonzales B, al. e. Final results of a phase I study of 
the histone deacetylase inhibitor vorinostat (suberoylanilde hydorxamic acit (SAHS) in patients 
with leukemia and myelodysplastic syndrome (Abs. 2801). Blood. 2005;106. 
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Richardson P, Schlossman RL, Mitsiades CS, et al. Phase I clinical trial of oral 
administration of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid 
(SAHA) in patients with relapsed/refractory multiple myeloma (abs. 1503) 
Blood. 2004;104:420a. 
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Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol. 2007;25:579-586. 
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Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to 
standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International 
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Cella D. Manual of the Functional Assessment of Chronic Illness Therapy (FACIT 
Scales)- Version 4. Evanston Northwestern Healthcare & Northwestern University. 1997. 


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37. 
Brown H, Prescott R. Applied Mixed Models in Medicine. 1999;New York, John Wiley 
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Troxel AB, Fairclough DL, Curran D, Hahn EA. Statistical analysis of quality of life with 
missing data in cancer clinical trials. Stat Med. 1998;17:653-666. 
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Curran D, Bacchi M, Schmitz SF, Molenberghs G, Sylvester RJ. Identifying the types of 
missingness in quality of life data from clinical trials. Stat Med. 1998;17:739-756. 
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Little R. Modeling the drop-out mechanism in repeated-measures studies. Journal of the 
American Statistical Association. 1995;90:1112-1121. 
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Schluchter MD. Methods for the analysis of informatively censored longitudinal data. 
Stat Med. 1992;11:1861-1870. 
42. 
Schluchter MD, Greene T, Beck GJ. Analysis of change in the presence of informative 
censoring: application to a longitudinal clinical trial of progressive renal disease. Stat Med. 
2001;20:989-1007. 
 
 
 
 
20.0 
APPENDICES 
Appendix 1: Schedule of Protocol Events 
Appendix 2: Thromboembolic Event Questionnaire 
Appendix 3: Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) 
Appendix 4: Patient diary to document oral medications on study 
Appendix 5: Global Rating of Change Questionnaire 
Appendix 6: Efficacy of Vorinostat 
Appendix 7: Serious Adverse Event Report Form