Clinical trial NCT00720876
Conditions: Lymphoma
Keywords: contiguous stage II grade 1 follicular lymphoma contiguous stage II grade 2 follicular lymphoma contiguous stage II grade 3 follicular lymphoma noncontiguous stage II grade 1 follicular lymphoma noncontiguous stage II grade 2 follicular lymphoma noncontiguous stage II grade 3 follicular lymphoma recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma stage I grade 1 follicular lymphoma stage I grade 2 follicular lymphoma stage I grade 3 follicular lymphoma stage III grade 1 follicular lymphoma stage III grade 2 follicular lymphoma stage III grade 3 follicular lymphoma stage IV grade 1 follicular lymphoma stage IV grade 2 follicular lymphoma stage IV grade 3 follicular lymphoma contiguous stage II marginal zone lymphoma extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue nodal marginal zone B-cell lymphoma noncontiguous stage II marginal zone lymphoma recurrent marginal zone lymphoma splenic marginal zone lymphoma stage I marginal zone lymphoma stage III marginal zone lymphoma stage IV marginal zone lymphoma contiguous stage II mantle cell lymphoma noncontiguous stage II mantle cell lymphoma recurrent mantle cell lymphoma stage I mantle cell lymphoma stage III mantle cell lymphoma stage IV mantle cell lymphoma
Sponsor: City of Hope Medical Center
Start date: 2008-07-23; Completion date: 2017-06-08
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving vorinostat together with rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying the side effects of giving vorinostat together with rituximab and to see how well it works in treating patients with indolent non-Hodgkin lymphoma.

Detailed description:
OBJECTIVES:

* To evaluate the anti-tumor activity of vorinostat and rituximab, in terms of objective response rate, time to progression, and survival, in patients with indolent non-Hodgkin lymphoma.
* To assess the toxicity profile of this regimen in these patients.

OUTLINE: Patients receive oral vorinostat twice daily on days 1-14 and rituximab IV on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

Arms: arm 1: Vorinostat by mouth two times (2X) per day for two weeks followed by one week of rest. Rituximab intravenously once every three weeks .
Interventions: intervention 1: rituximab intervention 2: vorinostat
Intervention descriptions: intervention 1: Rituximab will be administered at a dose of 375 mg/m2 on day 1 of every cycle, every 3 weeks. intervention 2: 200 mg twice daily, orally for 14 days followed by a seven day break on a 21 day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
CITY OF HOPE MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
Department of Hematology and Hematopoietic Cell Transplantation 
 
 
TITLE:  
A Phase II study of Vorinostat (Suberoylanilide Hydroxamic Acid) plus Rituximab in Indolent 
Non-Hodgkin’s Lymphoma. 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 07195  
 
 
VERSION: 12 
 
COH Initial Review                              October 2, 2007 
Version: 00 
COH Amendment 1                             June 17, 2008 
Version: 01 
COH Amendment 2 
(Title Page, 01/04/10) 
Version: 02 
COH Amendment 3 
 
 
(PI Change 07/19/10)  
 
 
 
      Version: 03 
COH Amendment 4 
 
 
(Protocol version 06/13/11) 
 
 
 
      Version: 04 
COH Amendment 5 
 
 
(Protocol Version 07/21/11)  
 
 
      Version: 05 
COH Amendment 6 
 
 
(Title Page, 12/06/11)  
 
 
    
      Version: 06 
COH Amendment 7 
 
 
(Protocol Version 11/08/11)  
 
 
      Version: 07 
COH Amendment 8 
 
 
(Protocol Version 01/23/12)  
 
 
     Version:  08 
COH Amendment 9 
 
 
(Title Page, 12/20/12)  
 
 
    
      Version: 09 
COH Amendment 10 ` 
 
(Title Page- Add Dr. Grover, 12/27/2012) 
 
      Version: 10 
COH Amendment 11  
 
(Protocol Version dated 10/8/13) 
 
 
      Version: 11 
COH Amendment 12  
 
(Title Page dated 01/14/14)  
 
       
      Version: 12 
 
 
DISEASE SITE:  
Acute NHL 
 
STAGE 
 
 
 
 
 
 
MODALITY(IES) 
 
 
 
 
 
TYPE  
 
   Phase 
II 
 
PRINCIPAL INVESTIGATOR: 
 
Robert Chen, M.D.  
 
COLLABORATING INVESTIGATOR(S): 
Leslie Popplewell, M.D., 
 
 
 
PARTICIPATING CLINICIANS: 
Ravi Bhatia, M.D., Ji-Lian Cai, M.D., Warren Chow, M.D.,  
Stephen Forman, M.D., Chatchada Karanes, M.D., Amrita, Krishnan, M.D., 
Auayporn Nademanee, M.D.,  
Ryotaro Nakamura, M.D., Margaret O’Donnell, M.D., Pablo Parker, M.D., 
Firoozeh Sahebi, M.D., David Snyder, M.D.,  
George Somlo, M.D., Ricardo Spielberger, M.D., Anthony Stein, M.D,  
Len Farol, M.D., Ahmed Aribi, M.D., Myo Htut, M.D., Samer Khaled, M.D., 
Rodrigo Maegawa, M.D., Nitya Nathwani, M.D.,  
Michael Rosenzweig, M.D, Tanya Siddiqi, M.D.,  
STATISTICIAN: 
  Paul 
Frankel, Ph.D. 
 
 


 
 
 
 
 
 
 
 
TITLE:  A Phase 2 Study of Vorinostat (Suberoylanilide Hydroxamic Acid) plus Rituximab in Indolent 
Non-Hodgkin’s Lymphoma. 
 
Version Number: 11 
Current Version Date: October 8, 2013  
 
 
 
Coordinating Center: 
 
Biostatistics Department, City of Hope National Medical Center 
 
1500 E. Duarte Road, Duarte, California 91010 
 
Telephone:  (626) 256-HOPE (4673), extension 65928 
 
Fax: (626) 256-8654 
 Email: 
  cccp@coh.org 
 
*Protocol Chair: 
Robert Chen, MD 
 
City of Hope National Medical Center 
 
1500 E. Duarte Road, Duarte, CA  91010 
 
Telephone:  (626) 256-HOPE (4673), extension 64762 
 
Fax: (626) 301-8116 
 Email: 
rchen@coh.org 
 
Statistician: 
Paul Frankel, Ph.D. 
 
City of Hope National Medical Center 
 
1500 E. Duarte Road, Duarte, CA  91010 
 
Telephone:  (626) 256-HOPE(4673) extension 62478 
 
Fax:  (626) 256-8654  
 Email 
address: pfrankel@coh.org 
 
 
Participating Centers: 
 
 
 
 
 
Local Principal Investigators and Contact Information for Participating Centers:  
 
City of Hope affiliates: 
Stephen Koehler, MD  
 
City of Hope Medical Group, Inc., (COHMG) 
South Pasadena Cancer Center 
209 Fair Oaks Ave. 
South Pasadena, CA 91030 
Telephone:  (626) 396-2900 
Fax:  (626) 396-2911 
Email:  skoehler@coh.org 
 
Solomon Hamburg, MD 
 
Tower Cancer ResearchFoundation(TOW) 
9090 Wilshire Blvd., 2nd Floor 
Beverly Hills, CA  90211 
Telephone:  310-285-7427 
Fax:  310-285-7298  
Email: hamburgs@toweroncology.com 
 


 
 
 
Responsible Research 
Nurse at COH: 
Bernadette Pulone, R.N. 
 
City of Hope National Medical Center 
 
1500 E. Duarte Road, Duarte, CA  91010 
 
Telephone:  (626) 256-HOPE (4673) extension 63469 
 
Fax:  (626) 256-8654  
 Email 
address:  bpullone@coh.org 
 
Responsible Data 
Manager at COH: 
Joel Conrad 
 
City of Hope National Medical Center 
 
1500 E. Duarte Road, Duarte, CA  91010 
 
Telephone:  (626) 256-HOPE (4673) extension 63524 
 
Fax:  (626) 301-8393  
 Email 
address:  jconrad@coh.org 
 
 
Merck Supplied Agent: 
Suberoylanilide Hydroxamic Acid (VORINOSTAT); NSC 701852    
 
 
 


 
 
 
SCHEMA 
 
Indolent Non Hodgkin’s Lymphoma newly diagnosed or with relapsed/refractory disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
REGISTRATION
Cycle: Vorinostat 200mg orally twice daily x 14 days, followed by one 
week rest.  
Rituximab 375 mg/m2 iv D1 q3w 
Lovenox 40 mg subcutaneous injection daily 
Cycle length is 21 days 
Toxicity evaluated on day 1 and 8 of every cycle  
 
Efficacy evaluated every three cycles  


 
 
TABLE OF CONTENTS 
 
 
 
SCHEMA ...................................................................................................................................................... i 
 
TABLE OF CONTENTS ........................................................................................................................... ii 
 
1. OBJECTIVES ....................................................................................................................................... 4 
 
2. BAC KGROUND .................................................................................................................................. 4 
2.1 
Current Status of Lymphoma Care....................................................................................... 4 
2.2 
Suberoylanilide Hydroxamic Acid (VORINOSTAT) .......................................................... 4 
2.3 
Rationale .................................................................................................................................. 4 
 
3. PATIENT SELECTION ...................................................................................................................... 7 
3.1 
Eligibility Criteria ................................................................................................................... 7 
3.2 
Exclusion Criteria ................................................................................................................... 8 
3.3 
Inclusion of Women and Minorities ...................................................................................... 9 
 
4. TREATM ENT PLAN ........................................................................................................................... 9 
4.1 
Suberoylanilide Hydroxamic Acid (VORINOSTAT) Administration ............................... 9 
4.2 
Rituximab Administration ................................................................................................... 10 
4.3 Lovenox 
Administration…………………………………………………………………….. 
4.3 
Supportive Care Guidelines ................................................................................................. 10 
4.4 
Duration of Therapy ............................................................................................................. 11 
 
5. DOSING DELAYS/DOSE MODIFICATIONS ............................................................................... 11 
 
5.1 
Dose Reductions for Toxicity ............................................................................................... 11 
 
5.2 
Treatment Delays and Schedule Modification ................................................................... 12 
 
6. PHARMACEUTICAL INFORMATION ......................................................................................... 12 
6.1 
Suberoylanilide Hydroxamic Acid (NSC 701852) .............................................................. 12 
6.2 
Rituximab .............................................................................................................................. 17 
6.3 Lovenox……………………………………………………………………………………….
 
 
7. STUDY CALENDAR ......................................................................................................................... 19 
 
8. MEASUREMENT OF EFFECT ....................................................................................................... 20 
 
9. REGULATORY AND REPORTING REQUIREMENTS ............................................................. 23 
9.1 
Expedited Adverse Event Reporting ................................................................................... 23 
9.2 Registration 
Guidelines ........................................................................................................ 23 
9.3 
COH DSMB Data Reporting ............................................................................................... 23 
9.4 
Records to be kept and Data Submission Schedule ........................................................... 25 
 
10. STATISTICAL CONSIDERATIONS .............................................................................................. 27 
10.1 
Study Design/Endpoints ....................................................................................................... 27 
10.2 
Sample Size/Accrual Rate .................................................................................................... 27 
10.3  
Stratification factors ............................................................................................................. 27 
10.4 
Reporting and Exclusions ..................................................................................................... 27 


 
 
10.5 
Evaluation of Toxicity ........................................................................................................... 27 
 
11.  CORRELATIVE STUDIES .............................................................................................................. 27 
 
REFERENCES ......................................................................................................................................... 28 
 
INFORMED CONSENT TEMPLATE FOR CANCER TREATMENT TRIALS ............................. 33 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria 
 
 
APPENDIX C 
Drugs known to be Metabolized by Selected CYP450 Isoenzymes 
 
APPENDIX D 
Notification of Toxicity 
 
 


 
 
 
1. OBJECTIVES  
 
1.1. To evaluate the anti-tumor activity of VORINOSTAT plus Rituximab as assessed by the objective response 
rate, time to progression and survival in subjects with indolent lymphoma. 
1.2. To assess the toxicity profile of VORINOSTAT plus Rituximab in this patient population. 
 
2. BACKGROUND  
 
2.1 Current Status of Lymphoma Care 
 
Despite thirty years of clinical trials, little progress has been made in the treatment of low grade lymphoma 
(Horning, 2003). Patients with low grade lymphomas, as classified by the Working Formulation classification, 
tend to respond initially to approaches as disparate as “watchful waiting”, anthracycline based chemotherapy (in 
conjunction with cyclophosphamide (Dana, et al, 1993) or fludarabine (Klasa, et al, 2002; Velasquez, et al, 2003), 
or stem cell transplant (Bierman, et al, 2003; van Besien, et al, 2003), but invariably the lymphoma recurs in over 
50% of patients within 5 years. There is as such no consensus on upfront therapy that can be designated as 
“standard”. 
 Upon recurrence, remissions can be achieved with further chemotherapy, but the disease free intervals tend to be 
shorter with each line of treatment (Dana, et al, 1993). Allogeneic transplant has been successful in selected 
patients, but with greater treatment related mortality (van Besien, et al, 2003), while autologous high dose 
therapy, with or without the addition of high dose radio-labeled antibodies has not been curative (Gopal 2003). In 
recent years, the additional of Rituxan, a targeted antibody,has shown improved outcome and survival in single 
agent and combination chemotherapy regimens, suggesting that aside from its single agent, it acts as a 
chemosensitizer in lymphoma treatment (Czuczman 2003, Czuczman 2004, Forstpointner 2004). Thus, newer, 
more effective agents are necessary. 
 
2.2 
Vorinostat (Suberoylanilide Hydroxamic Acid (VORINOSTAT)) 
 
Vorinostat, (Zolinza, Suberoylanilide hydroxamic acid; NSC 701852)) is a small molecule inhibitor of histone 
deacetylase (HDAC) that binds directly in the enzyme’s active site in the presence of a zinc ion (Finnin et al., 
1999).  Because aberrant HDAC activity has been implicated in a variety of cancers, development of HDAC 
inhibitors is a rational approach to the design of targeted anticancer therapeutics.  Several HDAC inhibitors from 
multiple chemical classes have been developed and are currently in clinical trials.  Trichostatin and butyric acid 
were among the first HDAC inhibitors to be administered to patients, but these were found to be clinically 
unsuitable due to potency and formulation issues (Gilbert et al., 2001; Gore et al., 2002).  Depsipeptide was 
originally selected for clinical study based on its antiproliferative effects; subsequently it was discovered to 
antagonize HDACs (Sausville, 2003) and was the first HDAC inhibitor to demonstrate clinical efficacy (Piekarz 
et al., 2001).  Of the three classes of HDACs, VORINOSTAT targets most human Class 1 (related to the yeast 
transcriptional regulator Rpd3) and Class 2 (similar to the yeast Hda1) enzymes (Marks et al., 2001a; Kelly et al., 
2002); the third class of HDACs (homologues of yeast sir2) requires NAD+ for activity and is not inhibited by 
VORINOSTAT.  Among those currently in clinical trials, VORINOSTAT is the most potent HDAC inhibitor that 
can be administered orally with excellent bioavailability.  It received FDA approval for treatment in patients with 
Cutaneous T Cell Lymphoma on October 6, 2006. Promising activity is being seen in a current CTEP trial for 
indolent lymphoma, with reports pending on several responses, CR and PR, in refractory indolent lymphoma. 
 
 
2.3 
Rationale 
 
2.3.1 
Mechanism of Action 
 


 
 
The HDACs exert their targeted action during post-translational acetylation of core nucleosomal histones, which 
affects chromatin structure, thereby regulating gene expression.  DNA that is wrapped around condensed, non-
acetylated histones is transcriptionally inactive, whereas acetylation of N-terminal histone lysine residues exposes 
DNA to important transcription factors that promote transcriptional activity (Workman and Kingston, 1998; Arts 
et al., 2003).  The dynamic equilibrium between histone acetylation and deacetylation is regulated by histone 
acetyltransferases (HATs) and HDACs.  The action of HDACs on nucleosomal histones leads to tight coiling of 
chromatin and silencing of expression of various genes, including those implicated in the regulation of cell 
survival, proliferation, differentiation, and apoptosis (Jones and Baylin, 2002).  The effects of HDACs are not 
limited to histone deacetylation.  HDACs also act as members of a protein complex to recruit transcription factors 
to the promoter region of genes, including those of tumor suppressors, and they affect the acetylation status of 
specific cell cycle regulatory proteins (Arts et al., 2003).   
 
2.3.2 Nonclinical 
Activity 
 
VORINOSTAT was identified originally by its ability to induce differentiation of murine erythroleukemia cells at 
micromolar concentrations (Richon et al., 1996; Richon et al., 1998). Subsequently, it was found to induce 
differentiation or arrest growth of a wide variety of human carcinoma cells.  To date, VORINOSTAT activity has 
been reported in transformed hematopoietic cells, such as multiple myeloma (MM) (Feinman et al., 2002; 
Mitsiades et al., 2002; Mitsiades, N. et al., 2003), acute promyelocytic leukemia (APL) (Amin et al., 2001), acute 
lymphocytic leukemia (Guo et al., 2002), chronic myelogenous leukemia (Nimmanapalli et al., 2003; Yu et al., 
2003), Waldenstrom’s macroglobulinemia (Mitsiades, C. et al., 2003), and cutaneous T-cell lymphoma (CTCL) 
(Zhang et al., 2003).  Activity has also been reported in cell lines representing other tumor types including 
bladder transitional cell carcinoma (Richon et al., 2000), breast cancer (Huang et al., 2000; Munster et al., 2001; 
Said et al., 2001), prostate cancer (Butler et al., 2000), head and neck squamous carcinoma (Gillenwater et al., 
2002), and colon carcinoma (Peart et al., 2003). 
The antitumor activity of VORINOSTAT was demonstrated in several in vivo models of cancer, including a 
xenograft model of human CWR22 prostate cancer cells (Butler et al., 2000), a mouse model of APL containing 
the promyelocytic leukemia zinc-finger-retinoic acid receptor α fusion gene (PLZF-RARα) (He et al., 2001), and 
an N-methylnitrosourea-induced mammary tumor model in rodents (Cohen et al., 1999).  VORINOSTAT has also 
showed activity when administered daily by intraperitoneal (IP) injections in the CWR22 and PLZF-RARα 
models and by oral (PO) administration in the carcinogen-induced mammary tumor model. 
 
2.3.3 
VORINOSTAT Combination Studies 
 
Accumulating evidence has demonstrated the effectiveness of HDAC inhibitors in combination with several other 
agents in vitro.  The combination of VORINOSTAT and DNA hypomethylating agents (5-azacytidine or 
decitabine) acts synergistically to induce apoptosis, differentiation, and/or cell growth arrest in various cancer cell 
lines (Tabe et al., 2002; Zhu and Otterson, 2003).  When VORINOSTAT was combined with the anti-metabolite 
5-fluorouracil, a supra-additive to additive antiproliferative effect in wild type and mutant-p53 colorectal cancer 
cells was observed (Di Gennaro et al., 2003).  VORINOSTAT with imatinib mesylate (Gleevec®) may be 
effective in chronic myelogenous leukemia (CML) cells that resist imatinib mesylate through increased Bcr-Abl 
expression (Nimmanapalli et al., 2003; Yu et al., 2003).  Minimally toxic concentrations of the proteasome 
inhibitor bortezimib combined with VORINOSTAT resulted in increased apoptosis in human leukemia cells (Yu 
et al., 2003).  In cells from RARα-PLZF/RARα-PLZF transgenic mice and in cells harboring t(15;17) (RARα-
PML fusion genes), VORINOSTAT induced significant apoptosis and growth inhibition, effects that were 
increased by adding all-trans retinoic acid (He et al., 2001).  Pre-treating four human cancer cell lines (including a 
brain tumor line) with VORINOSTAT increased the killing efficiency of etoposide, ellipticine, doxorubicin, or 
cisplatin, but not of the topoisomerase I inhibitor camptothecin (Kim et al., 2003).  However, treating cells in the 
reverse order (anticancer drug followed by VORINOSTAT) was no more cytotoxic than the anticancer drug 
alone.  Finally, overexpression of Bcl-2 or Bcl-XL in leukemia and MM cell lines abolished VORINOSTAT-


 
 
induced apoptosis but did not affect its differentiation or cell cycle regulatory effects (Vrana et al., 1999; 
Mitsiades, N. et al., 2003; Peart et al., 2003).  This suggests that agents blocking Bcl-2 expression or function 
could be effectively combined with VORINOSTAT.  Studies done with other HDACs have suggested that a 
consequence of HDAC inhibitor-induced heat shock protein 90 (Hsp 90) acetylation is depletion of the Hsp 90 
client protein Her-2 and increased apoptosis of breast cancer cell lines induced by taxotere, trastuzumab, 
epothilone B, and gemcitabine (Fuino et al., 2003; Yu et al., 2002).  In addition to these potentially additive or 
synergistic interactions between VORINOSTAT or other HDACs and various anticancer drugs, VORINOSTAT 
has shown synergistic activity when combined with radiotherapy in prostate cancer cell spheroids (Sgouros et al., 
2002). 
 
2.3.4 
Phase 1 Clinical Experience 
 
A phase 1 study evaluated VORINOSTAT administered intravenously (IV) to patients with advanced solid 
tumors and hematologic malignancies (Kelly et al., 2003).  VORINOSTAT was administered using two 
schedules:  2-hour IV infusion daily X 3 q21d, or daily X 5 for 1 to 3 weeks.  No dose-limiting toxicities (DLTs) 
were observed in eight patients administered VORINOSTAT daily X 3 q21d at doses of 75, 150, 300, 600, and 
900 mg/m²/day.  One solid tumor patient given 900 mg/m² on the daily X 5 schedule for 3 weeks developed acute 
respiratory distress and grade 3 hypotension.  Among five other patients at this dose, no additional DLTs were 
observed.  Among 12 hematologic and 17 solid tumor patients enrolled on the daily X 5 schedule (300, 600, and 
900 mg/m²/day), therapy was delayed >1 week for grade 3/4 leukopenia and/or thrombocytopenia in two of five 
patients with hematologic malignancies given 600 mg/m² for 3 weeks.  The maximum tolerated dose (MTD) for 
hematologic malignancy patients was 300 mg/m² daily X 5 for 3 weeks.  An MTD for solid tumors was not 
determined because the study was terminated when an oral formulation became available. The mean terminal half-
life (t1/2) ranged from 21 - 58 minutes, and the dose was linearly proportional to the area under the concentration 
versus time curve (AUC).  Acetylated histones were detected in peripheral blood mononuclear cells (PBMCs) up 
to 4 hours post-infusion at higher dose levels.  This observation was confirmed by immunohistochemical analyses 
of post-therapy tumor biopsies.  Four patients, including two with lymphoma and two with bladder cancer, 
experienced objective tumor regression with clinical improvement in tumor-related symptoms. 
 
As of June 2004, VORINOSTAT capsules have been administered to 143 patients with advanced solid tumors or 
hematologic malignancies in three phase 1 trials and three phase 2 trials (Investigator’s Brochure, 2004) at total 
daily doses ranging from 200 to 900 mg.  The MTD of continuous dosing (no rest period) of oral VORINOSTAT 
is 400 mg q.d. or 200 mg b.i.d.  When the agent is given intermittently, the MTD is 300 mg b.i.d. daily × 3 days 
per week or 250 mg t.i.d. x 14 days followed by 7 days of rest.  The DLTs are non-hematologic (anorexia, 
dehydration, diarrhea, and fatigue).  The most common hematologic adverse events are anemia and 
thrombocytopenia, which are rapidly reversible after study drug interruption.  Pharmacokinetic analysis of 26 
patients has indicated that the bioavailability of oral VORINOSTAT is approximately 46%.  VORINOSTAT 
doses in the range of 200 - 600 mg produced maximum concentration (Cmax) and drug exposure (AUC) curves that 
were linearly proportional.  The t1/2 of oral VORINOSTAT ranges from 92 to 150 minutes, and preliminary data 
suggest that administration of VORINOSTAT with food does not appear to substantially alter the rate or extent of 
absorption.  Inhibition of HDAC activity was achieved in PBMCs at the 200 mg dose level.  At dose levels of 400 
and 600 mg, the duration of HDAC inhibition lasted >10 hours.  
 
Significant antitumor activity has been observed among members of the above patient population.  In the ongoing 
phase 1 study of oral VORINOSTAT, seven patients with heavily pre-treated diffuse large B-cell lymphoma were 
entered.  Among these patients, one complete response (CR) and one partial response (PR) were observed.  In 
addition, one patient has had a significant PET scan response.  The PR lasted 5 months, the PET scan response 
lasted 6 months, and the CR is ongoing with a duration >12 months.  Decrease in tumor mass, pleural effusion, 
and improvement of tumor-related pain or shortness of breath have also been observed in patients with 
mesothelioma.  In an ongoing phase 2 study of VORINOSTAT in patients with heavily pretreated CTCL or 
peripheral T-cell lymphoma, objective responses have been observed (including PRs in 5 of 13 patients), and 8 of 


 
 
10 patients reported decreased pruritus. In the published Phase I study of VORINOSTAT, the MTD was 
identified as 200 mg PO bid for continuous dosing and 300 mg PO bid for three-day-per-week dosing (Kelly WK, 
et al 2005) 
 
Based on the data from these clinical studies, the recommended doses and schedules of oral VORINOSTAT 
administration for phase 2 trials are 400 mg q.d., 200 mg b.i.d., or 300 mg b.i.d. daily × 3 days per week in 
patients with either solid tumors or hematologic malignancies. 
 
2.3.5 
Potential for Drug Interactions 
 
In laboratory studies using cultured human hepatocytes, statistically significant and concentration-dependent 
suppression of the P450 isoenzymes CYP2B6, 2C9, and 2C19 was seen at concentrations exceeding the levels 
achieved following oral administration (10 to 50 μM) of VORINOSTAT, while CYP3A4 suppression was 
observed at clinically relevant (2 μM) concentrations of the agent (Investigator’s Brochure, 2004).  These effects 
could be the result of VORINOSTAT-induced changes in the cellular machinery that generates these enzymes or 
VORINOSTAT metabolites. These observations suggest that the potential exists for interactions between 
VORINOSTAT and concurrently administered drugs, over-the-counter medication, or alternative therapies.  For 
this reason, caution should be observed when treating patients taking any agent found in Appendix C, a list of 
drugs or substances known to affect or with the potential to affect selected P450 isoenzymes. 
 
2.3.6 
Use of VORINOSTAT in Lymphoma 
 
There is good preclinical evidence to support the use of HDAC inhibitors in lymphoid malignancies. Increased 
histone acetylation has been shown to regulate terminal B cell differentiation, as well as to cause apoptosis via 
upregulation of p21waf-1/cip1. .Several natural agents have been shown to have HDAC inhibitory activity, however 
the orally bioavailable synthetic compound, suberoylanilide hydroxamic acid, has to been shown to effectively 
bring about increased histone acetylation in B cell malignancies. VORINOSTAT induces growth arrest and 
apoptosis in B cell tumor lines,at least in part via upregulation of p21waf-1/cip1, in a caspase independent manner. B 
cell tumor lines were more sensitive to VORINOSTAT than solid tumor lines in vitro (Mitsiades, et al 2003).  
In clinical trials as well, responses among patients with lymphoid malignancies were prominent. In the initial 
phase I study using IV VORINOSTAT, of the four responders, two were lymphoma patients (Kelly, et al, 2003)  
In the ongoing phase I studies, there were two responders among the seven lymphoma patients, one CR and one 
PR. In a Phase II trial of VORINOSTAT in cutaneous T cell lymphoma presented at this year’s ASH meeting, 
five out of 13 patients were partial responders, and in a Phase I study presented at last year’s meeting reduction in 
tumor size was seen in six out of 21 heavily pretreated patients with NHL and Hodgkin’s lymphoma. In our 
ongoing phase II study of vorinostat alone in relapsed or refractory indolent lymphoma patients, at the first stage 
evaluation point, 4 CR, 2 PR, and several patients with prolonged stable disease were seen; the trial is currently 
accruing to the second stage. Thus, a combination trial with rituxan in upfront, relapsed, and refractory patients is 
indicated.  
 
2.3.7 
Rituximab (IDEC-C2B8, Rituxan) 
 
Rituximab is a chimeric IgG1 monoclonal antibody  targeting the CD20 surface antigen present on both normal 
lymphocytes and B-cell lymphomas. The activity of this agent is multifaceted, in that it leads to direct lysis by 
complement activation as well as antibody dependant cell mediated cytotoxicity, triggers apoptosis, and may lead 
to various signaling pathway changes in targeted cells (reviewed in Cartron 2004). Aside from its direct effect, it 
appears to also act as a chemosensitizer by blocking IL-10 binding, leading to decreased intracellular bcl-2 ,  and 
a pro-apoptotic environment (Demidem, 1997, Alas D 2001). This suggests that rituximab may synergise with 
vorinostat’s pro-apoptotic activity. It is thus reasonable to combine the two agents, vorinostat and rituximab, in 
indolent lymphomas. 


 
 
 
 
Given the activity seen in relapsed and refractory patients with vorinostat alone, we propose a Phase II study of 
vorinostat at 200 mg PO b.i.d. on a two week on, one week off schedule in patients with low grade lymphomas in 
combination with rituximab, at 375 mg/m2 given every three weeks on day 1 of the cycle along with vorinostat. 
Included in this cohort are patients with low-grade lymphomas according to the Working Formulation classification, 
newly diagnosed or who have recurred after rituxan and/or chemotherapy.  
 
3. PATIENT SELECTION 
 
3.1  Eligibility Criteria 
 
3.1.1 
Patients must have histologically or cytologically confirmed indolent Non-Hodgkin’s Lymphoma 
(Included in this category are newly diagnosed or relapsed/refractory follicular center lymphomas 
grade I, II, III, relapsed /refractory marginal zone B-cell lymphoma (nodal and extranodal), 
relapsed/refractory mantle cell lymphoma).    
 
3.1.2 
Patients must have measurable disease by CT scan. PET scan evaluations are desirable but not 
mandatory, so that patients with negative PET scans but measurable disease by CT are eligible. 
 
3.1.3 
Patients may have had up to four prior chemotherapeutic regimens. Steroids alone and local radiation 
do not count as regimens (Radiotherapy must have been completed at least 14 days prior to starting 
vorinostat). Rituxan alone does not count as a regimen, however, Bexxar or Zevalin do.  For treated 
patients, the most recent therapy must have failed to induce a complete response (i.e. there is 
persistent disease by CT or PET), or there must be disease progression or recurrence after the most 
recent therapy.  
 
3.1.4   
Patients may be enrolled who relapse after autologous stem cell transplant if they are at least three 
months after transplant, and after allogeneic transplant if they are at least six months posttransplant. 
To be eligible after either type of transplant, patients should have no active related infections (i.e. 
fungal or viral). In the case of allogeneic transplant relapse, there should be no active acute graft 
versus host disease (GvHD) of any grade, and no chronic Graft versus Host disease other than mild 
skin, oral, or ocular GvHD not requiring systemic immunosuppression.     
 
3.1.5 
Age 18 years.  Because no dosing or adverse event data are currently available on the use of 
VORINOSTAT in patients <18 years of age, children are excluded from this study but will be eligible 
for future pediatric single-agent trials, if applicable. 
 
3.1.6 
Life expectancy of greater than 3 months. 
 
3.1.7 
ECOG performance status 2 (Karnofsky 60%; see Appendix A). 
 
3.1.8 
Patients must have normal organ and marrow function as defined below: 
 
 
Absolute Neutrophil Count 
>1,000/mcL 
 
platelets 
>100,000/mcL 
 
total bilirubin 
within normal institutional limits; patients with elevation of 
unconjugated bilirubin alone, as in Gilbert’s Disease, are eligible. 
 
AST(SGOT)/ALT(SGPT) 
2.5 X institutional upper limit of 
 
 
 
 
 
 
 
 
 
normal creatinine up to and including 2 mg/dl 


 
 
 
3.1.9  
Pre-menopausal women must have a negative serum pregnancy test prior to entry on this study. The 
effects of VORINOSTAT on the developing human fetus at the recommended therapeutic dose are 
unknown.  For this reason and because HDAC inhibitors are known to be teratogenic, women of 
child-bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study participation.  
Should a woman become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 
 
3.1.10 
Ability to understand and the willingness to sign a written informed consent document. 
 
3.2  
Exclusion Criteria 
 
 3.2.1  
Patients who have had chemotherapy within 4 weeks, or radiotherapy within 2 weeks or those who 
have not recovered from adverse events due to agents administered more than 4 weeks earlier are 
excluded. This does not include use of steroids, which may continue until two days prior to 
enrollment. Low dose chlorambucil should be stopped two weeks prior to beginning VORINOSTAT. 
Valproic acid should be stopped at least two weeks prior to enrollment. Nitrosureas and mitomycin 
should be stopped 6 weeks prior to enrollment. 
 
3.2.2 
Patients may not be receiving any other investigational agents. 
 
3.2.3 
Patients with known brain metastases are excluded from this clinical trial unless the metastases are 
controlled after therapy and have not been treated with steroids within the past two months. 
 
3.2.4 
History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
VORINOSTAT. 
 
3.2.5 
There must be no plans for the patient to receive concurrent hormonal, biological or radiation therapy. 
 
3.2.6 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements.  
 
3.2.7 
Pregnant women are excluded from this study because VORINOSTAT is a HDAC inhibitor agent 
with the potential for teratogenic or abortifacient effects.  Because there is an unknown but potential 
risk for adverse events in nursing infants secondary to treatment of the mother with VORINOSTAT, 
breastfeeding should be discontinued if the mother is treated with VORINOSTAT. 
 
3.2.8 
HIV-positive patients receiving combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with VORINOSTAT.  In addition, HIV patients not 
receiving combination antiretroviral therapy are also ineligible as these patients are at increased risk 
of lethal infections when treated with marrow-suppressive therapy.    
 
 
 
3.2.9 
Patients with other active malignancies are ineligible for this study. 
 
3.2.10 Patients with preexisting or previous coagulation issues are not excluded from study as long as 1) 
previous pulmonary embolism or deep vein thrombosis have been adequately treated or 2) if they are 
actively receiving Coumadin or lovenox for anticoagulation.  Patients who are already on Coumadin 
or Lovenox do not need to take additional 40 mg subcutaneous injections daily.  
 


 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
4. TREATMENT PLAN 
 
4.1  
Suberoylanilide Hydroxamic Acid (VORINOSTAT) Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks are 
described in Section 6.  Appropriate dose modifications for VORINOSTAT are described in Section 5.  No 
investigational or commercial agents or therapies other than those described below may be administered with 
the intent to treat the patient’s malignancy. 
 
A cycle of therapy will consist of VORINOSTAT 200mg twice daily administered orally for 14 days 
followed by a seven day break on a 21 day cycle for the first cycle.  If tolerated, the dose may be increased 
after the 2nd cycle to 200 mg TID x 14/21 days. If necessary, dose de-escalation may be instituted by reducing 
one of the daily doses by 100 mg; so, for example, patients might receive an am dose of 300 mg and a pm 
dose of 200 mg. Rituximab will be infused on day 1 of each cycle at the standard dose of 375 mg/m2 
Radiological assessment by CT and/or PET scan will take place at baseline and after every three cycles (every 
3 months). Response will be assessed by standard criteria (Cheson BD, et al 1999). Toxicity will be assessed 
on days 1 and 8 of every cycle, and graded using the NCI CTCAE version 3.0. Patients with measurable 
response or stable disease may continue receiving VORINOSTAT until progression. Patients who achieve 
CR will receive two further cycles of VORINOSTAT plus rituximab and then discontinue drug. Patients who 
achieve complete response may be restarted on drug in the event of relapse six months or greater from the 
time of initial CR, given the chronic relapsing nature of indolent lymphomas. Compliance with treatment will 
be monitored by use of drug diaries.  
 
Because many drugs including antineoplastic agents are metabolized by the cytochrome P450 system, there is 
a potential for interaction of VORINOSTAT with concomitantly administered drugs.  The case report form 
must capture the concurrent use of all other drugs, over-the-counter medications, or alternative therapies.   
 
Patient compliance will be monitored using drug diaries, which will be reviewed on day 1 of each cycle after 
cycle 1. 
 
4.2 
Rituximab Administration 
 
Rituximab will be administered at a dose of 375 mg/m2 on day 1 of every cycle, every three weeks. 
The initial dose rate should be 50 mg/hour IV for the first hour.  If no toxicity is seen, the dose rate may be 
escalated gradually to a maximum of 400 mg/hour.  Subsequent doses have required much less infusion time. 
 If the first dose of rituximab is well tolerated, the starting flow rate for subsequent doses is 100 mg/hour, 
then increased gradually (100 mg/hour increments at 30-minute intervals) not to exceed 400 mg/hour.   
 
Patients may experience transient fever and rigors with infusion.  When these occur, the antibody infusion 
should be temporarily discontinued or slowed.  When symptoms improve, the infusion should be resumed, 
initially at half the previous rate.  Following the antibody infusion, the intravenous line should be kept open 
for medications, as needed.  If there are no complications, the intravenous line may be discontinued after one 
hour of observation. 
 
Oral premedication (acetaminophen and diphenhydramine hydrochloride) may be administered 30 to 60 
minutes prior to starting each infusion of rituximab. 
 


 
 
Lovenox Administration 
 
Lovenox (enoxaparin) will be administered at a dose of 40 mg subcutaneously daily.  Patients will be 
educated by nursing staff on how to perform daily injections.  Administration should be alternated between 
left and right anterolateral and left and right posterolateral abdominal wall.  The whole length of the needle 
should be introduced into a skin fold held between the thumb and the forefinger.  The skin fold should be 
held throughout the injection.   
 
 
4.3 
Supportive Care Guidelines 
 
4.3.1 Antiemetics 
 
Individualization of antiemetic treatment for patients receiving VORINOSTAT is required, as some patients 
require no antiemetic therapy, while others may require more intense therapy. Recommended antiemetics 
include: ondansetron, prochlorperazine, metoclopramide, lorazepan, or diphenhydramine. It is recommended 
that steroids not be used for anti-emesis. 
 
4.3.2  Chemotherapy 
 
 
 
 
Concurrent chemotherapy is not allowed in this study.  
 
4.3.3  Complimentary or Alternative medications 
 
Patients may not take CAM medications while on protocol. Routine vitamin supplementation is allowed. 
 
4.3.4  Growth Factors 
 
Patients already on erythropoeitin or aranesp for lymphoma related anemia may continue to use these agents. 
Use of G-CSF or erythropoeitin is allowed after the first cycle. 
 
4.3.5 Radiation Therapy 
 
Patients who require localized external beam radiotherapy at the time of protocol screening should receive it 
prior to study entry. 
 
Patients who require localized external beam radiotherapy during study will be considered to have 
progression of lymphoma and will be removed from study. 
 
4.3.6 Diarrhea 
 
Treat diarrhea promptly with appropriate supportive care, including loperamide. Instruct patients to begin taking 
loperamide at the first signs 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. Daily dose should not exceed 16 mg/day. 
Loperamide should not be taken prophylactically. Advise patients to drink plenty of clear fluids to help prevent 
dehydration caused by diarrhea. Avoid loperamide if there is the presence of blood or mucus in the stool or if 
diarrhea is accompanied by fever.  
4.3.7 Oral Intake and Hydration 
 


 
 
Care should be taken to ensure adequate hydration during and after treatment. Popsicles and Gatorade have 
been found to be useful in this setting. 
 
4.3.8 Anticoagulation prophylaxis 
 
Patient will need to take Lovenox 40 mg subcutaneously daily when patients are getting active treatment with 
vorinostat and rituxan.  Five research participants on this study have developed either pulmonary embolism or 
deep vein thrombosis.  These have been without symptoms and found on CT scans.       Lovenox (40 mg) 
subcutaneously will be taken starting from Cycle 1 Day 1 of study to prevent pulmonary embolus and deep 
vein thrombosis.  Lovenox will continue for at least 28 days status post last dose of vorinostat or rituximab.  
For patients with creatinine clearance less than 30 ml/min, lovenox dose will be 30 mg subcutaneously daily. 
 Elderly patients with creatinine clearance less than 50 ml/min should also be dosed at 30 mg subcutaneously 
daily. 
 
 
4.4  
Duration of Therapy 
 
Patients who achieve CR as defined in section 9 will receive two further cycles of VORINOSTAT plus 
rituximab and then discontinue drug. Radiologic studies will be continued every three months for the first 
year, and at a minimum of every six months for the next two years. 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the following 
criteria applies: 
 
 
Disease progression, 
 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Unacceptable adverse event(s), 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient’s condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
 
4.5 
Duration of Follow Up 
 
Patients will be followed until disease progression is noted or until death, whichever occurs first.  Patients 
removed from study for unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
 
5.1  
Vorinostat Dose Reductions for Toxicity: 
 
Treatment will be administered at 100 mg daily less than their previous dose for patients who present to 
treatment and are found to have ANC 500, but ≤ 1000, or platelet counts 50K but ≤75K. This dose 
reduction is reversible with normalization of counts.  
 
 
Treatment will be held for patients who present with: 


 
 
1. non-hematologic toxicity of grade 3 or 4, until toxicity resolves to below grade 2. These patients will 
restart at 100 mg daily less than their previous dose. If this dose leads to recurrence of the toxicity at grade 3 
or greater, the patient will come off study. 
2. hematologic toxicity of ANC <500, or platelet count <50K. Should dose need to be held for greater than 
two weeks, upon recovery of ANC >1000 or platelet count >50 patient may restart at 100 mg daily less than 
their previous dose. If this dose also leads to ANC<500 or platelet count <50, then patient should come off 
study. 
 
Treatment will be discontinued in patients who experience toxicity of grade 3 or greater that does not resolve 
within 3 weeks. Requirement for more than two dose reductions mandates removal from the study. Delay of 
protocol treatment for more than four weeks from date of scheduled treatment mandates removal from 
protocol treatment, unless there are extenuating circumstances and approved by the principal investigator.  
 
Lovenox Dose Reductions for Toxicity: 
Hematologic Toxicity:  If platelet count drops to <50K, lovenox should be held until platelets recover. 
 
 
 
5.2 
Treatment Delays and Schedule Modification 
 
Brief interruptions and delays in the 21-day cycle may occasionally be required due to travel delays, airport 
closure, inclement weather, family responsibilities, security alerts, government holidays, etc. This can also 
extend to complications of disease or unrelated medical illness not related to disease progression. These 
delays will not be considered protocol violations. 
 
 
6. PHARMACEUTICAL INFORMATION 
 
6.1 
Suberoylanilide Hydroxamic Acid (NSC 701852) 
 
Chemical Name: 
N-hydroxy-N’-phenyl-octane-1,8-diotic acid diamide;  
N-hydroxyl-N’-phenyl (9CI) octanediamide  
 
Other Names:  
VORINOSTAT, L-001079038, WIN 64652, MSK390, AP390 
 
Classification:  
Antineoplastic 
 
CAS Registry Number: 
149647-78-9 
 
Molecular Formula: 
C14H20N203 
 M.W.: 
264 
 
Approximate Solubility:  
Water < 5 mg/mL 
 
Description:  
Histone deacetylase (HDAC) inhibitor  
 
Mode of Action:  
Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling 
and gene transcription via the dynamic process of acetylation and deacetylation of core 
histones. 
 
Suberoylanilide hydroxamic acid, a potent inhibitor of HDAC activity, binds directly to the 
catalytic pocket of HDAC enzymes. VORINOSTAT causes G1 or G2 phase cell-cycle arrest, 
apoptosis, or differentiation in cultured transformed cells. 


 
 
 
How Supplied:  
Suberoylanilide hydroxamic acid is supplied by Merck and Co., Inc.  Suberoylanilide 
hydroxamic acid is supplied in the following strengths: 
1. a white, opaque gelatin capsule containing 100 mg (size 3 capsule) of 
suberoylanilide hydroxamic acid  
2. a white, opaque gelatin capsule containing 200 mg  (size 1 capsule) of 
suberoylanilide hydroxamic acid. 
 
The inactive ingredients contained in each capsule are microcrystalline cellulose, sodium 
croscarmellose, and magnesium stearate.  
 
Suberoylanilide hydroxamic acid 100 mg capsules are supplied in bottles of 120 capsules and 
200 mg capsules are supplied in bottles of 100 capsules. 
 
Storage:  
Store suberoylanilide hydroxamic acid capsules at room temperature, 15 to 30 ºC (59 to 86 
ºF).  Transient temperature spikes up to 40 ºC (104 ºF) for up to 24 hours are permissible. 
 
Stability: 
Shelf life stability studies of the intact bottles are ongoing. 
 
Route of Administration:  
Orally 
 
Method of Administration:  
Unless otherwise stated in the protocol, suberoylanilide hydroxamic acid 
capsules must be administered whole. The absolute bioavailability of 
suberoylanilide hydroxamic acid under fasted or fed conditions is approximately 
46%. Oral administration with food does not appear to substantially alter the rate 
or extent of absorption. 
 
Potential Drug Interactions: 
In cultured human hepatocytes, suberoylanilide hydroxamic acid was shown to 
inhibit CYP2B6, CYP2C9, CYP2C19, and CYP3A4 isoenzymes. Therefore, it 
is possible that suberoylanilide hydroxamic acid may interact with drugs that are 
metabolized by the P450 CYP isoenzymes. Caution should be exercised when 
combining the study agent with medications that are metabolized by these 
isoenzymes. 
 
Special Handling: 
VORINOSTAT is an anticancer drug. Powder spills from VORINOSTAT capsules 
due to damaged or broken capsules should be cleaned up carefully so as to 
minimize inhalation. The affected area must be washed at least 3 times with ethyl 
alcohol, followed by water. 
 
Patient Care Implications: 
Because VORINOSTAT’s dose limiting toxicities are anorexia, dehydration, 
diarrhea, and fatigue, patients should maintain adequate fluid and food intake. 
Encourage patients to seek a nutritional consult. 
 
Comprehensive Adverse Events and Potential Risks List (CAEPR):   
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential 
adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Agent Specific Adverse Event List (ASAEL), appears in a separate column and is 
identified with bold and italicized text. This subset of AEs (ASAEL) contains events that are considered 'expected' for 
expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/reporting/adeers.html for further clarification. Frequency is provided based on 299 patients. Below 


 
 
is the CAEPR for VORINOSTAT (vorinostat). 
 
Version 2.3, November 30, 20061 
 
Adverse Events with Possible 
Relationship to VORINOSTAT (Vorinostat) 
(CTCAE v3.0 Term) 
[n=299 patients] 
 
 
 
'Agent Specific Adverse 
Event List' 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
BLOOD/BONE MARROW 
Hemoglobin 
 
 
Hemoglobin 
Leukocytes (total WBC) 
 
 
Leukocytes 
 
Lymphopenia 
 
Lymphopenia 
Neutrophils/granulocyte
s (ANC/AGC) 
 
 
Neutrophils/granulocytes 
(ANC/AGC) 
Platelets 
 
 
Platelets 
CARDIAC ARRYTHMIA 
 
Prolonged QTc interval 
 
 
COAGULATION 
 
INR (International 
Normalized Ratio of 
prothrombin time 
 
 
CONSTITUTIONAL SYMPTOMS 
Fatigue (asthenia, 
lethargy, malaise) 
 
 
Fatigue (asthenia, lethargy, 
malaise) 
 
Fever (in the absence of 
neutropenia, where 
neutropenia is defined as 
ANC <1.0 x 10e9/L) 
 
 
 
Rigors/chills 
 
 
Weight loss 
 
 
Weight loss 
DERMATOLOGY/SKIN 
 
Hair loss/alopecia (scalp or 
body) 
 
 
 
 
Dermatology/Skin – 
Other:  skin necrosis 
 
GASTROINTESTINAL 
Anorexia 
 
 
Anorexia 
 
Constipation 
 
 
 
Dehydration 
 
Dehydration 
Diarrhea 
 
 
Diarrhea 
 
Dry mouth/salivary gland 
(xerostomia) 
 
 
 
Heartburn/dyspepsia 
 
 
Nausea 
 
 
Nausea 
 
Taste alteration (dysgeusia) 
 
 
Vomiting 
 
 
Vomiting 
INFECTION 


 
 
 
Febrile neutropenia (fever of 
unknown origin without 
clinically or 
microbiologically 
documented infection)(ANC 
<1.0 x 10e9/L, fever >=38.5 
degrees C) 
 
 
 
Infection with normal ANC 
or Grade 1 or 2 neutrophils - 
Select 
 
 
 
Infection (documented 
clinically  or 
microbiologically) with 
Grade 3 or 4 neutrophils 
(ANC <1.0 x 10e9/L - Select 
 
 
LYMPHATICS 
 
Edema: limb 
 
 
METABOLIC/LABORATORY 
 
Albumin, serum-low 
(hypoalbuminemia) 
 
 
 
Alkaline phosphatase 
 
 
 
ALT, SGPT (serum glutamic 
pyruvic transaminase) 
 
 
 
AST, SGOT (serum glutamic 
oxaloacetic transaminase) 
 
 
 
Bilirubin 
(hyperbilirubinemia) 
 
 
 
Calcium, serum-low 
(hypocalcemia) 
 
 
Creatinine 
 
 
 
Glucose, serum-high 
(hyperglycemia) 
 
 
Glucose, serum-
high(hyperglycemia) 
 
Magnesium, serum-high 
(hypermagnesemia) 
 
 
 
Phosphate, serum-low 
(hypophosphatemia) 
 
 
 
Potassium, serum-low 
(hypokalemia) 
 
 
 
Sodium, serum-low 
(hyponatremia) 
 
 
MUSCULOSKELETAL/SOFT TISSUE 
 
Musculoskeletal/Soft Tissue - 
Other (muscle spasms) 
 
 
 
Muscle weakness, 
generalized or specific area 
(not due to neuropathy) - 
Select 
 
 
NEUROLOGY 
 
Dizziness 
 
 
 
Neuropathy: sensory 
 
 


 
 
PAIN 
 
Pain - abdomen NOS 
 
 
 
Pain - head/headache 
 
 
PULMONARY/UPPER RESPIRATORY 
 
Cough 
 
 
 
Dyspnea (shortness of breath) 
 
 
VASCULAR 
 
Thrombosis/thrombus/emboli
sm 
 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting ADEERSMD@tech-res.com.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 


 
 
Also reported on VORINOSTAT (vorinostat) trials but with the relationship to VORINOSTAT (vorinostat) still 
undetermined: 
ALLERGY/IMMUNOLOGY - vasculitis 
CARDIAC ARRHYTHMIA - atrial fibrillation; palpitations; ventricular fibrillation 
CARDIAC GENERAL - cardiac ischemia/infarction; hypertension; hypotension 
COAGULATION - PTT 
CONSTITUTIONAL SYMPTOMS - insomnia; sweating 
DEATH – death NOS 
DERMATOLOGY/SKIN –nail changes; pruritus; rash; ecchymosis 
GASTROINTESTINAL - dysphagia; esophagitis; flatulence; gastritis; mucositis/stomatitis 
HEMORRHAGE/BLEEDING - epistaxis; hematuria; hemoptysis; petechiae 
INFECTION – infection – NOS 
METABOLIC/LABORATORY – hypercalcemia; hyperkalemia; hypernatremia; hypoglycemia; hypomagnesemia; 
proteinuria 
MUSCULOSKELETAL/SOFT TISSUE - gait/walking 
NEUROLOGY - confusion 
PAIN - back pain; chest/thorax pain; flank pain; gingival pain; joint pain; limb pain; muscle pain; pharyngolaryngeal pain 
PULMONARY/UPPER RESPIRATORY - sinus congestion 
RENAL/GENITOURINARY – urinary incontinence; urinary retention 
VASCULAR - deep vein thrombosis 
 
 
Note: VORINOSTAT (vorinostat) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously associated with 
either agent. 
 
Availability 
 
VORINOSTAT is an investigational agent supplied to investigators by Merck and Co. Inc. 
 
 
6.2 
Rituximab 
 
Other names 
IDEC-C2B8, Rituxan. 
Classification 
Monoclonal antibody.   
Mode of action 
This chimeric mouse/human anti-CD20 antibody binds human complement and causes lysis of B-cells. It 
has significant activity in assays for antibody dependent cellular cytotoxicity. 
Storage and stability 
Stored at 2-80 C.  Reconstituted antibody is stable for 24 hours upon refrigeration followed by 12 hours 
at room temperature. 
Preparation 
Diluted with normal saline to a concentration of 1 - 4 mg/mL.  Shaking can cause aggregation and 
precipitation of the antibody and should be avoided. 
 
 Route of Administration:  
Intravenous 
 
AVAILABILITY AND ACCOUNTABILITY 
 


 
 
Rituximab is commercially available in 10 mL (100 mg) and 50 mL (500 mg) single-use vials at a 
concentration of 10 mg /mL. Use of rituximab is considered standard care for this indication, and will not 
be provided by Merck.  
 
Incompatibilities 
 
Do not mix or dilute rituximab with other drugs. No incompatibilities between rituximab and 
polyvinylchloride or polyethylene bags have been observed. 
 
Side effects 
 
1. Infusion related symptoms: Fevers, chills, rigors, hypotension, anaphylaxis or hypersensitivity reactions, 
arrhythmia, dyspnea, bronchospasm, angioedema.  In rare cases, severe and fatal cardiopulmonary 
events, including hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial 
infarction, and cardiogenic shock, have occurred (4-7/10,000 patients or 0.04-0.07%.)  Nearly all fatal 
infusion-related events occurred in association with the first infusion. Patients with preexisting cardiac 
conditions, including arrhythmia and angina, have had recurrences of these cardiac events during 
rituximab infusions. 
 
2. Gastrointestinal: Nausea, vomiting. 
 
3. Hematologic: Leukopenia, anemia, thrombocytopenia.  In clinical trials, NCI CTC Grade 3 and 4 
cytopenias were reported in 48% of patients treated with rituximab; these include: lymphopenia (40%), 
neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%).  The median duration of 
lymphopenia was 14 days (range, 1 to 588 days) and of neutropenia was 13 days (range, 2 to 116 days).  
A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic 
anemia following rituximab therapy were reported.  
 
In addition, there have been a limited number of postmarketing reports of prolonged pancytopenia, 
marrow hypoplasia, and late onset neutropenia (defined as occurring 40 days after the last dose of 
rituximab) in patients with hematologic malignancies.  In reported cases of late onset neutropenia (NCI-
CTC Grade 3 and 4), the median duration of neutropenia was 10 days (range 3 to 148 days).  
Documented resolution of the neutropenia was described in approximately one-half of the reported cases; 
of those with documented recovery, approximately half received growth factor support.  In the remaining 
cases, information on resolution was not provided.  More than half of the reported cases of delayed onset 
neutropenia occurred in patients who had undergone a prior autologous bone marrow transplantation.  In 
an adequately designed, controlled, clinical trial, the reported incidence of NCI-CTC Grade  3 and 4 
neutropenia was higher in patients receiving rituximab in combination with fludarabine as compared to 
those receiving fludarabine alone (76% [39/51] vs. 39% [21/53]).33 
 
4. Dermatologic: Rash, pruritus, urticaria, and rarely severe mucocutaneous reactions.  
 
5. Infectious: Reactivation of hepatitis B; reactivation of other viral infections or increased susceptibility to 
other infections.  Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death 
has been reported in some patients with hematologic malignancies treated with rituximab.  The majority 
of patients received rituximab in combination with chemotherapy.  The median time to the diagnosis of 
hepatitis was approximately four months after the initiation of rituximab and approximately one month 
after the last dose. 
 
6. Renal and electrolyte: Renal toxicity has occurred in patients with high numbers of circulating malignant 
cells (>25,000/mm2 ) or high tumor burden who experience tumor lysis syndrome. Although rare, tumor 


 
 
lysis syndrome has been reported in postmarketing studies and is characterized in patients with a high 
number of circulating malignant cells (>25,000 ul) by rapid reduction in tumor volume, renal 
insufficiency, hyperkalemia, hypocalcemia, hyperuricemia, and hyperphosphatemia 
 
7. Other: Headache, asthenia.  The following immune serious adverse events have been reported to occur rarely 
(<0.1%) in patients following completion of rituximab infusions: arthritis, disorders of blood vessels 
(vasculitis, serum sickness and lupus-like syndrome), lung disorders including pleuritis and scarring of the 
lung (bronchiolitis obliterans), eye disorders (uveitis and optic neuritis), and severe bullous skin reactions 
(including toxic epidermal necrolysis and pemphigus) that may result in fatal outcomes.  Patients may have 
these symptoms alone or in combination with rash and polyarthritis.  Five patients have developed deep vein 
thrombosis or pulmonary embolism as well.  These were asymptomatic and found incidentally on CT scans.   
Nursing implications 
 
1. Monitor vital signs prior to Rituximab and if the patient has clinical deterioration during the infusion. 
 
2. Have epinephrine for subcutaneous injections, diphenhydramine for intravenous injection, and 
resuscitation equipment for emergency management of anaphylactoid reactions available. 
 
3. Monitor and alter infusion rates in the presence of toxicities. 
 
4. Prolonged pancytopenia and bone marrow hypoplasia have been submitted as postmarketing reports. 
Patients should be monitored closely. 
 
5. Prophylaxis for tumor lysis syndrome should be used in patients with high tumor burden, particularly 
with markedly elevated numbers of circulating malignant cells. Precautionary hospitalization should be 
made available for patients who experience severe infusion symptoms, which do not resolve after 
discontinuation or completion of the infusion. 
 
6. Observe the patient for mucositis with sore throat or mouth ulcers followed by a diffuse skin rash. Skin 
reactions can be life threatening and lead to fatal Stevens-Johnson syndrome or toxic epidermic 
necrolysis.  Patients should be instructed to be observant for signs and symptoms of skin reaction.  
Patients who develop a sore throat, mucositis should be evaluated and monitored very closely for 
development of skin reaction, and hospitalized and treated with corticosteroids if indicated. Patients who 
develop evidence of significant skin rash, oral pharyngeal mucositis that are thought to be related to 
rituximab should be taken off the study. 
6.3 
Lovenox 
 
LOVENOX®   
 
 
 
 
 
Prescribing Information
(enoxaparin sodium injection) for subcutaneous and  
Rx only 
intravenous use 
 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
 
These highlights do not include all the information needed to use Lovenox safely and effectively. See 
full prescribing information for Lovenox. 
 
Lovenox® (enoxaparin sodium injection) for subcutaneous and intravenous use 
Initial U.S. Approval: 1993 
 
 


 
 
WARNING: SPINAL/EPIDURAL HEMATOMA 
Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight 
heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These 
hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for 
spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these 
patients include: 
 
Use of indwelling epidural catheters  
 
Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs 
(NSAIDs), platelet inhibitors, other anticoagulants  
 
A history of traumatic or repeated epidural or spinal punctures  
 
A history of spinal deformity or spinal surgery.  
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is 
noted, urgent treatment is necessary. 
 
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated 
for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug Interactions (7)]. 
RECENT MAJOR CHANGES 
Administration (2.4) 
(04/2011) 
 
INDICATIONS AND USAGE 
Lovenox is a low molecular weight heparin [LMWH] indicated for: 
 
Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery, knee replacement 
surgery, or medical patients with severely restricted mobility during acute illness (1.1)  
 
Inpatient treatment of acute DVT with or without pulmonary embolism (1.2)  
 
Outpatient treatment of acute DVT without pulmonary embolism. (1.2)  
 
Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction [MI] (1.3)  
 
Treatment of acute ST-segment elevation myocardial infarction [STEMI] managed medically or with subsequent 
percutaneous coronary intervention [PCI] (1.4)
DOSAGE AND ADMINISTRATION 
Indication Dose 
DVT prophylaxis in abdominal surgery 
40 mg SC once daily 
DVT prophylaxis in knee replacement 
surgery 
30 mg SC every 12 hours 
DVT prophylaxis in hip replacement surgery 30 mg SC every 12 hours or 40 mg SC once daily 
DVT prophylaxis in medical patients  
40 mg SC once daily 
Inpatient treatment of acute DVT with or 
without pulmonary embolism 
1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily * 
Outpatient treatment of acute DVT without 
pulmonary embolism 
1 mg/kg SC every 12 hours * 
Unstable angina and non-Q-wave MI 
1 mg/kg SC every 12 hours (with aspirin) 
Acute STEMI in patients <75 years of age 
[For dosing in subsequent PCI, see Dosage 
and Administration (2.1)] 
30 mg single IV bolus plus a 1 mg/kg SC dose followed 
by 1 mg/kg SC every 12 hours (with aspirin) 
Acute STEMI in patients ≥75 years of age 
0.75 mg/kg SC every 12 hours (no bolus) (with aspirin) 
 
See recommended durations for Lovenox therapy (2.1)  
 
*See recommendations regarding transitioning to warfarin therapy (2.1)  
 
Adjust the dose for patients with severe renal impairment (2.2, 8.7) 
 


 
 
 
DOSAGE FORMS AND STRENGTHS 
100 mg/mL concentration (3.1): 
 
Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL  
 
Graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL,100 mg/1 mL  
 
Multiple-dose vial: 300 mg/3 mL  
150 mg/mL concentration (3.2): 
 
Graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/1 mL  
 
CONTRAINDICATIONS 
 
Active major bleeding (4)  
 
Thrombocytopenia with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium (4) 
 
Hypersensitivity to enoxaparin sodium (4)  
 
Hypersensitivity to heparin or pork products (4)  
 
Hypersensitivity to benzyl alcohol [for multi-dose formulation only] (4)  
 
WARNINGS AND PRECAUTIONS 
 
Increased risk of hemorrhage: Use with caution in patients at risk (5.1)  
 
Percutaneous coronary revascularization: Obtain hemostasis at the puncture site before sheath removal (5.2)  
 
Concomitant medical conditions: Use with caution in patients with bleeding diathesis, uncontrolled arterial 
hypertension or history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, or hemorrhage 
(5.3)  
 
History of heparin-induced thrombocytopenia: Use with caution (5.4)  
 
Thrombocytopenia: Monitor thrombocytopenia closely (5.5)  
 
Interchangeability with other heparins: Do not exchange with heparin or other LMWHs (5.6)  
 
Pregnant women with mechanical prosthetic heart valves and their fetuses, may be at increased risk and may need 
more frequent monitoring and dosage adjustment (5.7)  
 
ADVERSE REACTIONS 
Most common adverse reactions (>1%) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, 
diarrhea, and nausea (6.1) 
DRUG INTERACTIONS 
Discontinue agents which may enhance hemorrhage risk prior to initiation of Lovenox or conduct close clinical 
and laboratory monitoring (5.9, 7) 
 
USE IN SPECIFIC POPULATIONS 
 
Severe Renal Impairment: Adjust dose for patients with creatinine clearance <30mL/min (2.2, 8.7)  
 
Geriatric Patients: Monitor for increased risk of bleeding (8.5)  
 
Patients with mechanical heart valves: Not adequately studied (8.6)  
 
Hepatic Impairment: Use with caution. (8.8)  
 
Low-Weight Patients: Observe for signs of bleeding (8.9)  
 
7. STUDY 
CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to administration of protocol therapy.  
Scans and x-rays must be done within 4 weeks prior to the start of therapy.  For subsequent weeks, the 
studies may be performed within  2 days of the indicated dates. 
 


 
 
   
 
Pre- 
Study 
 
Wk 
1 
 
Wk 
2 
 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
 
Wk 
10 
Wk 
11 
Wk 
12+ g 
Off 
Study
 
VORINOSTATa, g 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
 
X 
 
 
Rituximab 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Lovenox 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B-HCG b 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record concurrent 
medications 
 
X 
 
X--------------------------------------------------------------------------X 
 
 
Physical exam 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Vital signs 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Weight 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Performance status 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
CBC w/diff, plts 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Serum chemistry c 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Correlativesi 
X 
 
X 
 
 
 
 
Adverse 
event 
evaluation 
 
 
 
X--------------------------------------------------------------------------X 
X 
 
 
Tumor 
measurements 
 
 
X 
 
Tumor measurements are repeated every 3 cycles (~9 weeks)j. Bone marrow 
assessment should be done within 4 weeks of starting therapy, and repeated every 3 
cycles if the initial marrow shows involvement by lymphoma. Documentation 
(radiologic) must be provided for patients removed from study for progressive disease. 
 
X d 
 
Radiologic 
evaluation 
 
X 
 
CT scans are repeated every 3 cycles (~9 weeks)j. Follow up PET scans for patients 
with PET positive disease is optional, but suggested.   
X d 
 
Bone marrow  
Xh 
 
 
 
 
 
 
 
 
X 
 
 
 
 
a:  VORINOSTAT:  Starting dose 200mg orally twice daily for 2 weeks, followed by 1 week of rest (21 day cycle).   
b: Serum pregnancy test (women of childbearing potential). 
c: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
d: Off-study evaluation.  
g. Patients with partial response or stable disease may continue to receive VORINOSTAT until progression. Patients who 
achieve CR will receive two further cycles of VORINOSTAT and then discontinue drug. Follow up radiological studies 
will continue every three months for one year, then every six months for the next two years. 
h. Bone Marrow aspiration and biopsy may be performed up to four weeks prior to starting study drug, and if positive 
should be repeated every three cycles. 
i. For details see section 11. 
j. After one year of treatment, if the patient achieved two consecutive PR based on prior CT scans or PET, the radiological 
assessment can be done after every 4 cycles instead of 3 cycles.  If patients achieved CR, follow up radiological studies 
will continue every 3 months for one year, then every six months for the next two years.   


 
 
 
8. MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients should be reevaluated for response every three cycles (~ 9 weeks) by 
radiological and marrow studies as described in the study calendar (section 8). After one year of treatment, if the 
patient achieved two consecutive PR based on prior CT scans or PET, the radiological assessment can be done after 
every 4 cycles instead of 3 cycles.  If patients achieved CR, follow up radiological studies will continue every 3 
months for one year, then every six months for the next two years.   
 
 
8.1 Response Criteria  


 
 
 
(as per 
Cheson BD, et 
al. J Clin 
Oncol. 2007 
Feb 
10;25(5):579-
86.)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) 
Variably 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 
measuable 
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 
 
 
 
 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, 
computed tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, 
progressive disease.  
CR: 
 
1. Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before 


 
 
therapy.  
2a. Typically FDG-avid lymphoma: in patients with no pretreatment PET scan or when the PET scan was positive before 
therapy, a post-treatment residual mass of any size is permitted as long as it is PET negative.  
2b. Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment PET scan, or if a 
pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on CT to normal size (  1.5 
cm in their greatest transverse diameter for nodes > 1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 
cm in their long axis and more than 1.0 cm in their short axis before treatment must have decreased to 1.0 cm in their 
short axis after treatment.  
3. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical examination or CT scan, should 
not be palpable on physical examination and should be considered normal size by imaging studies, and nodules related to 
lymphoma should disappear. However, determination of splenic involvement is not always reliable because a spleen 
considered normal in size may still contain lymphoma, whereas an enlarged spleen may reflect variations in anatomy, 
blood volume, the use of hematopoietic growth factors, or causes other than lymphoma.  
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone 
marrow biopsy. The biopsy sample on which this determination is made must be adequate (with a goal of > 20 mm 
unilateral core). If the sample is indeterminate by morphology, it should be negative by immunohistochemistry. A sample 
that is negative by immunohistochemistry but that demonstrates a small population of clonal lymphocytes by flow 
cytometry will be considered a CR until data become available demonstrating a clear difference in patient outcome.  
Cru 
 
The use of the above definition for CR and that below for PR eliminates the category of CRu.  
PR 
 
The designation of PR requires all of the following:  
1. At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or 
nodal masses. These nodes or masses should be selected according to all of the following: they should be clearly 
measurable in at least 2 perpendicular dimensions; if possible they should be from disparate regions of the body; 
and they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.  
2. No increase should be observed in the size of other nodes, liver, or spleen.  
3. Splenic and hepatic nodules must regress by 50% in their SPD or, for single nodules, in the greatest transverse 
diameter.  
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no 
measurable disease should be present.  
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was positive before treatment. 
However, if positive, the cell type should be specified (eg, large-cell lymphoma or small neoplastic B cells). 
Patients who achieve a CR by the above criteria, but who have persistent morphologic bone marrow involvement 
will be considered partial responders.  
When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow 
assessment after treatment, patients should be considered partial responders.  
6. No new sites of disease should be observed.  


 
 
7. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET scan was positive before 
therapy, the post-treatment PET should be positive in at least one previously involved site.  
8. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment PET scan, or if a 
pretreatment PET scan was negative, CT criteria should be used.  
In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only indicated with one or at most two 
residual masses that have regressed by more than 50% on CT; those with more than two residual lesions are unlikely to be 
PET negative and should be considered partial responders.  
 
Stable Disease 
 
Stable disease (SD) is defined as the following:  
1. A patient is considered to have SD when he or she fails to attain the criteria needed for a CR or PR, but does not 
fulfill those for progressive disease (see Relapsed Disease [after CR]/Progressive Disease [after PR, SD]).  
2. Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease with no new areas of 
involvement on the post-treatment CT or PET.  
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment PET scan or if the 
pretreatment PET was negative, there must be no change in the size of the previous lesions on the post-treatment 
CT scan.  
 
Relapsed Disease (after CR)/Progressive Disease (after PR, SD) 
 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless of the short axis. If a lymph 
node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if its short axis is more than 1.0. Lymph 
nodes 1.0 x 1.0 cm will not be considered as abnormal for relapse or progressive disease.  
1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions 
are decreasing in size. Increased FDG uptake in a previously unaffected site should only be considered relapsed or 
progressive disease after confirmation with other modalities. In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign. Thus, a therapeutic decision should not be made 
solely on the basis of the PET without histologic confirmation.  
2. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or 
the size of other lesions (eg, splenic or hepatic nodules). To be considered progressive disease, a lymph node with 
a diameter of the short axis of less than 1.0 cm must increase by 50% and to a size of 1.5 x 1.5 cm or more than 
1.5 cm in the long axis.  
3. At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short 
axis.  
4. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive 
before therapy unless the lesion is too small to be detected with current PET systems (< 1.5 cm in its long axis by 
CT).  
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. For these 
recommendations, the spleen is considered nodal disease. Disease that is only assessable (eg, pleural effusions, bone 
lesions) will be recorded as present or absent only, unless, while an abnormality is still noted by imaging studies or 
physical examination, it is found to be histologically negative.  
 
9. REGULATORY AND REPORTING REQUIREMENTS 


 
 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 will be utilized for adverse event reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 3.0.  A list of adverse events that have occurred or might occur (Comprehensive 
Adverse Events and Potential Risks list) can be found in Section 6 (Pharmaceutical Information).    A copy of the 
CTCAE version 3.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/reporting/ctc.html).   
 
9.1 
Expedited Adverse Event Reporting 
 
We agree to provide Merck (Attn: Worldwide Product Safety; FAX 215 993-1220) with copies of all 
serious adverse experiences within two working days. Additionally, we agree to report any pregnancy occurring 
in association with use of a Merck Product to Merck (Attn: Worldwide Product Safety; FAX 215 993-1220). A 
copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European Union 
(EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators by the investigator. We 
agree to cross reference this submission according to local regulations, to the Merck Investigational Compound 
number (IND, CSA, etc) at the time of submission. Additionally we agree to submit a copy of these reports to 
Merck (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of submission to the appropriate 
regulatory agency. 
Notes: 
* In studies involving human subjects, serious adverse experience means any experience that 
suggest a significant hazard, contraindication, side effect or precaution.  A serious adverse 
experience includes any experience that is fatal or immediately life threatening, results in a 
persistent or significant disability/incapacity, requires or prolongs in-patient hospitalization, 
or is a congenital anomaly, cancer, or overdose.  
 Other important medical events that may not result in death, not be life-threatening, or not 
require hospitalization may be considered a serious adverse experience when, based upon 
appropriate medical judgment, the event may jeopardize the subject/patient and may require 
medical or surgical intervention to prevent one of the outcomes listed previously. 
 
 
 
9.1.2 
Expedited Adverse Event Reporting Exclusions 
 
 
None 
 
 
9.2 Registration Guidelines 
 
 
 
 
Once the signed informed consent has been obtained and all pretreatment evaluations have been 
performed, patients will be entered on study.  To register a patient, the research nurse or data 
manager must complete the Eligibility Checklist and FAX a copy of this and the informed consent 
including the Bill of Rights to the Coordinator at the City of Hope (FAX #626-256-8654).  The 
research nurse or data manager will call the Coordinator at 626-256-HOPE (4673) extension 65928, 
and after verifying the eligibility, the Coordinator will register the patient onto the study and assign a 
patient accession number 
 
Protocol waivers and/or treatment deviations are not allowed other than in the case of delay as 
described in sections 5.1 and 5.2. 
 


 
 
9.3 COH DSMB Data Reporting 
 
A) 
Definition of Risk Level 
 
This is a Risk Level 3 study, as defined in the “City of Hope Data and Safety 
Monitoring Plan”, http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx 
because it is a Phase 2 clinical trial where the risks are at least balanced by the 
potential benefit to subjects and the importance of the knowledge that may result. 
 
 
B) 
Monitoring and Personnel Responsible for Monitoring 
 
The Protocol Management Team (PMT) consisting of the PI, Collaborating 
Investigator, CRA, protocol nurse, and statistician is responsible for monitoring the 
data and safety of this study, including implementation of any stopping rules for 
safety and efficacy. 
 
Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting 
Requirement 
RL 1, RL2, and Compassionate 
Use Studies 
No reports required 
3 
I 
Every 3 months from 
activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility,
II‐IV 
Every 6 months from 
activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility,
I‐IV 
Every 3 months from 
activation date, as 
indicated in MIDAS 
 
 
Data and safety will be reported to the COH DSMC using the PMT report and 
submitted according to the timelines in Table 1 above.  Protocol specific data 
collection will include the following items:.  hematologic response and toxicities of 
treatment. 
 
 
C) Definitions 
 
Adverse event (AE) - An adverse event is any untoward medical experience or change of an existing 
condition that occurs during or after treatment, whether or not it is considered to be related to the 
protocol intervention.  


 
 
 
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is unexpected if it is not listed in 
the investigator’s brochure and/or package insert; is not listed at the specificity or severity that has 
been observed; is not consistent with the risk information described in the protocol and/or consent; is 
not an expected natural progression of any underlying disease, disorder, condition, or predisposed risk 
factor of the research participant experiencing the adverse event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event OR is an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk factor 
of the research participant experiencing the adverse event 
 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or unexpected adverse 
event that results in any of the following outcomes: 
 Death 
 Is life-threatening experience (places the subject at immediate risk of death from the event as it 
occurred) 
 Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of existing 
hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Secondary Malignancy 
 Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasisas of convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse). 
 
Unanticipated problem (UP) – Any incident, experience, or outcome that meets all three of the 
following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the research procedures 
described in the protocol-related documents such as the IRB approved research protocol, informed 
consent document or Investigator Brochure (IB); and b) the characteristics of the subject 
population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by the 
drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than previously known or recognized. 
 
 
D. 
Reporting of Unanticipated Problems and Adverse Events 
 
Unanticipated Problems: Most unanticipated problems must be reported to the COH DSMC and IRB 
within 5 calendar days according to definitions and guidelines at 


 
 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem that occurs during the 
study conduct will be reported to the DSMC and IRB by submitting electronically in iRIS 
(http://iris.coh.org). 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed by the physician, 
nurse, or reported by the patient, will be reported according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and Table 2 below.  Those SAEs that require 
expedited reporting will be submitted electronically in iRIS (http://iris.coh.org/). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that do not meet the 
criteria of serious OR are not unanticipated problems will be reported only in the protocol 
continuation reports and PMT report (see Table 2 below). 
 
 
Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for the DSMC 
and IRB 
 
 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies  
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED 
EXPECTED 
  
Death while on active treatment or within 30 days of 
last day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of 
"serious" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
  
Grades 1 and 2 AND resulting in "hospitalization" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 


 
 
 
Externally Sponsored Studies 
Required Reporting Timeframe to DSMC
Attribution 
UNEXPECTED1 
EXPECTED 
  
Death while on active treatment or within 30 days 
of last day of treatment 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 3 and 4 AND meeting the definition of 
"serious" 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 1 and 2 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
 
An event determined by the IRB of record to be an Unanticipated Problem (UP) will be communicated 
to the Investigator and COH DSMC through the COH IRB Operations Director. The DSMC will review 
the case and make a determination as to whether the study will be suspended, terminated, amended, or 
allowed to continue without amendment. 
 


 
 
 
Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a 
UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
 
 
9.4  RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE 
 
9.4.1 Confidentiality of Records:  The original data collection forms will be stored in secure 
cabinets at the originating institution.  Copies of these forms will also be maintained in secure 
cabinets at the Data Coordinating Center. 
 
9.4.2 Patient Consent Form: At the time of registration, three signed and dated copies of the 
patient Informed Consent form must be available.  Non-COH institutions will FAX a copy of a 
signed informed consent to COH (see registration procedures in Appendix E) at the time of 
registration. 
 
 
9.4.3 Registration Eligibility Worksheet:  At the time of registration, the information requested 
on the On-Study/Eligibility Form will be submitted to the protocol coordinator at COH.  
 
 
9.4.4 Data Collection Forms and Submission Schedule 
 
 
All data will be collected using COH Biostatistics Information Tracking System (BITS) data 
collection forms.  Copies of the completed forms will be submitted to City of Hope Department 
of Biostatistics, the data coordinating center, c/o the Consortium Manager for data entry and 
stored in a secure location.  The original data collection forms will reside at the originating 
institution in secure location. 
 
9.4.5 
The data manager will complete the Eligibility Checklist Worksheet at the 
time of  registration. 
 
 
 
9.4.6 
 
Within two weeks of registration, the data manager will complete the On-


 
 
Study Form (Form OS). 
 
9.4.7 
 
Within four weeks of completion of each course of treatment, the data 
manager must complete the following: 
 
 
Treatment and Adverse Event Form  
 
Supplemental Data Form (if applicable) 
 
Flow Sheets (These are to be submitted along with each treatment form.) 
 
9.4.8 
 
Each time a patient is evaluated for response and/or new follow-up 
information is obtained the data manager will complete the Response/Off-
Study Follow-Up Form. 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1 
Study Design/Endpoints 
  
Response rate (CR+PR) will be the primary endpoint.  An underlying 20% response rate will be regarded as 
not sufficiently active, and the trial is designed to have little chance of missing a 40% response rate.  A two-
stage design will be used. In the first stage, 17 patients will be enrolled.  If 4 or more respond, accrual will 
continue to a total of 33 patients, with 10 or more responses regarded as evidence of sufficient activity to 
warrant further investigation.    If the true response rate is 20%, the proposed design has a 90% chance of 
declaring vorinostat plus rituximab insufficiently active, and a 55% chance of stopping early.  If the true 
response rate is 40%, there is a 89% chance of concluding VORINOSTAT is sufficiently active.  All 
patients beginning VORINOSTAT therapy will be included in response rates calculations, which will 
include exact binomial confidence intervals. 
  
All reportable adverse events will be monitored by the PI and CRA, and reported as described in section 
10. Reportable and non-reportable adverse events are routinely tabulated for phase II consortium trials 
as the reports arrive. The time to progression and overall survival will be estimated using the product-
limit method of Kaplan and Meier. Toxicity information recorded will include the type, severity, time of 
onset, time of resolution, and the probable association with the study regimen. Tables will be 
constructed to summarize the observed incidence by severity and type of toxicity.  Baseline information 
(e.g. the extent of prior therapy, extent of disease) and demographic information will be presented, as 
well, to describe the patients treated in this Phase II study.   
 
10.2 
Sample Size/Accrual Rate 
 
Estimated monthly accrual: 3 patients  
Proposed sample size: 17 to 33 patients as outlined in section 11.1 
 
10.3 
Stratification Factors 
 
 
 
None planned. 
 
10.4 
Reporting and Exclusions 
 


 
 
10.5 
Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment  with vorinostat. 
 
10.5.1 Evaluation of response.  All patients included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if they are 
ineligible.  Each patient will be assigned one of the following categories:  complete response, 
partial response, stable disease, progressive disease, early death from malignant disease, 
early death from toxicity, early death because of other cause, or unknown (not assessable, 
insufficient data).   
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) will be included in the main analysis of the response rate.  
Patients in any response categories other than complete response, partial response or stable 
disease will be considered as failing to respond to treatment (disease progression).  Thus, an 
incorrect treatment schedule or drug administration does not result in exclusion from the 
analysis of the response rate.   
 
All conclusions will be based on all eligible patients, with possible exploratory analysis of  
subset of patients in the event of early death due to other reasons, early discontinuation of 
treatment, major protocol violations, or similar circumstances requiring an assessment of the 
sensitivity of results.  However, such subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis will be clearly reported.  Exact binomial 95% confidence intervals will be provided 
for response rates.  
 
11. Correlative Studies:  
 
Cytokine analysis 
 
We have recently demonstrated (Li, et al PNAS, 2008) that  even low doses of vorinostat dramatically 
decrease pro-inflammatory cytokines such as IL-2, IFN-, TNF-, and IL-6. This suppression of 
cytokines may be of importance to the clinical effect of histone deacetylase inhibition on symptoms such 
as itching or the B symptoms of lymphoma, as well as potentially impacting upon lymphoma growth. 
 
The effects of treatment on systemic levels of immune cytokines will be evaluated by cytokine bead 
array analysis using Luminex X-MAP bead array technology.  This technology platform allows for the 
simultaneous measurement and quantification of multiple cytokines and other secreted factors from very 
small (10-50 l) samples.  This analysis is sensitive (generally single pictogram level), reproducible, and 
accurate.  The Clinical Immunobiology Correlative Studies Laboratory (CICSL) at COH is equipped 
with two Bioplex HTF units for these analyses.   
 
 
Preassembled multiplex panels are available commercially that allow for the simultaneous evaluation of 
the following 30 pro- and anti-inflammatory cytokine and immune factors: 
IL-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p40/p70, IL-13, IL-15, IL-17, 
TNF-α, IFN-α, IFN-γ, GM-CSF, MIP-1α, MIP-1β, IP-10, MIG, Eotaxin, RANTES, MCP-1, VEGF, G-


 
 
CSF, EGF, FGF-basic, and HGF. 
For these analyses, 2 ml peripheral blood will be collected prior to starting therapy, and on day 14. 
Whole blood will be collected in red-top tubes (Becton Dickinson) that are completely free of anti-
coagulant reagents.  Sample tubes should be set in an upright position at room temperature may be 
processed for up to 24 hours. 
 
To process serum:   
 
i. Allow whole blood samples to clot for 1 – 2 hours at room temperature.  
ii. Centrifuge at 1000 x g at 4°C for 15 minutes, max brake.  
iii. Using a micropipettor, collect the serum without disturbing the red cell pellet at the 
bottom of the tube and transfer to a flip-top microfuge tube or a 15-mL centrifuge 
tube (depending on the total volume).    
iv. Freeze and store at -80oC  in 100 ìL aliquots.   
  
 
Luminex analysis on serum samples will be performed in bulk.  Each sample will be evaluated in 
duplicate with the average value recorded.  Quantitative values will only be determined for samples with 
values that fall within the 80% observed/expected range for the standard curve. 
 
Samples should be sent to: 
 
Clinical Immunobiology Correlative Studies Laboratory 
Attn.  Vivi Tran 
1042 Shapiro 
City of Hope, 
Duarte, CA 91010 
 
 
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Model Informed Consent 
 
A Phase II Study of Suberoylanilide Hydroxamic Acid (VORINOSTAT) (NSC 701852) plus Rituximab in Indolent 
Non-Hodgkin’s Lymphoma 
 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to you.   Clinical trials 
include only people who choose to take part. Please take your time to make your decision about taking part.  You may 
discuss your decision with your friends and family.  You can also discuss it with your health care team.  If you have any 
questions, you can ask your study doctor for more explanation.  
 
You are being asked to take part in this study because you have slow growing Non-Hodgkin’s Lymphoma (NHL) or low-
grade lymphoma that has returned.  
 
Why is this study being done? 
 
The purpose of this study is to find out what effects, good and/or bad, vorinostat (Suberoylanilide Hydroxamic Acid 
(VORINOSTAT)) plus rituximab has on you and your lymphoma.  
 
This research is being done because lymphoma responds initially to chemotherapy but usually comes back within 5 years. 
The disease free interval between treatments becomes shorter and shorter.  Better and new methods of therapy are needed 
to treat low-grade lymphoma. 
 
How many people will take part in the study? 
 
About 37 people will take part in this study.   
 
What will happen if I take part in this research study?   
 
Treatment: 
 
If you are eligible and decide to take part in this treatment, you will take a drug called vorinostat, an drug approved by the 
Food and Drug Administration (FDA) in a different type of lymphoma, but experimental in this form of lymphoma.  
VORINOSTAT is an oral drug that will be given to you in capsule form that you will take by mouth two times a day, 
every day for two weeks followed by one week of rest (no drug).  Each 3 weeks, or 21 days, is considered one cycle of 
therapy.  You will continue to take VORINOSTAT for a total of 12 cycles or until your cancer begins to grow or you 
have side effects that are unmanageable. You will also receive a drug called rituximab, which is FDA approved for 
treatment of this type of lymphoma. 
 
Before you begin the study …  
 
You will need to have the following exams, tests or procedures to find out if you can be in the study.  These exams, tests 
or procedures are part of regular cancer care and may be done even if you do not join the study.  If you have had some of 
them recently, they may not need to be repeated.  This will be up to your study doctor. 


 
 
 
 
Medical history and physical examination 
 
Blood tests (about one tablespoon of blood) to look at the cellular and chemical make up of your blood  
 
Scans and/or X-rays to evaluate the extent of your disease 
 
You will also have your bone marrow examined (called "bone marrow aspiration and biopsy") at the start 
of this study, and at the end of the treatment period if the first bone marrow test indicates presence of 
lymphoma.  Your skin over your hipbone will be numbed by a shot of local anesthetic (lidocaine) given 
just under your skin.  A needle will be inserted through the numbed skin and into the hipbone.  The bone 
marrow will be removed by using suction and a twisting motion of the needle.  You may feel pain, and 
minor infection is also possible.  Rarely allergic reactions to the anesthetic may occur.  These are routine 
tests for many patients with lymphoma.  The bone marrow will be looked at to find out if any lymphoma 
cells are present.  This will be repeated every 3 cycles. 
 
During the study …  
 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, then you will need the 
following tests and procedures.  They are part of regular cancer care.  
 
You will be asked to keep track of your study medication by recording the date and time you take the study medication, 
any symptoms you experience and any questions you may have in a study diary.  You will be asked to bring the study 
diary with you each time you come in to see your doctor.   
 
 
Physical examinations every week for the first cycle, and every three weeks after that 
 
Blood tests every week for the first four weeks, and every three weeks after that (appropriate amount of 
blood collected per test will be 2 - 3 teaspoons) 
 
Scans and/or X-rays every nine weeks  
 
If your tumor shrinks and stays that way for 2 sets of scans, you may be able to go 12 weeks between 
scans 
 
When I am finished taking VORINOSTAT: 
 
After you complete treatment, your medical condition will be followed until your disease returns. 
 
Study Chart 
 
You will receive VORINOSTAT twice a day every day for 14 days in this study followed by a 7 day rest period. This 21 day 
period of time is called a cycle.  The cycle will be repeated up to 12 times.  Each cycle is numbered in order.  The chart below 
shows what will happen to you during Cycle 1 and future treatment cycles as explained previously.  The left-hand column 
shows the day in the cycle and the right-hand column tells you what to do on that day. 
 
Cycle 1 
 
Day 
What you do 
 
One week 
before 
beginning study 
 
Physical examination, blood tests (routine and research), EKG, pregnancy test (if you are a 
women of child bearing age), Scans and/or X-rays (may be done up to 28 days before 
treatment) 
Day 1 
 
Get physical examination, and routine blood tests. 
 
Begin taking VORINOSTAT twice a day. Keep taking VORINOSTAT for two weeks (14 
days), unless told to stop by your health care team. 


 
 
 
Receive the first dose of rituximab intravenously. 
Day 8 
 
Get routine blood tests and physical examination. 
Day 15 
 
Stop taking VORINOSTAT for one week. 
 
Get routine blood tests and physical examination 
Day 22 
 
Get routine blood tests.  
 
Return to your doctor’s office for your next exam and to begin the next cycle. 
 
 
Future cycles 
 
Day 
What you do 
 
Days 1-21 
 
Keep taking VORINOSTAT twice a day for 14 days if you have no bad side effects and 
cancer is not getting worse.  Call the doctor at (626) 256-HOPE (4673) ext. 63974 if you do 
not know what to do. 
 
Keep receiving rituximab by intravenous infusion every three weeks. 
 
Get routine X-rays, CT scans, or MRIs every other cycle (more if your doctor tells you to). 
Day 22 
 
Get routine blood tests (on day 22 of cycle 2, get research blood test too) 
 
Return to your doctor’s office for your next exam and to begin the next cycle. 
 
How long will I be in the study? 
 
You will be asked to take VORINOSTAT plus rituximab for up to 12 cycles (36 weeks) or until your disease worsens, or 
you have unmanageable side effects.  After you are finished taking VORINOSTAT, the study doctor will keep track of 
your medical condition until your disease returns. 
 
 
Can I stop being in the study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping or decide to stop.  He or 
she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the VORINOSTAT can be 
evaluated by your doctor.  Another reason to tell your doctor that you are thinking about stopping is to discuss what 
follow-up care and testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best interest; if you 
do not follow the study rules; or if the study is stopped. 
 
What side effects or risks can I expect from being in the study?  
 
You may have side effects while on the study.  Everyone taking part in the study will be watched carefully for any side 
effects.  However, doctors don’t know all the side effects that may happen.  Side effects may be mild or very serious. 
Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after you stop 
taking the VORINOSTAT. In some cases, side effects can be serious, long lasting, or may never go away.  
 


 
 
You should talk to your study doctor about any side effects that you have while taking part in the study.    
 
Risks and side effects related to the VORINOSTAT include those which are: 
 
Likely 
 
 
Nausea, which is temporary and may require additional medication 
 
Diarrhea, which is temporary and may require additional medication and/or a delay in your treatment 
 
Anemia: (low red blood cell count), which may make you feel tired and short of breath. If this happens, you may 
be started on a drug to increase your red blood cell count. Severe anemia may require a transfusion of red blood 
cells 
 
Decreased platelet count, which increases the risk of easy bleeding and/or bruising. This could result in the need 
for a platelet transfusion. 
 
Fatigue, which is temporary and should get better when treatment is stopped 
 
Loss of appetite, which is temporary and should get better when treatment is stopped 
 
 
 
High creatinine, which is temporary, seen on blood tests and is without symptoms. It should return to normal 
when treatment is stopped. 
 
High blood sugar, which is temporary and may require additional medication. 
 
Neutropenia,  
 
Weight loss,  
 
Vomiting, which is temporary and may require additional medication 
 
 Less Likely   
 
 
Changes in taste, which is temporary and should get better when treatment is stopped 
 
Low blood calcium, which is temporary and may require additional medication 
 
Low potassium, which is temporary, seen on blood tests and may require potassium supplements 
 
Abdominal pain, which is temporary and may require additional medication 
 
Low lymphocyte counts, a change in the number of lymphocytes in the blood, which doesn’t cause symptoms, is 
temporary and should get better when treatment is stopped. 
 
Prolonged QTc interval, which may cause increased risk for heart rhythm changes, which is temporary and 
should resolve when drug is stopped. 
 
Increased INR, which implies increased blocking of blood clotting when on coumadin, this may require decrease 
of your coumadin therapy and more frequent monitoring of your clotting profile. 
 
Fever,  in the absence of low white blood counts or other signs of infection. If caused by the drug, it should go 
away when drug is stopped. 
 
Shakes and chills, which is temporary and should go away when drug is stopped.  
 
Hair loss, which is temporary and tends to stop over time. 
 
Constipation, which is temporary and can be treated with standard anti-constipation medicines. 
 
Dry mouth, which is temporary and should go away when the drug is stopped. 
 
Heartburn, or a feeling of “stomach ache”, which is temporary and can be treated with standard heartburn 
medications. 
 
Increased risk of infection, even with normal blood counts, which may be related to the drug’s effect on immune 
cells, which are defective already in lymphoma. 
 
Edema, swelling of the lower limbs, which is temporary and should go away when drug is stopped. 
 
Changes in  liver function tests (AST, ALT, , Alkaline Phosphatase, Bilirubin) which are temporary and 
should go away when drug is stopped. 
 
Hypocalcemia, which means low calcium on blood tests, which is temporary, should resolve when drug is 


 
 
stopped, and can be replaced with supplements. 
 
Muscle spasms, which are temporary and should resolve over time.  
 
Muscle weakness, which is temporary and should resolve when drug is stopped. 
 
Headches, which are temporary and can be treated with additional medication 
 
Cough, which is temporary and should resolve when drug is stopped 
 
Shortness of breath, which is temporary and should resolve when drug is stopped. 
 
Blood clots, which may appear in the legs or lungs, and would necessitate further medical therapy such as anti-
clotting medicines.  
 
Hypermagnesemia, 
 
Hypophosphatemia, 
 
Hyponatremia, 
 
Dizziness 
 
Sensory neuropathy, 
 
Dehydration, which is temporary and may require additional fluids, either by mouth or by IV (intravenous, 
through a tube in your arm) infusion 
 
The following side effects have been reported by subjects on other studies with VORINOSTAT, but the 
relationship to VORINOSTAT is not known 
 
ALLERGY/IMMUNOLOGY – vasculitis- swelling around blood vessels which should resolve with stopping the drug 
if not due to underlying disease. 
CARDIAC ARRHYTHMIA - atrial fibrillation; palpitations; ventricular fibrillation- serious heart beat changes 
which may require additional medications. 
CARDIAC GENERAL - cardiac ischemia/infarction- “heart attacks”, which may be serious and require further 
medical treatment; hypertension; hypotension- changes in blood pressure which may require additional medicines for 
control, and should resolve with stopping drug if not related to underlying disease. 
COAGULATION – PTT- changes in blood clotting profile which may return to normal after stopping drug. 
CONSTITUTIONAL SYMPTOMS – insomnia- sleeplessness; sweating- both of which may be temporary and 
disappear with stopping of medication if not due to underlying disease. 
DEATH – unexplained death of uncertain relationship to study drug 
DERMATOLOGY/SKIN –nail changes; pruritus- itching; rash- these changes may disappear with stopping of drug; 
ecchymosis- bleeding into skin, which should heal over time. 
GASTROINTESTINAL – dysphagia- difficulty in swallowing; esophagitis- pain upon swallowing; flatulence- excess 
gas; gastritis- burning sensation in the stomach; mucositis/stomatitis- pain due to changes in the cells lining the mouth 
and throat; all of these should improve with stopping the drug. 
HEMORRHAGE/BLEEDING – epistaxis-nosebleed; hematuria- blood in the urine; hemoptysis- bloody cough; 
petechiae-tiny bleeds in the skin. These may improve when drug is stopped if not related to the underlying disease. 
INFECTION – infection – these may require the addition of further medications such as antibiotics. 
METABOLIC/LABORATORY – hypercalcemia- high blood levels of calcium, which may require additional 
medications; hyperkalemia- high blood levels of potassium, treated with additional medications; hypernatremia- high 
blood sodium, usually treated with intravenous fluid; hypoglycemia- low blood sugar treated with sugar supplements; 
hypomagnesemia- low blood magnesium, treated with magnesium supplements; proteinuria- protein in the urine, which 
may resolve with stopping of the drug.  
MUSCULOSKELETAL/SOFT TISSUE - gait/walking- changes in ability to walk which may get better with stopping 
of drug if not related to the underlying disease.  
NEUROLOGY – confusion- which may resolve with stopping of drug if not related to underlying disease. 
PAIN - back pain; chest/thorax pain; flank pain; gingival (gum) pain; joint pain; limb pain; muscle pain; 
pharyngolaryngeal pain- all these may disappear with stopping of drug if not due to underlying disease.  
PULMONARY/UPPER RESPIRATORY - sinus congestion- may resolve with stopping of drug if not due to 
underlying disease. 


 
 
RENAL/GENITOURINARY – urinary incontinence; urinary retention- difficulty controlling urination or difficulty 
in passing urine, both may disappear with stopping drug if not due to underlying disease. 
VASCULAR - deep vein thrombosis- blood clots in the arms, legs, or lungs, which may require anti-clotting 
medications for prevention of further abnormal clots.  
 
 
Biopsy and blood tests: The biopsies and blood tests that will be done as a part of this study may cause pain at the site 
where the needle enters the skin, bleeding, or infection.  Pain lasting several days may also result after the biopsies.  This 
side effect may be treated with pain medication. 
 
Bone Marrow Aspiration and Biopsy: The local anesthesia used to numb the hip area may initially cause a burning 
sensation in the skin and bone surface lasting several seconds.  During the actual procedure, you may temporarily feel 
pressure and/or pain of varying degrees.  If necessary, you may ask your physician for additional local anesthesia or a 
medication to ease your stress.  After the procedure is completed, you may bleed, have a bruise, and may experience 
soreness in the area for a few days.  Rarely an infection can develop. 
 
Reproductive risks:  You should not become pregnant or father a baby while on this study because the drugs in this 
study can affect an unborn baby.  Women should not breastfeed a baby while on this study.  It is important you 
understand that you need to use birth control while on this study.  Check with your study doctor about what kind of birth 
control methods to use and how long to use them.  Some methods might not be approved for use in this study.  
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
 
Taking part in this study may or may not make your health better.  While doctors hope VORINOSTAT will be more 
useful against cancer compared to the usual treatment, there is no proof of this yet. We do know that the information from 
this study will help doctors learn more about VORINOSTAT as a treatment for cancer.  This information could help 
future cancer patients. 
 
What other choices do I have if I do not take part in this study? 
 
Your other choices may include: 
 
 
Getting treatment or care for your cancer without being in a study, including other chemotherapy, 
 
Taking part in another study 
 
Getting no treatment 
 
Getting comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, appetite problems 
and other problems caused by the cancer.  It does not treat the cancer directly, but instead tries to improve how 
you feel.  Comfort care tries to keep you as active and comfortable as possible.   
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will my medical information be kept private?  
 
We will do our best to make sure that the personal information in your medical record will be kept private.  However, we 
cannot guarantee total privacy.  Your personal information may be given out if required by law.  If information from this 
study is published or presented at scientific meetings, your name and other personal information will not be used.  
 


 
 
Organizations that may look at and/or copy your medical records for research, quality assurance, and data 
analysis include: 
 
 
The City of Hope Medical Group, Pasadena, t 
 
Merck and Co., Inc, the maker of VORINOSTAT  
 
The National Cancer Institute (NCI) and other government agencies, like the Food and Drug Administration 
(FDA), involved in keeping research safe for people 
 
What are the costs of taking part in this study? 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating your cancer in 
this study.  Some health plans will not pay these costs for people taking part in studies.  Check with your health plan or 
insurance company to find out what they will pay for.  Taking part in this study may or may not cost your insurance 
company more than the cost of getting regular cancer treatment.  
 
Merck and Co, Inc, will provide you with the investigational agent, VORINOSTAT, free of charge for this study and with 
rituximab. Every effort has been made to ensure adequate supplies of the investigational agent(s), free of charge, for all 
participants. If, however, the investigational agent(s) become(s) commercially available while you are being treated, there 
is a possibility that you would be asked to purchase subsequent supplies. 
 
You and/or your insurance carrier will be responsible for the other costs of treatment and diagnostic or laboratory 
procedures.  You and/or your insurance carrier will be billed in the same way as if you were not in a research study.  
However, you and your insurance carrier will not be asked to bear the costs of any tests or procedures done solely for 
research purposes. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s Web site 
at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.    You can print a copy of the “Clinical Trials and 
Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy. 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you have 
been injured because of taking part in this study.  You can tell the doctor in person or call him/her at 
__________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You and/or your health plan will 
be charged for this treatment.   The study will not pay for medical treatment.   
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the study.  If you decide 
to take part in this study, you may leave the study at any time.   No matter what decision you make, there will be no 
penalty to you and you will not lose any of your regular benefits.  Leaving the study will not affect your medical care.  
You can still get your medical care from our institution.    
 


 
 
We will tell you about new information or changes in the study that may affect your health or your willingness to continue 
in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this 
form.   
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  Contact your study doctor 
__________________ [name(s)] at __________________ [telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ [name of center] 
Institutional Review Board (a group of people who review the research to protect your rights) at __________________ 
[telephone number].  [Note to Local Investigator: Contact information for patient representatives or other individuals in 
a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed 
here.]    
 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 
 
 
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
 
 
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
 
You will get a copy of this form.    If you want more information about this study, ask your study doctor. 
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I have read it or it has 
been read to me.  I understand the information and have had my questions answered.  I agree to take part in this 
study. 
 
 
 
Participant _____________________________________ 
 
Date ____________________________________________ 
     
 
 
 


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


 
 
  
 
 
 
 
 
APPENDIX C 
 
Drugs Known To Be Metabolized By Selected CYP450 Isoenzymes 
 
 
 


 
 
 
 
 
 
Potential Cytochrome P450 (CYP) Drug Interactions – CYP2A6 
 
 
 
 
 
 
 
 
 
 
 
 
CYP2A6 
Generic Name 
Trade Names 
Substrate
1 
Inhibitor2 Inducer3
Amiodarone 
CORDARONE, PACERONE  
 
++ 
 
Amlodipine 
NORVASC 
 
± 
 
Amobarbital 
AMYTAL SODIUM 
 
 
Y 
Buprenorphine 
BUPRENEX 
 
± 
 
Clofibrate 
 
 
± 
 
Clotrimazole 
GYNE-LOTRIMIN, LOTRIMIN, MYCELEX 
 
± 
 
Desipramine 
NORPRAMIN, PERTOFRANE 
 
++ 
 
Dexmedetomidine PRECEDEX 
Y 
 
 
Disulfiram 
ANTABUSE 
N 
± 
 
Entacapone 
COMTAN 
 
± 
 
Isoniazid 
INH, NYDRAZID, PMS-ISONIAZID  
 
++ 
 
Ketoconazole 
NIZORAL 
 
++ 
 
Letrozole 
FEMARA 
N 
± 
 
Methimazole 
TAPAZOLE 
 
± 
 
Methoxsalen 
8-MOP, OXSORALEN, OXSORALEN-
ULTRA, UVADEX  
N 
+++ 
 
Metyrapone 
METOPIRONE 
 
± 
 
Miconazole 
LOTRIMIN, MICATIN, MICONAZOLE 7, 
MONISTAT 
 
+++ 
 
Modafinil 
PROVIGIL 
 
± 
 
Nicotine 
CLEAR NICODERM CQ, HABITROL, 
NICOTROL 
N 
± 
 
Orphenadrine 
FLEXOR, NORFLEX  
 
± 
 
Pentobarbital 
NEMBUTAL SODIUM 
 
 
Y 
Phenobarbital 
LUMINAL 
 
 
Y 
Pilocarpine 
ISOPTO CARPINE, OCUSERT PILO, 
PILOCAR, PILOPINE HS, SALAGEN 
 
± 
 
Rifampin 
RIFADIN, RIMACTANE  
Y 
 
Y 
Secobarbital 
SECONAL 
 
 
Y 
Selegiline 
ELDEPRYL 
N 
± 
 
Sulconazole 
EXELDERM 
 
± 
 
Tioconazole 
MONISTAT 1, VAGISTAT-1  
 
± 
 
Tranylcypromine PARNATE  
 
+++ 
 
 
 
Adapted from Lacy et al. “Drug Information Handbook”, 12th edition, 2004  
 
1   Substrates 
Yes (Y): Enzyme plays a clinically significant role (≥ 30%) in drug metabolism.  Therefore, competitive inhibition 
may occur resulting in increased serum levels of the drug and/or study agent.  
 No (N): Enzyme plays clinically insignificant role (<30%) in drug metabolism.  Therefore, competitive inhibition 
is unlikely to occur.  


 
 
 
 
 
 
 
2 Inhibitors 
Degree of inhibition was determined by evaluating Ki values set in a ratio with achievable serum drug 
concentrations under normal dosing conditions (Cmax).  The following parameters for predicting clinical relevance of 
competitive CYP inhibition were employed:  
+++:  likely, Cmax/Ki ≥ 1. Clinically relevant inhibition will likely result in increased serum levels of the study 
agent.  
++:  possible, Cmax/Ki=0.1-1. Clinically relevant inhibition may possibly result in increased serum levels of the 
study agent. 
±:  
remote, Cmax/Ki<0.1. 
Clinically relevant inhibition is remotely possible.  
 
3 Inducers 
Yes (Y): Enzyme was effectively induced by drug.  Therefore, lowered serum levels of the study agent may occur.  
No (N): Enzyme was not effectively induced by drug. Therefore, serum levels of the study agent are not expected to 
be altered.  
 
 
 


 
 
Potential Cytochrome P450 (CYP) Drug Interactions – CYP2C8/9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP2C8/
9 
Generic Name 
Trade Names 
Substrat
e1 
Inhibitor
2 
Inducer3
Alosetron 
LOTRONEX 
Y 
 
 
Amiodarone 
CORDARONE, PACERONE  
Y 
++ 
 
Amitriptyline 
ELAVIL 
N 
± 
 
Amlodipine 
NORVASC 
 
± 
 
Anastrozole 
ARIMIDEX 
 
± 
 
Aprepitant 
EMEND 
 
± 
N 
Atazanavir 
REYATAZ 
 
± 
 
Azelastine 
ASTELIN, OPTIVAR, RHINOLAST  
 
± 
 
Bortezomib 
VELCADE 
N 
± 
 
Bosentan 
TRACLEER 
Y 
 
N 
Candesartan 
ATACAND 
N 
± 
 
Carbamazepine 
CARBATROL, TEGRETOL  
N 
 
Y 
Carvedilol 
COREG 
Y 
 
 
Chloramphenico
l 
CHLOROMYCETIN, CHLOROPTIC SOP, 
OCU-CHLOR  
 
± 
 
Cholecalciferol/ 
vitamin D3 
CALEL-D, CALTRATE PLUS, CLOCREAM, 
DELTA-D 
 
± 
 
Cimetidine 
TAGAMET 
 
± 
 
Clopidogrel 
PLAVIX 
 
± 
 
Clotrimazole 
GYNE-LOTRIMIN, LOTRIMIN, MYCELEX 
 
± 
 
Clozapine 
CLOZARIL 
N 
± 
 
Cyclosporine 
GENGRAF, NEORAL, RESTASIS, 
SANDIMMUNE 
 
± 
 
Delavirdine 
RESCRIPTOR 
 
+++ 
 
Dexmedetomidi
ne 
PRECEDEX 
 
± 
 
Diclofenac 
CATAFLAM, VOLTAREN 
N 
± 
 
Diltiazem 
CARDIZEM, DILACOR XR, TIAZAC  
N 
± 
 
Dimethyl 
sulfoxide 
RIMSO-50 
 
± 
 
Disulfiram 
ANTABUSE 
 
± 
 
Drospirenone 
YASMIN (w/ethinyl estradiol) 
 
± 
 
Efavirenz 
SUSTIVA 
 
± 
 
Entacapone 
COMTAN 
 
± 
 
Eprosartan 
TEVETEN 
 
± 
 
Etoposide 
ETOPOPHOS, VEPESID 
 
± 
 
Felodipine 
PLENDIL 
 
± 
 
Fluconazole 
DIFLUCAN 
 
+++ 
 
Fluoxetine 
PROZAC, SARAFEM  
Y 
± 
 
Fluphenazine 
PROLIXIN 
 
± 
 
Flurbiprofen 
ANSAID, OCUFEN  
N 
+++ 
 
Fluvastatin 
LESCOL 
N 
++ 
 
Fluvoxamine 
LUVOX 
 
± 
 
Fosphenytoin 
CEREBYX 
Y 
 
Y 
Gemfibrozil 
LOPID  
 
+++ 
 


 
 
Glimepiride 
AMARYL 
Y 
 
 
Glipizide 
GLUCOTROL 
Y 
 
 
Ibuprofen 
ADVIL, MOTRIN, NUPRIN, RUFEN  
N 
+++ 
 
Imatinib 
GLEEVEC 
N 
± 
 
Indinavir 
CRIXIVAN 
 
± 
 
Indomethacin 
INDOCIN 
N 
+++ 
 
Irbesartan 
AVAPRO  
N 
++ 
 
Isoniazid 
INH, NYDRAZID, PMS-ISONIAZID  
 
++ 
 
Ketamine 
KETALAR  
Y 
 
 
Ketoconazole 
NIZORAL 
 
+++ 
 
Ketoprofen 
ORUDIS, ORUVAIL 
 
± 
 
Lansoprazole 
PREVACID 
N 
± 
 
Leflunomide 
ARAVA 
 
± 
 
Losartan 
COZAAR 
Y 
++ 
 
Lovastatin 
ALTOCOR, MEVACOR  
 
± 
 
Mefenamic acid 
PONSTEL 
N 
+++ 
 
Meloxicam 
MOBIC  
N 
± 
 
Mephenytoin 
MESANTOIN 
Y 
 
 
Mestranol 
NECON 1/50, NORINYL 1/50, ORTHO-
NOVUM 1/50  (w/ norethindrone) 
Y 
 
 
Methimazole 
TAPAZOLE 
 
± 
 
Methoxsalen 
8-MOP, OXSORALEN, UVADEX  
 
± 
 
Metronidazole 
FLAGYL, METROGEL, NORITATE  
 
± 
 
Miconazole 
LOTRIMIN, MICATIN, MICONAZOLE 7, 
MONISTAT 
 
+++ 
 
Midazolam 
VERSED 
 
± 
 
Modafinil 
PROVIGIL 
 
± 
 
Montelukast 
SINGULAIR 
Y 
± 
 
Nateglinide 
STARLIX 
Y 
± 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Generic Name 
Trade Names 
Substrat
e1 
Inhibitor
2 
Inducer3
Nelfinavir 
VIRACEPT 
N 
± 
 
Nicardipine 
CARDENE 
N 
+++ 
 
Nifedipine 
ADALAT, PROCARDIA  
 
± 
 
Olanzapine 
ZYPREXA, ZYPREXA ZYDIS  
 
± 
 
Omeprazole 
PRILOSEC 
N 
++ 
 
Ondansetron 
ZOFRAN 
N 
± 
 
Orphenadrine 
FLEXOR, NORFLEX  
 
± 
 
Paclitaxel 
TAXOL 
Y 
 
 
Pantoprazole 
PANTOLOC, PROTONIX  
 
++ 
 
Paroxetine 
PAXIL 
 
± 
 
Pentamidine 
NEBUPENT, PENTAM 300  
 
± 
 
Phenobarbital 
LUMINAL 
N 
 
Y 
Phenytoin 
DILANTIN, PHENYTEK, PHENYTOIN 
SODIUM  
Y 
 
Y 
Pioglitazone 
ACTOS 
Y 
+++ 
 
Piroxicam 
FELDENE 
N 
+++ 
 
Pravastatin 
PRAVACHOL  
 
± 
 
Primidone 
MYSOLINE 
 
 
Y 


 
 
 
 
 
 
 
 
 
 
 
 
CYP2C8/
9, 
continued 
 
Progesterone 
CRINONE, PROGESTASERT, 
PROMETRIUM  
N 
± 
 
Propafenone 
RYTHMOL 
 
± 
 
Propofol 
DIPRIVAN 
Y 
± 
 
Propoxyphene 
DARVON 
 
± 
 
Pyrimethamine 
DARAPRIM 
 
++ 
 
Quinidine 
QUINAGLUTE DURA, CARDIOQUIN, 
QUINIDEX 
N 
± 
 
Quinine 
LEGATRIN, QUINAMM 
 
++ 
 
Rifampin 
RIFADIN, RIMACTANE  
Y 
 
Y 
Rifapentine 
PRIFTIN 
 
 
Y 
Ritonavir 
NORVIR 
 
± 
N 
Rosiglitazone 
AVANDIA 
Y 
++ 
 
Saquinavir 
INVIRASE, FORTOVASE 
 
± 
 
Secobarbital 
SECONAL 
 
 
Y 
Selegiline 
ELDEPRYL 
Y 
± 
 
Sertraline 
ZOLOFT 
Y 
± 
 
Sildenafil 
VIAGRA 
N 
± 
 
Simvastatin 
ZOCOR 
 
± 
 
Sulconazole 
EXELDERM 
 
± 
 
Sulfadiazine 
 
Y 
+++ 
 
Sulfamethoxazol
e 
BACTRIM, SEPTRA, SULFATRIM (all 
w/Trimethropim) 
Y 
++ 
 
Sulfinpyrazone 
ANTURANE 
Y 
++ 
 
Sulfisoxazole 
GANTRISIN 
Y 
+++ 
 
Tamoxifen 
NOLVADEX 
Y 
± 
 
Teniposide 
VUMON  
 
± 
 
Thioridazine 
MELLARIL 
 
± 
 
Ticlopidine 
TICLID 
 
± 
 
Tioconazole 
MONISTAT 1, VAGISTAT-1  
 
± 
 
Tolbutamide 
ORINASE 
Y 
+++ 
 
Tolcapone 
TASMAR 
 
± 
 
Torsemide 
DEMADEX 
Y 
 
 
Tranylcypromin
e 
PARNATE  
 
± 
 
Tretinoin 
AVITA, RENOVA, RETIN-A, VESANOID  
N 
± 
 
Triazolam 
HALCION 
 
± 
 
Trimethoprim 
PRIMSOL, PROLOPRIM 
Y 
++ 
 
Valdecoxib 
BEXTRA 
N 
± 
 
Valproic acid 
DEPAKENE 
N 
± 
 
Valsartan 
DIOVAN 
 
± 
 
Verapamil 
CALAN, CHRONOVERA, COVERA-HS, 
ISOPTIN, VERELAN  
N 
± 
 
Voriconazole 
VFEND 
Y 
± 
 
Warfarin 
COUMADIN 
Y 
++ 
 
Zafirlukast 
ACCOLATE 
Y 
++ 
 
Zopiclone 
RTIO-ZOPICLONE 
Y 
 
 
 
 


 
 
 


 
 
Potential Cytochrome P450 (CYP) Drug Interactions – CYP2C19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP2C19 
Generic Name 
Trade Names 
Substrate
1 
Inhibitor2 Inducer3
Amiodarone 
CORDARONE, PACERONE  
N 
± 
 
Aminoglutethimid
e 
CYTADREN  
 
 
Y 
Amitriptyline 
ELAVIL 
N 
± 
 
Amprenavir 
AGENERASE 
 
± 
 
Azelastine 
ASTELIN, OPTIVAR, RHINOLAST  
N 
± 
 
Bortezomib 
VELCADE 
N 
++ 
 
Buprenorphine 
BUPRENEX 
 
± 
 
Carbamazepine 
CARBATROL, TEGRETOL  
 
 
Y 
Carisoprodol 
SOMA 
Y 
 
 
Cholecalciferol/ 
vitamin D3 
CALEL-D, CALTRATE PLUS, CLOCREAM, 
DELTA-D 
 
± 
 
Cimetidine 
TAGAMET 
 
++ 
 
Citalopram 
CELEXA 
Y 
± 
 
Clomipramine 
ANAFRANIL  
Y 
 
 
Clotrimazole 
GYNE-LOTRIMIN, LOTRIMIN, MYCELEX 
 
± 
 
Clozapine 
CLOZARIL 
N 
± 
 
Delavirdine 
RESCRIPTOR 
 
+++ 
 
Desogestrel 
CYCLESSA, DESOGEN, MIRCETTE, 
ORTHO-CEPT (w/ethinyl estradiol) 
Y 
 
 
Diazepam 
DIASTAT, DIZAC, VALIUM  
Y 
± 
 
Dimethyl 
sulfoxide 
RIMSO-50 
 
± 
 
Drospirenone 
YASMIN (w/ethinyl estradiol) 
 
± 
 
Efavirenz 
SUSTIVA 
 
± 
 
Entacapone 
COMTAN 
 
± 
 
Escitalopram 
LEXAPRO 
Y 
 
 
Esomeprazole 
NEXIUM 
Y 
 
 
Ethinyl estradiol 
ESTINYL, ORTHO TRI-CYCLEN 
(w/norgestimate) 
TRI-LEVLEN, TRIPHASIL (w/levonorgestrel) 
 
± 
 
Ethotoin 
PEGANONE 
 
± 
 
Felbamate 
FELBATOL 
 
± 
 
Fluconazole 
DIFLUCAN 
 
+++ 
 
Fluoxetine 
PROZAC, SARAFEM  
N 
++ 
 
Fluvoxamine 
LUVOX 
 
+++ 
 
Fosamprenavir 
LEXIVA 
 
± 
 
Fosphenytoin 
CEREBYX 
Y 
 
Y 
Gefitinib 
IRESSA 
 
± 
 
Gemfibrozil 
LOPID  
 
+++ 
 
Imipramine 
TOFRANIL 
Y 
± 
 
Indinavir 
CRIXIVAN 
 
± 
 
Indomethacin 
INDOCIN 
N 
± 
 
Isoniazid 
INH, NYDRAZID, PMS-ISONIAZID  
 
+++ 
 
Ketoconazole 
NIZORAL 
 
++ 
 


 
 
Lansoprazole 
PREVACID 
Y 
++ 
 
Letrozole 
FEMARA 
 
± 
 
Loratadine 
CLARITIN 
 
++ 
 
Losartan 
COZAAR 
 
± 
 
Mephenytoin 
MESANTOIN 
Y 
 
 
Mephobarbital 
MEBARAL 
Y 
± 
 
Mestranol 
NECON 1/50, NORINYL 1/50, ORTHO-
NOVUM 1/50  (w/ norethindrone) 
 
± 
 
Methimazole 
TAPAZOLE 
 
± 
 
Methoxsalen 
8-MOP, OXSORALEN, UVADEX  
 
± 
 
Methsuximide 
CELONTIN 
Y 
± 
 
Miconazole 
LOTRIMIN, MICATIN, MICONAZOLE 7, 
MONISTAT 
 
+++ 
 
Modafinil 
PROVIGIL 
 
+++ 
 
Nelfinavir 
VIRACEPT 
Y 
± 
 
Nicardipine 
CARDENE 
 
++ 
 
Nilutamide 
NILANDRON 
Y 
± 
 
Olanzapine 
ZYPREXA, ZYPREXA ZYDIS  
 
± 
 
Omeprazole 
PRILOSEC 
Y 
+++ 
 
Orphenadrine 
FLEXOR, NORFLEX  
 
± 
 
Oxcarbazepine 
TRILEPTAL 
 
± 
 
Pantoprazole 
PANTOLOC, PROTONIX  
Y 
 
 
Paroxetine 
PAXIL 
 
± 
 
Pentamidine 
NEBUPENT, PENTAM 300  
Y 
± 
 
Phenobarbital 
LUMINAL 
Y 
 
 
Phenytoin 
DILANTIN, PHENYTEK, PHENYTOIN 
SODIUM  
Y 
 
Y 
Pimozide 
ORAP 
 
± 
 
Pioglitazone 
ACTOS 
 
± 
 
 
 
 
 
 
 
 
 
 
CYP2C19, 
continued 
Generic Name 
Trade Names 
Substrate
1 
Inhibitor2 Inducer3
Probenecid 
BENEMID, PROBALAN  
 
± 
 
Progesterone 
CRINONE, PROGESTASERT, PROMETRIUM 
Y 
± 
 
Propofol 
DIPRIVAN 
N 
++ 
 
Propranolol 
INDERAL, INNOPRAN XL 
Y 
 
 
Rabeprazole 
ACIPHEX 
Y 
++ 
 
Rifampin 
RIFADIN, RIMACTANE  
 
 
Y 
Ritonavir 
NORVIR 
 
± 
 
Rosiglitazone 
AVANDIA 
 
± 
 
Saquinavir 
INVIRASE, FORTOVASE 
 
± 
 
Selegiline 
ELDEPRYL 
 
± 
 
Sertraline 
ZOLOFT 
Y 
++ 
 
Sildenafil 
VIAGRA 
 
± 
 
Sulconazole 
EXELDERM 
 
± 
 
Telmisartan 
MICARDIS 
 
± 
 
Ticlopidine 
TICLID 
 
+++ 
 
Tioconazole 
MONISTAT 1, VAGISTAT-1  
 
± 
 
Topiramate 
TOPAMAX 
 
± 
 
Torsemide 
DEMADEX 
 
± 
 


 
 
Tranylcypromine PARNATE  
 
++ 
 
Trimipramine 
SURMONTIL 
Y 
 
 
Valdecoxib 
BEXTRA 
 
± 
 
Valproic acid 
DEPAKENE 
N 
± 
 
Voriconazole 
VFEND 
Y 
± 
 
Warfarin 
COUMADIN 
N 
± 
 
Zafirlukast 
ACCOLATE 
 
± 
 
 
 
Potential Cytochrome P450 (CYP) Drug Interactions – CYP3A4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP3A4 
Generic Name 
Trade Names 
Substrate
1 
Inhibitor2 Inducer3
Acetaminophen 
TYLENOL 
N 
± 
 
Acetazolamide 
DIAMOX 
 
± 
 
Albuterol 
PROVENTIL, VENTOLIN, VOLMAX  
Y 
 
 
Alfentanil 
ALFENTA 
Y 
 
 
Alprazolam 
ALPRAZOLAM INTENSOL, XANAX  
Y 
 
 
Aminoglutethimid
e 
CYTADREN  
 
 
Y 
Amiodarone 
CORDARONE, PACERONE  
N 
++ 
 
Amlodipine 
NORVASC 
Y 
± 
 
Amprenavir 
AGENERASE 
Y 
+++ 
 
Anastrozole 
ARIMIDEX 
 
± 
 
Aprepitant 
EMEND 
Y 
± 
N 
Aripiprazole 
ABILIFY 
Y 
 
 
Atazanavir 
REYATAZ 
Y 
+++ 
 
Atorvastatin 
LIPITOR  
Y 
± 
 
Azelastine 
ASTELIN, OPTIVAR, RHINOLAST  
N 
± 
 
Azithromycin 
ZITHROMAX 
N 
± 
 
Benzphetamine 
DIDREX 
Y 
 
 
Betamethasone 
CELESTONE, SOLUSPAN, DIPROSONE  
 
± 
 
Bisoprolol 
ZEBETA 
Y 
 
 
Bortezomib 
VELCADE 
Y 
± 
 
Bosentan 
TRACLEER 
Y 
 
N 
Bromazepam 
LECTOPAM, LEXOTAN, LEXOTANIL  
Y 
 
 
Bromocriptine 
PARLODEL 
Y 
± 
 
Buprenorphine 
BUPRENEX 
Y 
 
 
Buspirone 
BUSPAR 
Y 
 
 
Busulfan 
BUSULFEX, MYLERAN  
Y 
 
 
Caffeine 
 
N 
++ 
 
Carbamazepine 
CARBATROL, TEGRETOL  
Y 
 
Y 
Cerivastatin 
BAYCOL 
Y 
± 
 
Chloramphenicol 
CHLOROMYCETIN, CHLOROPTIC SOP, 
OCU-CHLOR  
 
± 
 
Chlordiazepoxide 
LIBRITABS, LIBRIUM  
Y 
 
 
Chloroquine 
ARALEN 
Y 
 
 
Chlorpheniramine CHLOR-TRIMETON 
Y 
 
 
Chlorzoxazone 
PARAFLEX  
N 
± 
 


 
 
Cimetidine 
TAGAMET 
 
++ 
 
Ciprofloxicin 
CILOXAN, CIPRO 
 
+++ 
 
Cisapride 
PREPULSID, PROPULSID 
Y 
± 
 
Citalopram 
CELEXA 
Y 
 
 
Clarithromycin 
BIAXIN 
Y 
+++ 
 
Clemastine 
ALLERHIST, TAVIST 
 
± 
 
Clobazam 
FRISIUM 
Y 
 
 
Clofazimine 
LAMPRENE 
 
± 
 
Clonazepam 
KLONOPIN 
Y 
 
 
Clorazepate 
TRANXENE, T-TAB 
Y 
 
 
Clotrimazole 
GYNE-LOTRIMIN, LOTRIMIN, MYCELEX 
 
++ 
 
Clozapine 
CLOZARIL 
N 
± 
 
Cocaine 
 
Y 
± 
 
Colchicine 
COLBENEMID, COLSALIDE 
Y 
 
N 
Cyclophosphamide CYTOXAN, NEOSAR  
Y 
± 
 
Cyclosporine 
GENGRAF, NEORAL, RESTASIS, 
SANDIMMUNE 
Y 
++ 
 
Danazol 
DANOCRINE 
 
± 
 
Dantrolene 
DANTRIUM 
Y 
 
 
Dapsone 
 
Y 
 
 
Delavirdine 
RESCRIPTOR 
Y 
± 
 
Desipramine 
NORPRAMIN, PERTOFRANE 
 
++ 
 
Dexmedetomidine PRECEDEX 
 
± 
 
Diazepam 
DIASTAT, DIZAC, VALIUM  
Y 
± 
 
Diclofenac 
CATAFLAM, VOLTAREN 
N 
+++ 
 
Digitoxin 
CRYSTODIGIN 
Y 
 
 
Dihydroergotamin
e 
D.H.E. 45, MIGRANAL  
Y 
± 
 
Diltiazem 
CARDIZEM, DILACOR XR, TIAZAC  
Y 
++ 
 
Disopyramide 
NORPACE  
Y 
 
 
Disulfiram 
ANTABUSE 
N 
± 
 
Docetaxel 
TAXOTERE 
Y 
± 
 
Doxepin 
ADAPIN, SINEQUAN, ZONALON  
Y 
 
 
Doxorubicin 
ADRIAMYCIN 
Y 
± 
 
Doxycycline 
ADOXA, ATRIDOX, DORYX, MONODOX, 
PERIOSTAT, VIBRAMYCIN   
Y 
+++ 
 
Drospirenone 
YASMIN (w/ethinyl estradiol) 
N 
± 
 
 
 
 
 
 
 
 
 
 
 
 
Generic Name 
Trade Names 
Substrate
1 
Inhibitor2 Inducer3
Efavirenz 
SUSTIVA 
Y 
± 
N 
Eletriptan 
RELPAX 
Y 
 
 
Enalapril 
VASOTEC 
Y 
 
 
Enoxacin 
PENETREX 
 
+++ 
 
Entacapone 
COMTAN 
 
± 
 
Eplerenone 
INSPRA 
Y 
 
 
Ergoloid mesylates GERIMAL, HYDERGINE 
Y 
 
 
Ergonovine 
ERGOTRATE 
Y 
 
 
Ergotamine 
GENERGEN  
Y 
± 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP3A4, 
continued 
Erythromycin 
A/T/S, AKNE-MYCIN, EES, ERY-TAB, 
ERYC, ERYPED, ERYTHROCIN 
Y 
++ 
 
Escitalopram 
LEXAPRO 
Y 
 
 
Estradiol 
ALORA, CLIMARA, ESTRACE, 
ESTRADERM, ESTRING, FEMRING, 
VAGIFEM 
Y 
 
N 
Estrogens, 
conjugated 
A/synthetic 
CENESTIN 
Y 
 
N 
Estrogens, 
conjugated equine PREMARIN 
Y 
 
N 
Estrogens, 
conjugated 
esterified 
MENEST 
Y 
 
 
Estrone 
KESTRONE 
Y 
 
 
Estropipate 
OGEN, ORTHO-EST 
Y 
 
 
Ethinyl estradiol 
ESTINYL, ORTHO TRI-CYCLEN 
(w/norgestimate)                     TRI-LEVLEN, 
TRIPHASIL (w/levonorgestrel) 
Y 
± 
 
Ethosuximide 
ZARONTIN 
Y 
 
 
Etoposide 
ETOPOPHOS, VEPESID 
Y 
± 
 
Felbamate 
FELBATOL 
Y 
 
N 
Felodipine 
PLENDIL 
Y 
± 
 
Fentanyl 
ACTIQ, DURAGESIC, SUBLIMAZE 
Y 
± 
 
Fluconazole 
DIFLUCAN 
 
++ 
 
Fluoxetine 
PROZAC, SARAFEM  
N 
± 
 
Flurazepam 
DALMANE 
Y 
 
 
Flutamide 
EULEXIN 
Y 
 
 
Fluvastatin 
LESCOL 
N 
± 
 
Fluvoxamine 
LUVOX 
 
± 
 
Fosamprenavir 
LEXIVA 
Y 
+++ 
 
Fosphenytoin 
CEREBYX 
N 
 
Y 
Fulvestrant 
FASLODEX  
Y 
 
 
Gefitinib 
IRESSA 
Y 
 
 
Glyburide 
DIABETA, GLYNASE PRESTAB, 
MICRONASE  
 
± 
 
Grapefruit juice 
 
 
++ 
 
Halofantrine 
HALFAN 
Y 
 
 
Haloperidol 
HALDOL 
Y 
++ 
 
Hydralazine 
APRESOLINE 
 
± 
 
Ifosfamide 
IFEX  
Y 
± 
 
Imatinib 
GLEEVEC 
Y 
+++ 
 
Indinavir 
CRIXIVAN 
Y 
+++ 
 
Irbesartan 
AVAPRO  
 
± 
 
Irinotecan 
CAMPTOSAR 
Y 
 
 
Isoniazid 
INH, NYDRAZID, PMS-ISONIAZID  
 
+++ 
 
Isosorbide dinitrate DILATRATE, ISORDIL, SORBITRATE  
Y 
 
 
Isosorbide 
mononitrate 
IMDUR, ISMO 
Y 
 
 
Isradipine 
DYNACIRC  
Y 
± 
 


 
 
Itraconazole 
SPORANOX 
Y 
+++ 
 
Ketamine 
KETALAR  
Y 
 
 
Ketoconazole 
NIZORAL 
Y 
+++ 
 
Lansoprazole 
PREVACID 
Y 
± 
 
Letrozole 
FEMARA 
Y 
 
 
Levomethadyl 
acetate 
hydrochloride 
ORLAAM 
Y 
 
 
Levonorgestrel 
MIRENA, PLAN B 
Y 
 
 
Lidocaine 
XYLOCAINE 
Y 
++ 
 
Lomustine 
CEENU 
 
± 
 
Losartan 
COZAAR 
Y 
± 
 
Lovastatin 
ALTOCOR, MEVACOR  
Y 
± 
 
Medroxyprogester
one 
DEPO-PROVERA, PROVERA 
Y 
 
N 
Mefloquine 
LARIAM 
Y 
± 
 
Mestranol 
NECON 1/50, NORINYL 1/50, ORTHO-
NOVUM 1/50  (w/ norethindrone) 
Y 
± 
 
Methadone 
DISKETS, DOLOPHINE, METHADONE 
HYDROCHLORIDE INTENSOL  
Y 
± 
 
Methimazole 
TAPAZOLE 
 
± 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Generic Name 
Trade Names 
Substrate
1 
Inhibitor2 Inducer3
Methoxsalen 
8-MOP, OXSORALEN, UVADEX  
 
± 
 
Methylergonovine METHERGINE 
Y 
 
 
Methylprednisolon
e 
MEDROL, DEPO-MEDROL, A-
METHAPRED, SOLU-MEDROL 
N 
± 
 
Methysergide 
SANSERT 
Y 
 
 
Metronizadole 
FLAGYL, METROGEL, NORITATE  
 
++ 
 
Miconazole 
LOTRIMIN, MICATIN, MICONAZOLE 7, 
MONISTAT 
Y 
+++ 
 
Midazolam 
VERSED 
Y 
± 
 
Mifepristone 
MIFEPREX 
N 
± 
 
Miglustat 
ZAVESCA 
Y 
 
 
Mirtazapine 
REMERON 
Y 
± 
 
Mitoxantrone 
NOVANTRONE 
 
± 
 
Modafinil 
PROVIGIL 
Y 
± 
N 
Montelukast 
SINGULAIR 
Y 
 
 
Moricizine 
ETHMOZINE 
Y 
 
N 
Nafcillin 
NAFCIL, NALLPEN  
 
 
Y 
Nateglinide 
STARLIX 
Y 
 
 
Nefazodone 
SERZONE 
Y 
+++ 
 
Nelfinavir 
VIRACEPT 
Y 
+++ 
 
Nevirapine 
VIRAMUNE 
Y 
± 
Y 
Nicardipine 
CARDENE 
Y 
+++ 
 
Nifedipine 
ADALAT, PROCARDIA  
Y 
± 
 
Nimodipine 
NIMOTOP 
Y 
 
 
Nisoldipine 
SULAR 
Y 
± 
 
Nitrendipine 
 
Y 
± 
 


 
 
 
 
 
 
 
 
 
 
 
CYP3A4, 
continued 
Nizatidine  
AXID 
 
± 
 
Norethindrone 
AYGESTIN, NOR-QD, ORTHO MICRONOR 
Y 
 
 
Norfloxacin 
NOROXIN 
 
++ 
 
Norgestrel 
LO/OVRAL, LO/OVRAL-28, OVRAL-21, 
OVRAL-28 (w/ethinyl estradiol)  
Y 
 
 
Olanzapine 
ZYPREXA, ZYPREXA ZYDIS  
 
± 
 
Omeprazole 
PRILOSEC 
N 
± 
 
Ondansetron 
ZOFRAN 
Y 
 
 
Orphenadrine 
FLEXOR, NORFLEX  
N 
± 
 
Oxcarbazepine 
TRILEPTAL 
 
 
Y 
Oxybutynin 
OXYTROL, DITROPAN 
N 
± 
 
Paclitaxel 
TAXOL 
Y 
 
N 
Paroxetine 
PAXIL 
 
± 
 
Pentamidine 
NEBUPENT, PENTAM 300  
 
± 
 
Pentobarbital 
NEMBUTAL SODIUM 
 
 
Y 
Pergolide 
PERMAX 
Y 
± 
 
Phencyclidine 
 
Y 
± 
 
Phenobarbital 
LUMINAL 
 
 
Y 
Phenytoin 
DILANTIN, PHENYTEK, PHENYTOIN 
SODIUM  
N 
 
Y 
Pilocarpine 
ISOPTO CARPINE, OCUSERT PILO, 
PILOCAR, PILOPINE HS, SALAGEN 
 
± 
 
Pimozide 
ORAP 
Y 
± 
 
Pioglitazone 
ACTOS 
Y 
 
N 
Pravastatin 
PRAVACHOL  
N 
± 
 
Prednisolone 
AK-PRED, ECONOPRED, INFLAMASE, 
ORAPRED, PEDIAPRED, PRED FORTE, 
PRED MILD, PRELONE 
N 
± 
 
Primaquine 
 
Y 
± 
 
Primidone 
MYSOLINE 
 
 
Y 
Progesterone 
CRINONE, PROGESTASERT, 
PROMETRIUM  
Y 
± 
 
Propofol 
DIPRIVAN 
N 
+++ 
 
Propoxyphene 
DARVON 
 
± 
 
Quetiapine 
SEROQUEL 
Y 
 
 
Quinidine 
QUINAGLUTE DURA, CARDIOQUIN, 
QUINIDEX 
Y 
+++ 
 
Quinine 
LEGATRIN, QUINAMM 
N 
± 
 
Quinupristin 
SYNERCID (w/dalfopristin) 
 
± 
 
Rabeprazole 
ACIPHEX 
Y 
± 
 
Repaglinide 
PRANDIN 
Y 
 
 
Rifabutin 
MYCOBUTIN 
Y 
 
Y 
Rifampin 
RIFADIN, RIMACTANE  
Y 
 
Y 
Rifapentine 
PRIFTIN 
 
 
Y 
Risperidone 
RISPERDAL 
N 
± 
 
Ritonavir 
NORVIR 
Y 
+++ 
N 
Saquinavir 
INVIRASE, FORTOVASE 
Y 
++ 
 
Selegiline 
ELDEPRYL 
N 
± 
 
Sertraline 
ZOLOFT 
Y 
++ 
 


 
 
Sibutramine 
MERIDIA 
Y 
 
 
Sildenafil 
VIAGRA 
Y 
± 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP3A4, 
continued 
Generic Name 
Trade Names 
Substrate
1 
Inhibitor2 Inducer3
Simvastatin 
ZOCOR 
Y 
 
 
Sirolimus 
RAPAMUNE 
Y 
± 
 
Sufentanil 
SUFENTA 
Y 
 
 
Sulconazole 
EXELDERM 
 
± 
 
Tacrolimus 
PROGRAF, PROTOPIC  
Y 
± 
 
Tamoxifen 
NOLVADEX 
Y 
± 
 
Tamsulosin 
FLOMAX 
Y 
 
 
Telithromycin 
KETEK 
Y 
+++ 
 
Teniposide 
VUMON  
Y 
± 
 
Terbinafine 
DESENEX MAX, LAMISIL  
Y 
 
N 
Testosterone 
ANDRODERM, ANDROGEL, TESTIM, 
TESTODERM  
N 
± 
 
Tetracycline 
SUMYCIN 
Y 
++ 
 
Theophylline 
ELIXOPHYLLIN, SLO-BID, SLO-PHYLLIN, 
THEO-24, THEO-DUR, THEOCHRON, 
UNIPHYL  
Y 
 
 
Tiagabine 
GABITRIL 
Y 
 
 
Ticlopidine 
TICLID 
Y 
± 
 
Tolterodine 
DETROL 
Y 
 
 
Toremifene 
FARESTON 
Y 
 
 
Tranylcypromine 
PARNATE  
 
± 
 
Trazodone 
DESYREL 
Y 
± 
 
Triazolam 
HALCION 
Y 
 
 
Trimethoprim 
PRIMSOL, PROLOPRIM 
Y 
 
 
Trimipramine 
SURMONTIL 
Y 
 
 
Troleandomycin 
CYCLAMYCIN, TAO 
Y 
++ 
 
Valproic acid 
DEPAKENE 
 
± 
 
Vardenafil 
LEVITRA 
Y 
 
 
Venlafaxine 
EFFEXOR 
Y 
± 
 
Verapamil 
CALAN, CHRONOVERA, COVERA-HS, 
ISOPTIN, VERELAN  
Y 
++ 
 
Vinblastine 
VELBAN, VELBE 
Y 
± 
 
Vincristine 
ONCOVIN 
Y 
± 
 
Vinorelbine 
NAVELBINE 
Y 
± 
 
Voriconazole 
VFEND 
N 
++ 
 
Zafirlukast 
ACCOLATE 
 
± 
 
Ziprasidone 
GEODON 
N 
± 
 
Zolpidem 
AMBIEN 
Y 
 
 
Zonisamide 
ZONEGRAN 
Y 
 
 
Zopiclone 
RTIO-ZOPICLONE 
Y 
 
 
 


 
 
 
Appendix D 
 
City of Hope National Medical Center  
 
NOTIFICATION OF TOXICITY 
 
THIS FORM OR A COPY OF A SUBMITTED AdEERS REPORT MUST BE FAX'D (626-256-8654) TO THE 
CONSORTIUM COORDINATOR WITHIN 24 HOURS OF ONSET OF ADVERSE EVENT.  
 
Consortium Protocol Number:  PH___- ______  
NCI # (if applicable):  ________________ 
 
Protocol Title:  _________________________________________________________________ 
 
Treating Institution (check one)   ___COH   ___USC   ___UCD   ___UOP   ___Other_____ 
 
Reporter:  ______________________________________ 
Phone #:_________________________ 
 
 
 
 
 
 
 
 
 
Email:   _________________________ 
PATIENT INFORMATION 
 
Patient Name________________________________________ Pt Study ID:  _____________________ 
 
 
ADVERSE EVENT INFORMATION 
 
Adverse Event:  _______________________________  
Start Date of AE: ____/____/____ 
 
 
If Phase I trial, is the adverse event considered dose-limiting? 
 __ No    __ Yes 
Is toxicity reportable as defined by NCI Guidelines? 
 
  
 __ No    __ Yes 
 
REPORTING INFORMATION 
 
Has the event been reported to the following: 
 
Institutional IRB  
__ No    __ Yes  
Date: __ __ / __ __  / __ __ 
 
FDA 
 
 
__ No    __ Yes  
Date: __ __ / __ __  / __ __ 
 
NCI  
 Telephone 
__ No    __ Yes  
Date: __ __ / __ __  / __ __ 
Ticket# _______________ 
 
 
AdEERS 
__ No    __ Yes  
Date: __ __ / __ __  / __ __ 
Ticket# _______________ 
 
Report sent to DCC? 
__ No    __ Yes  
Date: __ __ / __ __  / __ __