Conditions: Recurrent Mantle Cell Lymphoma Recurrent Non-Hodgkin Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 65
Healthy volunteers: no

Brief summary:
This phase II trial studies how well bortezomib and vorinostat work in treating patients with recurrent mantle cell lymphoma or recurrent and/or refractory diffuse large B-cell lymphoma. Bortezomib and vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
This was a multicenter, non-randomized phase 2 trial using a Simon two-stage design with 3 cohorts.

PRIMARY OBJECTIVES:

I. Estimate the response rates of mantle cell and diffuse large B-cell lymphomas to bortezomib and vorinostat combination therapy.

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of the study regimen. II. Observe progression-free survival and response durations. III. Observe the relationship between pretreatment lymphoma cell nuclear v-rel reticuloendotheliosis viral oncogene homolog A (relA) and response.

OUTLINE:

Patients receive vorinostat orally (PO) once daily (QD) on days 1-5 and 8-12. Patients also receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Arms:
arm 1: Participants receive vorinostat orally (PO) once daily (QD) on days 1-5 and 8-12. Participants also receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Vorinostat precedes bortezomib on days of concurrent administration. Courses repeat every 3 weeks in the absence of disease progression - or unacceptable toxicity. After completion of study therapy, participants are followed periodically.

Treatment arm consists of 3 cohorts, all receiving the same treatment:

A: Mantle Cell Lymphoma (MCL) - with no prior bortezomib.

B: Mantle Cell Lymphoma (MCL) - with no prior bortezomib.

C: Diffuse Large B-Cell Lymphoma (DLBCL) - with no prior bortezomib.

Interventions: intervention 1: Bortezomib intervention 2: Laboratory Biomarker Analysis intervention 3: Vorinostat
Intervention descriptions: intervention 1: Bortezomib: 1.3 mg/m\^2/d IV days 1, 4, 8, and 11. intervention 2: Correlative studies intervention 3: Vorinostat: 400 mg (total daily dose as a single dose) days 1-5 and 8-12.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 Phase II Trial of Bortezomib and Vorinostat in Mantle Cell and Diffuse Large B-
Cell Lymphomas 
NCT00703664 
 
Version 18.0 
April 10, 2014 


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NCI Protocol #: 8064 
 
Local Protocol #: MCC-8064 
 
TITLE:  Phase II Trial of Bortezomib and Vorinostat in Mantle Cell and Diffuse Large B-Cell 
Lymphomas 
 
 
Coordinating Center: 
Southeast Phase II Consortium (SEP2C) 
H. Lee Moffitt Cancer Center and Research Institute 
University of South Florida 
12902 Magnolia Drive, Tampa, FL 33612 
 
Study Chair: 
Beata Holkova, MD 
 
Massey Cancer Center 
 
Virginia Commonwealth University 
 
  
 
  
 
 
 
 
 
 
 
 
 
Co-Investigators: 
Dan Sullivan, MD (N01 PI – CM-62208) 
 
H. Lee Moffitt Cancer Center and Research Institute 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Statistician: 
 
 
 
 
 
 
 
 
 
Correlative Studies: 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 


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Correlative Studies  
 
and Pathologist: 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Entities  
 
SCD# 
Mantle Cell Lymphoma  
 
10026799 
Diffuse Large B-cell Lymphoma  
10012820 
 
NCI Supplied Agents: 
 
Bortezomib (Velcade) NSC# 681239; IND# 58,443 
 
 
 
 
 
Vorinostat (Zolinza) 
NSC# 701852; IND# 71,976 
 
Protocol Type / Version # / Version Date:  Phase II, Version 18, Version Date 04/10/2014 


 
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SCHEMA 
Phase II Study of Bortezomib and Vorinostat in Mantle Cell and Diffuse Large B-Cell Lymphoma. 
Patient cohorts: 
A:  Mantle cell lymphoma - No prior bortezomib 
B:  Mantle cell lymphoma - Prior bortezomib [closed with Protocol Version 8] 
C:  Diffuse large B-cell lymphoma - No prior bortezomib [closed 6/25/2013] 
 
 
Days 
1 
2 
3 
4 
5 
6 7 
8 
9 
10 
11 
12 
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14 
15 
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18 
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21 
V 
V 
V 
V 
V 
 
 
V 
V 
V 
V 
V 
 
 
 
 
 
 
 
 
 
B 
 
 
B 
 
 
 
B 
 
 
B 
 
 
 
 
 
 
 
 
 
 
 
V = vorinostat 400 mg (total dose) po 
B = bortezomib 1.3 mg/m2/d iv 
 
Vorinostat precedes bortezomib on days of concurrent administration. 
Repeat every 3 weeks. 


 
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TABLE OF CONTENTS 
SCHEMA ........................................................................................................................................... 5 
1 
OBJECTIVES ............................................................................................................................. 8 
1.1 PRIMARY OBJECTIVE ............................................................................................................ 8 
1.2 SECONDARY OBJECTIVES .................................................................................................... 8 
2 
BACKGROUND .......................................................................................................................... 8 
2.1 STUDY DISEASES ................................................................................................................. 8 
2.2 STUDY AGENTS .................................................................................................................. 10 
2.3 STUDY DESIGN CONSIDERATIONS ...................................................................................... 12 
2.4 CORRELATIVE STUDIES BACKGROUND ............................................................................... 13 
2.5 RATIONALE FOR VERSION 4.0 ............................................................................................. 13 
2.6 RATIONALE FOR VERSION 5.0 ............................................................................................. 13 
2.7 RATIONALE FOR VERSION 6.0 ............................................................................................. 13 
2.8 RATIONALE FOR VERSION 7.0 ............................................................................................. 13 
2.9 RATIONALE FOR VERSION 8.0 ............................................................................................. 14 
2.10 RATIONALE FOR VERSION 9.1 ............................................................................................. 14 
2.11 RATIONALE FOR VERSION 10.0........................................................................................... 14 
2.12 RATIONALE FOR VERSION 10.1........................................................................................... 14 
2.13 RATIONALE FOR VERSION 11 .............................................................................................. 14 
2.14 RATIONALE FOR VERSION 12 .............................................................................................. 15 
2.15 RATIONALE FOR VERSION 13 .............................................................................................. 15 
2.16 RATIONALE FOR VERSION 14 .............................................................................................. 15 
2.17 RATIONALE FOR VERSION 15 .............................................................................................. 16 
2.18 RATIONALE FOR VERSION 16 .............................................................................................. 16 
2.19 RATIONALE FOR VERSION 17 .............................................................................................. 17 
2.20 RATIONALE FOR VERSION 18 .............................................................................................. 17 
3 
PATIENT SELECTION ............................................................................................................. 17 
3.1 ELIGIBILITY CRITERIA ......................................................................................................... 17 
3.2 EXCLUSION CRITERIA ......................................................................................................... 19 
3.3 INCLUSION OF WOMEN AND MINORITIES ............................................................................. 19 
4 
REGISTRATION PROCEDURES ............................................................................................ 20 
4.1 GENERAL GUIDELINES ....................................................................................................... 20 
4.2 REGISTRATION PROCESS ................................................................................................... 20 
5 
TREATMENT PLAN ................................................................................................................. 20 
5.1 SCHEDULE AND DOSING ..................................................................................................... 20 
5.2 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES....................... 21 
5.3 DURATION OF THERAPY ..................................................................................................... 22 
5.4 DURATION OF FOLLOW UP ................................................................................................. 22 
5.5 CRITERIA FOR REMOVAL FROM STUDY ............................................................................... 23 
6 
DOSING DELAYS/DOSE MODIFICATIONS ........................................................................... 23 
7 
ADVERSE EVENT LIST AND REPORTING REQUIREMENTS ............................................. 24 
7.1 COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST (CAEPR) ........................ 24 


 
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7.2 CAEPR - BORTEZOMIB ...................................................................................................... 24 
7.3 CAEPR - VORINOSTAT....................................................................................................... 28 
7.4 ADVERSE EVENT CHARACTERIZATION ................................................................................ 31 
7.5 EXPEDITED ADVERSE EVENT REPORTING ........................................................................... 31 
7.6 ROUTINE ADVERSE EVENT REPORTING .............................................................................. 32 
7.7 SECONDARY MALIGNANCY ................................................................................................. 33 
7.8 SECOND MALIGNANCY ....................................................................................................... 33 
8 
PHARMACEUTICAL INFORMATION ...................................................................................... 33 
8.1 BORTEZOMIB (NSC 681239) .............................................................................................. 33 
8.2 VORINOSTAT (NSC 701852) .............................................................................................. 34 
8.3 AGENT ORDERING .............................................................................................................. 35 
8.4 AGENT ACCOUNTABILITY .................................................................................................... 35 
9 
CORRELATIVE STUDIES ........................................................................................................ 35 
10 STUDY CALENDAR ................................................................................................................. 37 
11 MEASUREMENT OF EFFECT ................................................................................................. 38 
12 SUBMISSION OF MATERIALS FOR CORRELATIVE STUDIES, CENTRAL 
PATHOLOGICAL REVIEW, DATA REPORTING, AND REGULATORY REQUIREMENTS . 40 
12.1 SUBMISSION OF MATERIALS FOR CORRELATIVE STUDIES AND PATHOLOGICAL REVIEW ...... 40 
12.2 DATA REPORTING .............................................................................................................. 41 
12.3 DATA AND SAFETY MONITORING ......................................................................................... 41 
12.4 CTEP MULTICENTER GUIDELINES ...................................................................................... 41 
12.5 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)/CLINICAL TRIALS 
AGREEMENT (CTA) ............................................................................................................ 42 
13 STATISTICAL CONSIDERATIONS ......................................................................................... 43 
13.1 MANTLE CELL LYMPHOMA .................................................................................................. 43 
13.2 DIFFUSE LARGE B-CELL LYMPHOMA ................................................................................... 44 
13.3 STRATIFICATION FACTORS ................................................................................................. 44 
13.4 CORRELATIVE STUDIES ...................................................................................................... 44 
14 REFERENCES.......................................................................................................................... 46 
RADIOLOGY EXAM TRANSMISSION NOTIFICATION FORM ................................................... 49 
TISSUE NOTIFICATION FORM ..................................................................................................... 50 
 
 
 


 
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1 OBJECTIVES 
1.1 Primary Objective 
Estimate the response rates of mantle cell and diffuse large B-cell lymphomas to bortezomib and 
vorinostat combination therapy. 
1.2 Secondary Objectives 
1.2.1 Assess the safety and tolerability of the study regimen 
1.2.2 Observe progression-free survival and response durations 
1.2.3 Observe relationship between pretreatment lymphoma cell nuclear relA and response. 
2 BACKGROUND 
2.1 Study Diseases 
Mantle Cell Lymphoma (MCL) 
From the National Comprehensive Cancer Network (NCCN) Physician Guidelines (v2.2007): 
Mantle cell lymphoma has the worst characteristics of both indolent and aggressive non-Hodgkin's 
lymphomas.  Like many of the more common indolent lymphoid neoplasms, mantle cell lymphoma 
appears to be incurable with conventional chemotherapy. However, mantle cell lymphoma does 
not have an indolent natural history; rather, it has the shorter disease-free and overall survivals 
more characteristic of aggressive lymphomas. Therefore, there is no established standard of care. 
In the absence of standard management for mantle cell lymphoma, patients with this disease 
should be referred for participation in prospective clinical trials. Few patients present with localized 
MCL and the available published literature on management is retrospective and anecdotal. 
Outside of a clinical trial the panel recommended either combined modality therapy or involved 
field radiation therapy though this was based on treatment principles as there was not data to 
guide these recommendations. 
The overwhelming majority of patients with MCL will have advanced stage disease and require 
systemic therapy. For patients who do not have access to clinical trials for first line therapy, several 
regimens have shown significant activity including R-HyperCVAD (rituximab, cyclophosphamide, 
vincristine, doxorubicin, dexamethasone) alternating with methotrexate and cytarabine, R-CHOP, 
and REPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) 
though relapse is common with a median time of 15-18 months without adjuvant stem cell 
transplant (autologous or allogeneic). 
Initial remission should be followed by stem cell transplantation (category 2B) in eligible patients as 
this has been associated with some evidence of durable remission. Allogeneic stem cell transplant 
alone or in the context of a clinical trial is considered as the first line consolidation therapy. The 
optimal approach to recurrent disease remains to be defined. For this reason, the entry of patients 
into clinical trials is strongly encouraged. Data has demonstrated a role for single agents such as 
cladribine and bortezomib. Combination such as cyclophosphamide and fludarabine, PCR 
(pentostatin, cyclophosphamide, rituximab), and FCMR (fludarabine, cyclophosphamide, 
mitoxantrone, rituximab) also have activity. Marked anti-tumor activity has been shown for 
rituximab plus thalidomide in patients with relapsed/refractory MCL. Patients who obtain only a 


 
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partial response to induction therapy are also appropriate candidates for clinical trials of high-dose 
therapy and additional therapeutic modalities. Radioimmunotherapy has shown to be active for 
both untreated and relapsed MCL. 
Diffuse Large B-cell Lymphoma (DLBCL) 
From the National Comprehensive Cancer Network (NCCN) Physician Guidelines (v2.2007): 
The realistic goal of induction therapy for DLBCL is to cure the disease. In fact, almost half of the 
patients with DLBCL may be cured with conventional therapy. Approaches to the treatment of 
DLBCL differ between patients with localized (Ann Arbor stage I-II) and advanced (Ann Arbor 
stage III-IV) disease. In patients with localized disease, treatment approaches also differ between 
patients with non-bulky (<10 cm) disease and those with bulky (≥ 10 cm) and/or extranodal 
disease. Patients with non-bulky localized disease who do not have adverse risk factors such as 
an elevated LDH, stage II disease, age >60 or an ECOG performance status 2 have an extremely 
good prognosis and may be treated with an abbreviated course (three cycles) of RCHOP 
(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) combined with involved-
field RT. For patients with any of the adverse features listed above, the recommendation is 6-8 
cycles of CHOP+R. Patients could receive additional adjuvant RT (category 2B). Patients who 
present with bulky disease and/or local extranodal disease may be more effectively treated with a 
full course (six to eight cycles) of CHOP chemotherapy with rituximab and involved-field RT 
(category 1). 
Treatment options for patients with advanced-stage disease vary depending on additional 
prognostic information provided by the Age-Adjusted International Index. Patients who fall into the 
low or low-intermediate risk category, as indicated by a normal LDH serum level and normal 
performance status (Eastern Cooperative Oncology Group [ECOG] 0 or 1) are appropriate 
candidates for full course anthracycline-based chemotherapy. This therapy would include six to 
eight cycles of R-CHOP for patients of all ages (category 1). An alternative is CHOP-14 (bi-weekly 
CHOP) for patient >60. However, participation in clinical trials of new regimens is recommended if 
available. In patients with bulky disease or impaired renal function, initial therapy should include 
monitoring and prophylaxis for tumor lysis syndrome (i.e., vigorous hydration and administration of 
allopurinol). Patients who fall into the IPI high-intermediate- or high-risk category have less than a 
50% chance of being cured with standard therapy. For this reason, the consensus of the panel is 
that, if possible, these patients should be treated in the context of appropriate clinical trials. Most 
current trials are evaluating augmented chemotherapy in the form of up-front or consolidative high-
dose therapy, with or without stem cell rescue, in this patient group. In patients who are not 
candidates for placement on a clinical trial protocol or who do not have access to a protocol, an 
alternative would be 6-8 cycles of CHOP (category 1) with rituximab. 
Patients who are receiving induction therapy should undergo repeat radiographic evaluation, 
including all positive studies, after three to four cycles of treatment. This early restaging is 
performed to identify, at the earliest point possible, patients whose disease has not responded or 
has progressed despite induction therapy. Upon completion of induction therapy, all positive 
radiographic studies should be repeated. Functional imaging (gallium or PET scans) may be 
particularly useful in determining whether residual masses represent fibrosis or viable tumor. A 
repeat biopsy of residual masses is recommended if the masses remained positive on a functional 
imaging scan upon completion of induction therapy. For patients having complete response (CR) 
or complete response/unconfirmed (CRu), the planned course of treatment is completed. 
Consideration of autologous stem cell transplant or completing the course of therapy with a higher 
RT dose (40-45 Gy) is recommended for stage I-II patients with partial response (PR). Stage III-IV 
PR patients need to continue with R-CHOP to a total of 6-8 cycles. In addition, appropriate clinical 
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disease is observed, patients are treated as relapsed. Patients who experience relapse following 
an initial complete response or have refractory disease and who are candidates for high-dose 
chemotherapy should be treated with a non-cross-resistant combination chemotherapeutic 
regimen, such as ICE±R (ifosfamide, carboplatin and etoposide), DHAP (dexamethasone, 
cytarabine [cytosine arabinoside], and cisplatin), MINE (mitoxantrone, ifosfamide, mesna, 
etoposide), miniBEAM (carmustine, etoposide, cytarabine, melphalan), and ESHAP 
(methylprednisolone, etoposide, cytarabine, cisplatin) in an attempt to achieve a second response. 
Patients who respond (CR or PR) to a non-cross-resistant chemotherapy regimen should be 
considered for further consolidation with high-dose therapy and stem cell support (category 1 for 
second response in relapse, category 2A for all others). There are multiple approaches to high-
dose therapy with stem cell support; however, none of these has emerged as the preferred 
alternative. Additional RT can be given before or after stem cell transplant to sites of bulky disease. 
Pertinent clinical trials are considered another option in this case. Patients who achieve complete 
remission and are not eligible for high-dose therapy should be treated individually. Similarly, 
patients with disease recurrence following high-dose therapy should be treated in the context of a 
clinical trial or individually. However, patients with disease progression despite three successive 
chemotherapeutic regimens are not likely to benefit from currently available standard therapy, 
except for patients with a long disease-free interval. 
2.2 Study agents 
2.2.1 Bortezomib 
Bortezomib (Velcade, PS-341), the prototypical clinically relevant proteasome inhibitor, is a 
dipeptidyl boronic acid derivative that has recently been approved for use in myeloma and 
mantle cell lymphoma and has also shown activity in other hematologic malignancies (1-3). 
Bortezomib inhibits the chymotryptic activity of the 20S proteasome, and in so doing, 
disrupts the proteasome-mediated degradation of diverse cellular proteins (4). Bortezomib 
activity has been postulated to reflect interference with NF-B signaling secondary to 
inhibition of degradation of the NF-κB-inhibitory protein IκBα (5). However, multiple other 
mechanisms of lethality have been proposed, including increased generation of reactive 
oxygen species (ROS), which has been demonstrated in lung cancer and leukemia cells (6). 
Moreover, proteasome inhibitors have been shown to kill cells in association with induction 
of ER stress, presumably by interfering with the disposition of unfolded proteins. For 
reasons that are incompletely understood, proteasome inhibitors selectively induce 
apoptosis in tumor as compared with normal cells (7, 8). 
2.2.2 Vorinostat 
Vorinostat, a Class I/II histone deacetylase inhibitor (HDI), was the first approved agent of 
this class on the basis of activity in refractory cutaneous T cell lymphoma (9, 10). In phase I 
and phase II trials vorinostat also has elicited responses in acute leukemia, lymphoma, and 
a variety of solid tumors (11, 12). 
HDIs are a chemically diverse group of compounds that share the ability to inhibit histone 
deactylases (HDs) and thereby promote acetylation of histones that in turn results in 
chromatin uncoiling and transcription of otherwise silenced genes (12). HDIs also promote 
acetylation of diverse non-histone proteins, and this may cause protein dysfunction (13). 
Downstream effects are diverse, and, in many or most cases, it is unclear whether these 
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HDIs can induce apoptosis in leukemic cells through processes regulated by induction of 
the cyclin-dependent kinase inhibitor p21CIP1 (14), generation of reactive oxygen species 
and Bid activation (15). Further, HDIs can inactivate cytoprotective signaling pathways (e.g., 
Raf/MEK/ERK and Akt) (16). Certain HDIs, including vorinostat, promote acetylation of 
HSP90, tubulin and dynein (17, 18). Acetylation and inactivation of Hsp90 induces 
increases in misfolded proteins that form protein aggregates. These protein aggregates are 
transported by dynein along a microtubule network to the aggresome where they are further 
processed for ultimate proteasomal degradation. HD6 is responsible for maintenance of 
deacetylation and proper functioning of dynein and other components of the aggresome. 
Disruption of HD6 results in dynein acetylation, aggresome dysfunction, and cell death 
manifested by the formation of dysmorphic perinuclear aggresomes. HDIs also can induce 
differentiation of tumor cells (9). 
2.2.3 Bortezomib and Vorinostat in Combination 
In preclinical studies involving both Bcr/Abl+ and Bcr/Abl- leukemia cells, including Bcr/Abl+ 
cells resistant to imatinib, we have shown synergistic cytotoxic interactions between 
bortezomib and vorinostat and other HDIs (19, 20). More recently, we have observed 
comparable synergistic interactions between bortezomib and vorinostat in continuously 
cultured human multiple myeloma cells as well as fresh CD138+ bone marrow cells 
(presumptive myeloma cells) from patients with multiple myeloma (21). 
Three mechanisms have been proposed to explain synergism between these agents: 
(1) HDI-mediated inhibition of class I, nuclear HDs may result in sustained activation of NF-
B, and lethal effects of HDIs may be intrinsically limited by this activation (22). Concurrent 
proteasome inhibition may disrupt NF-B activation and thereby potentiate HDI antitumor 
activity (23, 24). 
(2) Cell death resulting from HDI-mediated HSP90 and aggresome dysfunction may be 
potentiated by concurrent inhibition of the proteasome (25, 26). 
(3) HDI-mediated accumulation of unfolded proteins in the endoplasmic reticulum may 
provoke an evolutionarily conserved adaptive response referred to as the unfolded protein 
response (UPR) (27, 28). It consists of multiple components that can be broadly 
characterized as alarm, adaptive, and apoptotic responses, including cell cycle arrest, 
chaperone protein synthesis, up-regulation of cytoprotective signaling pathways (including 
NF-κB), inhibition of protein translation, and enhanced protein degradation. When the UPR 
is overwhelmed, it triggers events that lead to apoptosis. Because proteasome inhibitors 
both promote accumulation of unfolded proteins and down-regulate NF-κB, it is plausible to 
propose that concurrent proteasome inhibition may potentiate the lethality of the UPR. 
Recent studies in pancreatic cancer cells implicate this mechanism in the enhanced lethality 
of proteasome/HDI regimens (29). 
Recent preclinical studies from our laboratories in human U937 cells (derived from a patient 
with diffuse large B-cell lymphoma), T-lymphoblastic Jurkat cells, and primary AML blasts 
demonstrate a high degree of synergism between non-toxic concentrations of bortezomib 
and vorinostat. Similar results have been obtained in other lymphoma lines (e.g., SU-DHL 
16, Karpas, and Raji). In each case, low, relatively non-toxic concentrations of bortezomib 
(e.g., 3-5 nM) and vorinostat (e.g., 1 μM), administered concurrently for 24 hrs resulted in a 
significant increase in apoptosis. The enhancement of lethality for the combination is at 
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cells, raising the possibility that this strategy may be effective in lymphoproliferative 
malignancies such as lymphoma. 
In an ongoing phase I trial of the combination of bortezomib iv days 1, 4, 8, and 11 and 
vorinostat po on days 4 through 11 on a 21 day cycle in patients with previously treated 
myeloma, maximum tolerated doses of bortezomib and vorinostat appear to be 1.3 
mg/m2/dose and 400 mg/dose, respectively (30). These doses are being confirmed in an 
expansion of the maximum tolerated dose patient cohort. Dose limiting toxicities were 
fatigue and QT interval prolongation. Other toxicities have included infections and 
thrombocytopenia. Toxicities appear to be cumulative, and schedule adherence in later 
cycles will be a focus in the ongoing study. Preliminary analysis suggests that the 
combination is active including activity in patients with bortezomib-refractory disease. 
2.3 Study Design Considerations 
Vorinostat typically displays cumulative toxicities and often is administered by an interrupted 
schedule. As the basis of this study is evidence of synergistic interactions between bortezomib and 
vorinostat, it seems appropriate to administer the two agents concurrently as much as feasible. 
Based upon the ongoing phase I trial it appears that 10 days of vorinostat is the most that is 
tolerated within a conventional bortezomib schedule (days 1, 4, 8, and 11 repeated every 21 days). 
In this study patients will receive two 5 day courses of vorinostat concurrent with twice weekly 
dosing of bortezomib. 
After discussions with CTEP, it has been decided to target two entities within the spectrum of 
lymphoma: mantle cell lymphoma and diffuse large B-cell lymphoma. Mantle cell lymphoma is an 
attractive target as bortezomib has single agent activity against this entity and as there is a 
pressing need for better therapies for this usually lethal condition. Diffuse large B-cell lymphoma is 
another attractive target as with current therapy most patients are not cured of this most common 
of the aggressive lymphomas. 
As the primary endpoint is disease response, patients must have measurable disease. 
Presumably response rates that would be considered promising would differ depending upon 
whether patients had received prior bortezomib. Although it might be preferable to test the 
combination exclusively in patients who have not received prior bortezomib, the recent approval of 
bortezomib for the treatment of mantle cell lymphoma makes it unclear whether it would be 
feasible to enroll sufficient numbers of such patients with mantle cell lymphoma in a reasonable 
time frame. Therefore, we propose enrollment of 3 patient cohorts: mantle cell lymphoma, without 
prior bortezomib; mantle cell lymphoma, with prior bortezomib; and diffuse large B-cell lymphoma 
(without prior bortezomib). Should it become apparent during the course of the study that one or 
the other mantle cell lymphoma cohort is not likely to be completed, then that cohort will be closed 
to further enrollment. 
Prior high dose therapy with autologous stem cell transplant raises similar issues with regard to 
promising response rates as well as tolerance for the combination regimen. Rather than establish 
separate cohorts for this parameter (potentially requiring 6 patient cohorts, each with different 
response rate targets), however, we propose to stratify patients according to this parameter in 
order to establish the appropriateness of an analysis of study outcomes on the basis of this factor. 
Patients with persistent/recurrent lymphoma following prior allogeneic transplantation usually have 
resistant tumors and impaired host tolerance of further treatments. Inclusion of such patients might 
bias the study against an otherwise active regimen. 


 
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As the effects of bortezomib and vorinostat on the developing human fetus at the recommended 
therapeutic dose are potentially devastating, 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 and to report pregnancy or suspected 
pregnancy while participating in the study. For similar reasons, women who are pregnant or 
nursing may not participate. 
As there is no phase I experience with the combination in children, they are excluded. 
2.4 Correlative Studies Background 
Two of the three proposed mechanisms for synergistic interaction among the two agents involve 
interactions with NF-kappaB. Nuclear RelA by immunohistochemical staining is a semi-quantitative 
measure of NF-kappaB activation with which the investigators have prior experience (31). It is 
reasonable to propose that the combination of bortezomib and vorinostat might be more active in 
lymphomas in which there is baseline activation of NF-kappaB, and this is a testable hypothesis. 
Lymphoma cell nuclear relA will be assayed in tumor samples obtained previously to confirm 
eligibility. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3  PATIENT SELECTION 
3.1 Eligibility Criteria 
3.1.1 Histologically confirmed mantle cell or diffuse large B-cell lymphoma. Histological material must 
be available for central pathological review. Unstained histological material -- slides or blocks -- 
must be available for correlative studies. Archived material from previous biopsies is acceptable, 
unless a patient’s lymphoma has been known to undergo histological transformation in the past, in 
which case a repeat biopsy to confirm histology prior to enrollment is required. Availability of 
material must be confirmed at the time of registration, but material may be submitted 
subsequent to registration and initiation of study treatment. 
3.1.2 Measurable disease according to the Revised Response Criteria for Malignant Lymphoma (35). 
This requires at least one lesion greater than 1.0 cm in diameter in both the long and short axis 
as measured by spiral CT scan or physical exam. 
3.1.3 Prior allogeneic stem cell transplant is allowed provided that all of the following conditions are 
met: 
 
≥ 6 months have elapsed since allogeneic transplant 
 
No Graft vs. Host Disease (GVHD) is present 
 
Not currently on immunosuppressive therapy 
3.1.4 Prior therapy: 
Mantle cell lymphoma: 
 
Previously treated or untreated. 
 
No prior bortezomib. 


 
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Diffuse large B-cell lymphoma: 
 
At least one prior systemic therapy. 
 
No prior bortezomib. 
Note: Not intended for patients in first relapse who are candidates for high dose therapy with 
stem cell support. 
3.1.5 Age ≥18 years. As no dosing or adverse event data are available for the combination of 
bortezomib and vorinostat in patients <18 years of age, children are excluded. 
3.1.6 Life expectancy of greater than 3 months. 
3.1.7 ECOG performance status 0, 1, or 2. 
 
ECOG Performance Status 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
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). 
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. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
 
3.1.8 Able to tolerate loperamide or other anti-diarrheal medications.  
3.1.9 Adequate organ and marrow status: 
o absolute neutrophil 
count 
≥ 1.5 x 109/L 
o platelets 
≥ 75 x 109/L 
o total bilirubin 
≤ 1.5 x ULN 
o AST(SGOT)/ALT(SGPT) ≤ 2.5 x institutional upper limit of normal 
o creatinine 
within normal institutional limits 
or 
calculated creatinine clearance ≥ 60 mL/min 
according to the Cockcroft-Gault Formula 
 
 
Calculated Creatinine Clearance (Cockcroft and Gault) 
 
Creatinine clearance (mL/min) = {(140 - Age) * Wt in kg * G}/ (Creat * 72) 
 
G= 1 (males); G=0.85 (females) 
3.1.10 For patients with known HIV infection, a CD4 count ≥ 0.5 x 109/L. 
3.1.11 For patients whose last treatment included bendamustine or fludarabine, a CD4 count ≥ 0.4 x 
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3.1.12 The effects of bortezomib and vorinostat on the developing human fetus at the recommended 
therapeutic dose are unknown. For this reason 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 and to report pregnancy or 
suspected pregnancy while participating in the study. 
3.1.13 Ability to understand and the willingness to sign a written informed consent document. 
3.2 Exclusion Criteria 
3.2.1 Chemotherapy or large field radiotherapy within 3 weeks prior to entering the study. 
3.2.2 Prior histone deactylase inhibitor as cancer treatment. 
3.2.3 Concurrent treatment with other investigational agents. 
3.2.4 Plans for other concurrent cancer treatment. If steroids for cancer control have been used, 
patients must be off these agents for ≥ 1 week before starting treatment. Exception: 
maintenance therapy for non-malignant disease with prednisone or steroid equivalent dose < 
10 mg/day is permitted. 
3.2.5 History of brain metastasis including leptomeningeal metastasis. 
3.2.6 Grade ≥ 2 neuropathy, regardless of cause. 
3.2.7 Unable to take oral medications. 
3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic composition 
to bortezomib or vorinostat. 
3.2.9 Not sufficiently recovered from previous treatment. 
3.2.10 Medical or other condition (for example: uncontrolled infection; potentially life threatening 
changes on EKG) or concurrent treatment (for example, marrow suppressive agents such as 
zidovidine) that represents an inappropriate risk to the patient or likely would compromise 
achievement of the primary study objective. Note that bortezomib is a 1A2, 2C9, 2C19, 2D6, and 
3A4 substrate. Therefore, patients should be closely monitored when given bortezomib in 
combination with the CYP3A4 inhibitors and inducers listed in Section 5.2.2. 
3.2.11 Pregnant women are excluded from this study because bortezomib and vorinostat are potential 
teratogens. Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with bortezomib and vorinostat, breastfeeding should be 
discontinued. 
3.2.12 Active concurrent malignancy, except adequately treated non-melanoma skin cancer. 
3.3 Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this trial. 


 
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4 REGISTRATION PROCEDURES 
4.1 General Guidelines 
Patients are registered on study centrally at the Moffitt Cancer Center. 
Following registration, patients should begin protocol treatment within one week. Notify the SEP2C 
Administrator of longer delays or a decision not to initiate study treatment and document. 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP. Agents may be ordered by a participating site only after the initial IRB 
approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov). 
4.2 Registration Process 
To register a patient, the following should be faxed (813-745-5944) or e-mailed 
(SEP2C@moffitt.org) to the SEP2C Administrator: 
 
Copy of signed and dated eligibility form (attached in Oncore) 
The SEP2C administrator will then complete the registration process by: 
 
Registering the patient to Cohort A: mantle cell lymphoma, no prior bortezomib (Cohorts B and 
C are closed) 
 
Assigning a registration number 
 
Assigning stratification 
 
Stratum SG01: prior autologous transplant 
 
Stratum SG02: no prior autologous transplant 
 
Transmitting the patient number to the participating site. 
The research nurse or data manager must then enter subject registration information into Moffitt’s 
Oncore prior to starting study treatment. 
5 TREATMENT PLAN 
5.1 Schedule and Dosing 
Patients whose serum total bilirubin > 1.5 x ULN within 4 days prior to Cycle 1 Day 1 should not 
receive study treatment and must be taken off-study. 
Vorinostat 400 mg (total daily dose as a single dose) days 1-5 and 8-12. 
Bortezomib 1.3 mg/m2/d iv days 1, 4, 8, and 11. 
Vorinostat precedes bortezomib on days of concurrent administration. 
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Minor modifications in schedule may be made to accommodate scheduling difficulties. Modification 
and cause should be documented. In any event, bortezomib doses should not be administered 
closer than 72 hours apart. 
5.2 General Concomitant Medication and Supportive Care Guidelines 
5.2.1 Agent Related Supportive Care 
Advise patients that vorinostat may cause anorexia, dehydration, diarrhea, nausea and 
emesis. 
Encourage and monitor for adequate fluid and food intake. 
Prescribe anti-emetics as clinically indicated. 
Instruct patients to begin loperamide (or similar anti-diarrheal agent) at the first signs of: 1) 
poorly formed or loose stool, 2) more bowel movements than usual in one day, or 3) 
unusually high volume of stool. Loperamide dose and schedule is 4 mg (generally, 2 tablets) 
at first onset of diarrhea, then 2 mg (1 tablet) after each unformed stool, but not to exceed 
16 mg/day (8 tablets/day). Loperamide should not be taken prophylactically. Avoid 
loperamide if there is the presence of blood or mucus in the stool or if diarrhea is 
accompanied by fever. If grade 3 or 4 diarrhea develops, discontinue vorinostat. 
Consider intravenous hydration with each infusion of bortezomib. Intravenous infusion of 
1000 mLs of normal saline or D5W over 30-60 minutes is recommended, or, in patients with 
cardiac concerns or fluid overload issues, intravenous infusion of 500 mLs normal saline or 
D5W via over 60 minutes. 
Prophylactic antiviral treatment is recommended for all patients receiving bortezomib. 
Acyclovir 400 mg po bid or a similar regimen is recommended. Prophylactic antiviral 
treatment is allowed for all patients at the discretion of the treating physician. 
In general, because of the risk of confounding response assessments, corticosteroids are to 
be avoided concurrent with study participation with the following exceptions: 
 
Corticosteroids for nausea control are allowed. 
 
Topical, intra-articular, and eye drop steroids are allowed. 
Steroids for other indications should be discussed with the study chair prior to use. 
Provide other supportive care measures as clinically indicated. 


 
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5.2.2 CYP3A4 Inhibitors and Inducers 
Co-administration of a strong CYP3A4 inhibitor may increase the exposure of the patient to 
bortezomib, while co-administration of a CYP3A4 inducer may reduce the efficacy of 
bortezomib. Therefore, patients should be closely monitored when given bortezomib in 
combination with the CYP3A4 inhibitors and inducers listed in the table below. 
Strong CYP3A4 Inhibitors 
CYP3A4 Inducers 
indinavir 
carbamazepine 
neflinavir 
phenobarbital 
ritonavir 
phenytoin 
clarithromycin 
pioglitazone 
itraconazole 
rifabutin 
ketoconazole 
rifampin 
nefazodone 
St. John’s wort 
 
troglitazone 
Source: http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.aspx 
“Clinically Relevant Table”, Updated November 14, 2011 
5.2.3 Concurrent Cancer Treatment 
Concurrent non-study cancer treatment is not permitted. Non-prescription nutritional and 
dietary supplements are discouraged but not prohibited and, if used, should be 
documented. 
5.3 Duration of Therapy 
Continue treatment until: 
 
Disease progression or requirement of palliative irradiation 
 
Unacceptable toxicity 
 
Patient decision to discontinue treatment 
 
Investigator decision that treatment no longer is in the patient’s best medical interest 
 
Study closure 
Patients who experience a complete or partial response following at least one year of treatment 
may go off study treatment but remain on study and resume study treatment upon disease 
progression if the study remains open. 
5.4 Duration of Follow Up 
Continue disease status follow up until disease progression or initiation of another treatment. 
Continue toxicity follow-up until resolution or stabilization of treatment related toxicity or initiation of 
another treatment that confounds ongoing toxicity evaluation. 


 
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5.5 Criteria for Removal from Study 
Patients are off study when off treatment and disease status and toxicity follow up is complete. 
Certain subsequent events, however (for example, secondary malignancies) may remain subject to 
reporting if identified. See Section 7. 
6 DOSING DELAYS/DOSE MODIFICATIONS 
Scheduled agent doses are administered or omitted, not delayed, with the exception that initial 
doses of a new cycle are delayed pending resolution of dose-modifying toxicity. If dose-modifying 
toxicity requires treatment delay for longer than 3 weeks, consider whether patient should be taken 
off study treatment as per Section 5.3. If dose omission for toxicity, omit one or both agents 
according to clinical judgment with regard to attribution and severity. 
Vorinostat and bortezomib have both overlapping and non-overlapping toxicities; for example, 
fatigue or sensory neuropathy might be due to either/both agents, but motor neuropathy most likely 
would be due to bortezomib. Investigators adjust the administration of either/both agents according 
to the nature, severity, and attribution of toxicity in the suggested sequences. 
Dose Level Modifications for Toxicities  
See following tables for independent dose adjustments of drugs. 
 
Hematologic 
 
Non-hematologic 
(excluding bortezomib-induced neuropathy and 
excluding hyperbilirubinemia) 
*See instructions below 
 
Grade 
Action 
Grade 
Action 
Grade ≥ 3 
Omit; resume dosing at 
next lower dose level 
upon resolution to 
Grade ≤ 2. 
Grade 2, 
optional. 
 
Grade ≥ 3, 
required. 
Omit; resume dosing at next lower 
dose level upon resolution to 
Grade ≤ 2 (Grade 1 preferred). 
 
Vorinostat Dose/Schedule Reduction Schema 
1 
Reduce vorinostat to 300 mg/dose 
2 
Reduce vorinostat to 200 mg/dose 
3 
Reduce vorinostat to 100 mg/dose 
4 
Discontinue vorinostat 
 
Bortezomib Dose/Schedule Reduction Schema, excluding neuropathy1 
1 
Reduce bortezomib dose to 1.0 mg/m2 
2 
Reduce bortezomib dose to 0.7 mg/m2 
3 
Reduce bortezomib dosing to once weekly (in weeks 1 & 2 of cycle) 
4 
Reduce bortezomib dosing to once per cycle 
5 
Discontinue bortezomib2 
 


 
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Bortezomib-Induced Hyperbilirubinemia Dose Reduction Schema 
Patients with mild hepatic impairment (bilirubin ≤ 1.5  ULN) do not require a starting dose 
adjustment. Please note that patients with bilirubin levels > 1.5 ULN are excluded from 
enrollment in this protocol. If a patient develops moderate or severe hepatic impairment with 
bilirubin ≥ Grade 2 (> 1.5 X ULN) while on study, the investigator should hold bortezomib until 
the toxicity returns to < Grade 2. Restarting bortezomib at the next lower dose level could be 
considered at the Investigator’s discretion following exclusion of bortezomib-induced liver 
impairment and careful consideration of liver disease due to other causes, such as, but not 
limited to, active infection. Bortezomib doses may be re-escalated subsequently at the 
discretion of the investigator, but not to levels higher than the patient’s initial dose. 
Bortezomib-Induced Neuropathy Dose/Schedule Reduction Schema1 
Grade 1 (paresthesias and/or loss of 
reflexes) without pain or loss of function 
No action 
Grade 1 with pain or 
Grade 2 (interfering with function but not 
with activities of daily living) 
Reduce bortezomib dose by one dose level, 
according to table above 
Grade 2 with pain or 
Grade 3 (interfering with activities of daily 
living) 
Withhold bortezomib therapy until toxicity 
resolves to Grade 1 or less, then resume at 0.7 
mg/m2 and change treatment schedule to once 
per week (in weeks 1 & 2 of cycle); except if 
already at 0.7 mg/m2 once per week, then 
discontinue bortezomib.2 
Grade 4 (disabling) 
Discontinue bortezomib2 
1 If both bortezomib dose/schedule reduction schemas apply, administer lower/less frequent bortezomib 
dose/schedule. 
2 If bortezomib must be discontinued due to dose reductions and vorinostat is tolerable, patient may 
continue on vorinostat alone at treating physician’s discretion until next scheduled response assessment. 
At that time, if patient continues without evidence of progression or intolerable vorinostat toxicity, patient 
may continue on vorinostat alone. 
7 ADVERSE EVENT LIST AND REPORTING REQUIREMENTS 
7.1 Comprehensive Adverse Events and Potential Risks List (CAEPR) 
Adverse events will be categorized in terms of nature, severity, and attribution and documented 
according to the NCI CTCAE v4.0 beginning April 1, 2011 (http://ctep.cancer.gov). 
7.2 CAEPR - Bortezomib 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Bortezomib (PS-341, 
NSC 681239) 
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 Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is 
identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted 
below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 


 
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http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2042 patients. Below is the CAEPR for 
bortezomib (PS-341). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the 
grades to determine if expedited reporting is required. 
 
Version 2.4, February 26, 20131 
 
 Adverse Events with Possible  
 Relationship to Bortezomib (PS-341) 
 (CTCAE 4.0 Term) 
[n= 2042] 
 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
 
(formerly known as ASAEL) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
  
EYE DISORDERS 
  
 
Blurred vision 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
Constipation 
 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Gastrointestinal hemorrhage2 
 
  
 
 
 Gastrointestinal perforation3   
 
Ileus 
 
 Ileus (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
Edema limbs 
 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
Fever 
 
 
 Fever (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
Infection4 
 
 
 Infection4 (Gr 3) 
 
Infections and infestations - 
Other (Opportunistic infection 
associated with >= Grade 2 
Lymphopenia) 
 
  
INVESTIGATIONS 
  
 
Lymphocyte count decreased  
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased  
(Gr 4) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 


 
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Back pain 
 
 Back pain (Gr 2) 
 
Bone pain 
 
 Bone pain (Gr 2) 
 
Generalized muscle weakness  
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 3) 
 
Headache 
 
 Headache (Gr 2) 
 
 
Leukoencephalopathy 
  
 
Neuralgia 
 
 Neuralgia (Gr 3) 
Peripheral motor 
neuropathy 
 
 
 Peripheral motor neuropathy  
(Gr 3) 
Peripheral sensory 
neuropathy 
 
 
 Peripheral sensory neuropathy 
(Gr 3) 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
 
Syncope 
 
  
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
 
Epistaxis 
 
  
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
Pleural effusion 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
  
 
Hypotension 
 
 Hypotension (Gr 3) 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed 
to all Principal Investigators at the time of revision. The current version can be obtained by 
contacting PIO@ctep.nci.nih.gov. Your name, the name of the investigator, the protocol and the 
agent should be included in the e-mail. 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, 
Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under 
the GASTROINTESTINAL DISORDERS SOC. 
3Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small 
intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
Also reported on bortezomib (PS-341) trials but with the relationship to bortezomib (PS-341) 
still undetermined: 


 
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BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (lymphadenopathy); Disseminated intravascular coagulation 
CARDIAC DISORDERS - Asystole; Atrial fibrillation; Atrial flutter; Cardiac disorders - Other 
(cardiac amyloidosis); Heart failure; Left ventricular systolic dysfunction; Myocardial infarction; 
Pericardial effusion; Right ventricular dysfunction; Sinus bradycardia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Conjunctivitis; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(conjunctival hemorrhage); Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Dry mouth; Dysphagia; 
Esophagitis; Flatulence; Gastritis; Gastrointestinal disorders - Other (ischemic bowel); 
Gastrointestinal disorders - Other (eructation); Mucositis oral; Oral pain; Pancreatitis; Small 
intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Gait 
disturbance; General disorders and administration site conditions - Other (hepato-renal syndrome); 
Injection site reaction; Non-cardiac chest pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (portal vein thrombosis) 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine aminotransferase 
increased; Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin 
increased; CPK increased; Creatinine increased; GGT increased; INR increased; Serum amylase 
increased; Weight gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; Hyperkalemia; 
Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (hypoproteinemia); Metabolism and 
nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Buttock pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of 
consciousness; Dysgeusia; Dysphasia; Intracranial hemorrhage; Ischemia cerebrovascular; 
Memory impairment; Nervous system disorders - Other (spinal cord compression); Nervous system 
disorders - Other (cranial palsy); Nervous system disorders - Other (dysautonomia); Seizure 
PSYCHIATRIC DISORDERS - Agitation; Confusion; Depression; Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Hematuria; Proteinuria; Renal and urinary 
disorders - Other (calculus renal); Renal and urinary disorders - Other (bilateral hydronephrosis); 
Renal and urinary disorders - Other (glomerular nephritis proliferative); Urinary frequency; Urinary 
incontinence; Urinary retention; Urinary tract pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Allergic rhinitis; Atelectasis; Bronchopulmonary hemorrhage; Bronchospasm; Hiccups; 
Hypoxia; Pharyngolaryngeal pain; Pneumonitis; Pulmonary hypertension; Respiratory, thoracic and 
mediastinal disorders - Other (obstructive airways disease); Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pruritus; 
Purpura; Skin and subcutaneous tissue disorders - Other (leukoclastic vasculitis); Urticaria 
VASCULAR DISORDERS - Capillary leak syndrome; Flushing; Hematoma; Thromboembolic 
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Note: Bortezomib (PS-341) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
7.3 CAEPR - Vorinostat 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Vorinostat (SAHA, NSC 
701852) 
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 Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is 
identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 702 patients. Below is the CAEPR for 
vorinostat (SAHA). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the 
grades to determine if expedited reporting is required. 
Version 2.8, December 18, 20131 
 
 Adverse Events with Possible  
 Relationship to Vorinostat (SAHA, Zolinza) 
 (CTCAE 4.0 Term) 
[n= 1076] 
 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased  
(Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 


 
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Blood bilirubin increased 
 
  
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
Lymphocyte count decreased  
 Lymphocyte count decreased (Gr 4) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased  
 
 Platelet count decreased (Gr 3) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr 2) 
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle weakness3 
 
 Muscle weakness3 (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
 
Skin and subcutaneous 
tissue disorders - Other 
(skin necrosis) 
  
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed 
to all Principal Investigators at the time of revision. The current version can be obtained by 
contacting PIO@ctep.nci.nih.gov. Your name, the name of the investigator, the protocol and the 
agent should be included in the e-mail. 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
3Muscle weakness includes Generalized muscle weakness, Muscle weakness left-sided, Muscle 
weakness lower limb, Muscle weakness right-sided, Muscle weakness trunk, and Muscle 
weakness upper limb under the MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
SOC. 
4Prolongation of prothrombin time and International Normalized Ratio have been observed in 
patients using vorinostat concomitantly with coumarin-derivative anticoagulants.  
Also reported on vorinostat (SAHA, Zolinza) trials but with the relationship to vorinostat 
(SAHA, Zolinza) still undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other (supraventricular 
arrhythmia); Chest pain - cardiac; Left ventricular systolic dysfunction; Myocardial infarction; 
Palpitations; Pericardial effusion; Sinus bradycardia; Sinus tachycardia; Ventricular fibrillation 
EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
EYE DISORDERS - Blurred vision; Eye disorders - Other (retinal tear) 


 
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GASTROINTESTINAL DISORDERS - Abdominal distension; Anal hemorrhage; Bloating; Cheilitis; 
Colitis; Dysphagia; Esophageal hemorrhage; Esophagitis; Flatulence; Gastric hemorrhage; 
Gastritis; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (duodenitis); Lower 
gastrointestinal hemorrhage; Mucositis oral; Oral hemorrhage; Oral pain; Small intestinal 
obstruction; Stomach pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Gait 
disturbance; General disorders and administration site conditions - Other (failure to thrive); 
Malaise; Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (angioedema) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Vascular access 
complication; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged4; Alkaline phosphatase 
increased; Cardiac troponin I increased; Electrocardiogram QT corrected interval prolonged; GGT 
increased; INR increased4; Investigations - Other (increased lactate dehydrogenase); Lipase 
increased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hyperuricemia; Hypoalbuminemia; Hyponatremia; Metabolism and nutrition 
disorders - Other (decreased total protein); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Chest wall pain; 
Musculoskeletal and connective tissue disorder - Other (muscle spasms); Musculoskeletal and 
connective tissue disorder - Other (myositis); Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage); 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Abducens nerve disorder; Ataxia; Cognitive disturbance; 
Depressed level of consciousness; Dysphasia; Encephalopathy; Facial muscle weakness; Facial 
nerve disorder; Headache; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Memory 
impairment; Nervous system disorders - Other (Guillain-Barre syndrome); Nervous system 
disorders - Other (head injury); Nervous system disorders - Other (polyneuropathy); Paresthesia; 
Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; Stroke; 
Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Euphoria; Personality 
change; Psychosis 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria; Urinary 
frequency; Urinary incontinence; Urinary retention; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Pelvic pain; 
Uterine hemorrhage; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Epistaxis; Hypoxia; Pharyngeal mucositis; Pleural effusion; Pleuritic pain; 
Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; Palmar-
plantar erythrodysesthesia syndrome; Purpura; Rash maculo-papular; Skin and subcutaneous 
tissue disorders - Other (brittle nails) 


 
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VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypertension; Hypotension; 
Thromboembolic event; Visceral arterial ischemi 
Note: Vorinostat (SAHA, Zolinza) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result 
in events never previously associated with either agent. 
7.4 Adverse Event Characterization  
 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting beginning April 1, 2011. All appropriate treatment areas should have 
access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Sections 7.2 and 7.3 above) for 
expedited reporting purposes only. ‘Expected’ AEs (the ASAEL) are bold and italicized in the 
CAEPR (Sections 7.2 and 7.3). 
 
Attribution of the AE: 
 
Definite – The AE is clearly related to the study treatment. 
 
Probable – The AE is likely related to the study treatment. 
 
Possible – The AE may be related to the study treatment. 
 
Unlikely – The AE is doubtfully related to the study treatment. 
 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.5 Expedited Adverse Event Reporting 
7.5.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP home page (http://ctep.cancer.gov). The reporting procedures 
to be followed are presented in the “CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements” which can be downloaded from the CTEP home page (http://ctep.cancer.gov). 
These requirements are briefly outlined in the table below (Section 7.5.3). 
In the rare event when Internet connectivity is disrupted, a 24-hour notification is to be made 
to NCI by telephone at: 301-897-7497. An electronic report MUST be submitted immediately 
upon re-establishment of internet connection.  
7.5.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals: SEP2C Administrator (SEP2C@moffitt.org), Study Chair, and the local treating 
physician. CTEP-AERS provides a copy feature for other e-mail recipients. 


 
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7.5.3 Expedited Reporting Guidelines – CTEP-AERS Reporting Requirements for Adverse Events 
that occur within 30 Days1 of the Last Dose of the Investigational Agent on phase 2 and 3 Trials 
Phase 2 and 3 Trials 
 
Grade 1 Grade 2 Grade 2 
Grade 3 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
Unex-
pected 
Expected 
Unexpected 
Expected 
Unex-
pected 
Expected 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 
Adverse events with attribution of possible, probable, or definite that occur greater than 30 days 
after the last dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
 
Grade 4 and Grade 5 unexpected events  
CTEP-AERS 10 calendar day report: 
 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
 
Grade 5 expected events 
2 
Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive 
disease, a full report is required as outlined in the table. 
December 15, 2004 
Note: All deaths on study require both routine and expedited reporting regardless of 
causality. Attribution to treatment or other cause must be provided. 
 
Expedited AE reporting timelines defined: 
 
“24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-AERS 
within 24 hours of learning of the event followed by a complete CTEP-AERS report within 5 
calendar days of the initial 24-hour report. 
 
“10 calendar days” - A complete CTEP-AERS report on the AE must be submitted within 10 
calendar days of the investigator learning of the event. 
 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions. 
 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via CTEP-AERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
7.6 Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions. AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 


 
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7.7 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
 
Myelodysplastic syndrome (MDS)  
 
Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported 
via routine reporting.  
7.8 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified.  
8 PHARMACEUTICAL INFORMATION 
8.1 Bortezomib (NSC 681239) 
Chemical Name: N-Pyrazinecarbonyl-L-phenylalanine-L-leucine boronic acid 
Other Names: MLN341, LDP-341, PS-341, Velcade® 
Classification: Proteasome Inhibitor 
CAS Registry Number: 179324-69-7 
Molecular Formula: C19H25BN4O4 
 
M.W.: 384.25 
How Supplied: PS-341 is supplied by the DCTD, NCI as a 3.5 mg vial for injection. Each sterile 
single use 10 mL vial contains 3.5 mg PS-341 as a lyophilized powder with 35 mg mannitol, USP. 
Preparation: When the 3.5 mg vial is reconstituted with 3.5 mL normal saline, USP, each milliliter 
of solution will contain 1 mg of PS-341 at a pH of approximately 5 to 6. The drug is to be given 
without further dilution as an IV bolus (over 3-5 seconds). 
Storage: Store intact vials at room temperature. Protect from light. 
Stability: Shelf life surveillance of the intact vials is ongoing. The solution as reconstituted is stable 
for 43 hours at room temperature. CAUTION: The single-use lyophilized dosage form contains no 
antibacterial preservatives. Therefore, it is advised that the reconstituted product be discarded 8 
hours after initial entry. 


 
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Route of Administration: Intravenous 
Potential Drug Interactions: Substrate for CYP450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4. 
Bortezomib is provided to the NCI under a Collaborative Agreement between Millennium 
Pharmaceutics, Inc. and the DCTD, NCI (see Section 12.5). 
8.2 Vorinostat (NSC 701852) 
Chemical Name: N-hydroxy-N’-phenyl-octane-1,8-diotic acid diamide; N-hydroxyl-N’-phenyl (9CI) 
octanediamide; suberoylanilide hydroxamic acid 
Other Names: SAHA, L-001079038, WIN 64652, MSK390, AP390, Zolinza® 
Classification: Antineoplastic 
CAS Registry Number: 149647-78-9 
Molecular Formula: C14H20N203 
M.W.: 264.32 
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. Vorinostat, a potent inhibitor of HDAC activity, binds directly to the catalytic pocket of HDAC 
enzymes. It causes G1 or G2 phase cell-cycle arrest, apoptosis, or differentiation in cultured 
transformed cells. 
How Supplied: Supplied by Merck and Co., Inc. and distributed by the CTEP, DCTD, NCI as a 
white, opaque gelatin, size 3 capsule, containing 100 mg of vorinostat. The inactive ingredients 
contained in each capsule are microcrystalline cellulose, sodium croscarmellose, and magnesium 
stearate. Vorinostat 100 mg capsules are supplied in bottles containing 120 capsules. 
Storage: Store at room temperature, 15 to 30 ºC (59 to 86 ºF). Do not store above 30ºC. Avoid 
exposure to excessive moisture. 
Stability: Shelf life stability studies of the intact bottles are on-going. 
Route of Administration: Orally 
Method of Administration: Unless otherwise stated in the protocol, vorinostat capsules must be 
administered whole. Administer doses of vorinostat with food, if possible. 
Potential Drug Interactions: The major pathways of vorinostat metabolism involve glucuronidation 
and β-oxidation. As vorinostat is not eliminated via CYP450 pathways, no drug-drug interactions 
are expected with known CYP450 inhibitors or inducers. Prothrombin time and INR prolongations 
have been reported in patients taking vorinostat concomitantly with coumarin derivative 
anticoagulants. Monitor these patients more frequently for alterations in their coagulation 
parameters. 


 
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Special Handling: Vorinostat is an anticancer drug. Clean powder spills from broken or damaged 
vorinostat capsules carefully minimizing inhalation. Wash spill area at least 3 times with ethyl 
alcohol, followed by water. 
Vorinostat is provided to the NCI under a Collaborative Agreement between Merck Pharmaceutics, 
Inc. and the DCTD, NCI (see Section 12.5). 
8.3 Agent Ordering 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized designees) 
at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that 
the agent be shipped directly to the institution where the patient is to be treated. PMB does not 
permit the transfer of agents between institutions (unless prior approval from PMB is obtained). 
The CTEP-assigned protocol number must be used for ordering all CTEP-supplied investigational 
agents. The responsible investigator at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA form 1572 (Statement of Investigator), Curriculum 
Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If there 
are several participating investigators at one institution, CTEP-supplied investigational agents for 
the study should be ordered under the name of one lead investigator at that institution. 
Active CTEP-registered investigators and investigator-designated shipping designees and ordering 
designees can submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account (https://eapps-
ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status and a “current” password. 
For questions about drug orders, transfers, returns, or accountability, call (240) 276-6575 Monday 
through Friday between 8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov. 
8.4 Agent Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all agents received from DCTD using the NCI Drug 
Accountability Record Form (DARF). (See the CTEP home page at http://ctep.cancer.gov for the 
Procedures for Drug Accountability and Storage and to obtain a copy of the DARF and Clinical 
Drug Request form.) 
9 CORRELATIVE STUDIES 
Baseline nuclear relA expression as a predictive marker of response to the combination of 
bortezomib and vorinostat in the treatment of mantle cell and diffuse large B-cell lymphoma. 
The rationale is described in Section 2.4. 
Directions for obtaining and submitting tissue samples for correlative studies are found in Section 
12.1. 
Before subjecting the samples to immunohistochemical evaluation,the available histological material 
will undergo central pathological review 
 at the 
Moffitt Cancer Center. 
The expression of Rel A protein will be evaluated by immunohistochemistry using a specific antibody 
for testing on paraffin slides. We will use a mouse monoclonal anti-NF-κB antibody, p65 subunit 
(Chemicon International, Temecula CA, clone 12H11). This antibody is selective to the activated 


 
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form of NF-κB. This monoclonal antibody recognizes an epitope overlapping the nuclear localization 
signal (NLS) of the RelA/p65 transactivation subunit. 
Briefly, pretreatment for antigen retrieval is performed using the DAKO Antigen Retrieval kit 
(Cat#S1700). Samples are preheated to 98C for 15 min. After cooling for 20 min @ room 
temperature in solution, the samples are washed in milliQ-water for 4-5 min. The samples are 
incubated in quenching buffer for 10 min, washed in milliQ-water for 4-5 min, and incubated for 10 
min with Avidin blocking buffer (Vector Labs Cat#SP-2001). After washing with PBS for 5 min, the 
slides are blocked with Biotin blocking buffer, and placed in blocking buffer (1% BSA, 0.2% Milk) for 
an hour. This is followed by incubation with the anti-NF-kB primary antibody (2 ug /mL) in blocking 
buffer overnight at 4C. After rinsing with PBS for 5 min, the slides are incubated with a biotinylated 
goat anti-mouse secondary antibody, diluted in blocking buffer (0.334 ug/mL) for 1 hr at room 
temperature. After washing with PBS for 5 min, the slides are incubated with streptavidin–HPR 
diluted in blocking buffer 1:100 for 30 min (Invitrogen TSA Kit #21 cat# T20931), and washed again. 
The slides are next incubated in biotin –XX tyramide (in kit amplification buffer/0.0015% H2O2) for 10 
min. After an additional washing, the sample is incubated with ABC for 30 min (Vector labs Cat# PK-
6100) and developed with 3,3-diaminobenzidine (DAB) for 1-7 min (Vector labs Cat# SK-4100). All 
of the slides are lightly counterstained with hematoxylin for 10s before dehydration and mounting. 
Immunostaining is observed with a Leitz Orthoplan 2 microscope and images are captured by a 
CCD camera with the Smart Capture Program (Vysis, Downers Grove, IL). Positive controls will be 
run with each set of slides according to the manufacturer’s instructions. Negative controls will be 
included by omitting the primary antibody during the primary antibody incubation. 
The stained slides will be read by 
, MD in a blinded fashion, and scored for the 
presence of Rel A protein. The positive antibody reaction will consist in a nuclear dark-brown stain. 
The stain will be scored into four grades, according to the intensity of the staining: 0, 1+, 2+, and 3+. 
The percentages of positive cells will also be scored into four categories: 0 (0%), 1 (1-33%), 2 (34-
66%), and 3 (67-100%). The product of the intensity and the percentage scores will be used as the 
final score. 
To define the B cell immunophenotype (germinal center B cell-like or activated B cell-like) we will 
subject the samples to immunostains with CD10 and CD23. To identify germinal center B cells we 
will use a mouse monoclonal anti CD10 Ab (abCam Inc., Cambridge, MA; clone 56C6, dilution1: 25), 
and for the detection of activated B cell-like we will use a mouse monoclonal Ab to CD23 (abCam 
Inc., Cambridge, MA; clone 1B12; dilution1:10). In addition the samples will be stained for CD20 
using a mouse monoclonal Ab (abCam Inc., Cambridge, MA; clone L26; dilution 1:300). All of the 
immunostains will be performed as described above. 


 
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10 STUDY CALENDAR 
 
BASELINE 
WHILE ON STUDY 
TREATMENT 
FOR PATIENTS 
OFF-
TREATMENT & 
STILL ON 
STUDY 
OFF-STUDY 
H&P 
A 
Every cycle 
 
 
Vorinostat 
Tablet Counts 
and Concurrent 
Meds 
A 
Every cycle 
End of treatment 
 
Adverse Events 
Assessment 
A 
Twice weekly during 
treatment weeks 
End of treatment 
and at least every 
12 weeks(K) 
X 
CBC with 
differential 
A 
Twice weekly 
during treatment weeks 
 
 
Comprehensive 
Metabolic Panel 
B, I 
Every cycle 
 
 
LDH 
B 
 
 
 
CD4 
B, H 
 
 
 
Serum 
Pregnancy Test 
C 
C 
 
 
Tumor 
Measurements 
(G) 
D 
Every 9 weeks (E) 
End of treatment 
and at least every 
12 weeks (L) 
 
Bortezomib (F) 
 
Days 1, 4, 8, 11; repeat 
every 3 weeks 
 
 
Vorinostat (F) 
 
Days 1 thru 5 and 8 thru 
12; repeat every 3 
weeks. 
 
 
EKG, 12 lead 
J 
 
 
 
A 
Update within one week of start of treatment. 
B 
Within two weeks of start of treatment. 
C 
Advise patients of pregnancy related risks prior to enrollment. Advise patients who might become pregnant that 
they may request pregnancy test upon first suspicion of pregnancy. 
D 
Within one month of start of treatment. 
E 
By calendar, not by treatment cycle (cycles may deviate from every 3 weeks as per protocol); weeks may be 
adjusted ± 1 week for convenience. 
F 
Days may be adjusted ± 1 for convenience; however, bortezomib may not be administered on consecutive days. 
Following 3 cycles, patients may take “drug holidays” of up to 3 weeks.  
G By spiral CT or physical exam; bone marrow if needed to follow disease status; PET recommended but not 
required (see Section 11). 
H 
CD4 testing required in subjects known to be HIV positive, or any patient whose last treatment included either 
bendamustine or fludarabine. 
I 
Serum total bilirubin must be repeated within 4 days of Cycle 1 Day 1. 
J 
For patients with a known cardiac history. 
K 
In general, subjects should be followed for adverse event resolution, stabilization, or onset until 30 days following 
the last dose of study drug or until a new regimen begins (whichever comes first). Occasionally, study treatment 


 
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related AEs which are felt by the treating physician or study chair to be significant may need to be followed longer if 
not stabilized or resolved. 
L 
Unless started on other anticancer treatment, the response status should be followed every 12 weeks for those 
patients who go off-treatment with stable disease, a partial response, or a complete response. 
11 MEASUREMENT OF EFFECT 
Response will be assessed according to the Revised Response Criteria for Malignant Lymphoma 
(35). These criteria with reference to mantle cell and diffuse large B-cell lymphoma are summarized 
and modified for this study according to the following two tables; otherwise, see the publication. 
These criteria stipulate that each measureable lesion be evaluated by the bi-dimensional 
measurements and that the sum of the product of the diameters be reported in case report forms. 
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 
measurable 
disease and no 
new sites 
≥ 50% decrease in SPD of up to 6 
largest dominant masses; no 
increase in size of other nodes 
(a) FDG-avid or PET positive prior 
to therapy; one or more PET 
positive at previously involved site 
(b) Variably FDG-avid or PET 
negative; regression on CT 
≥ 50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET positive prior 
to therapy; PET positive at prior 
sites of disease and no new sites 
on CT or PET 
(b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT 
 
 
Relapsed 
disease 
or PD 
Any new lesion 
or increase by 
≥ 50% of 
previously 
involved sites 
from nadir 
Appearance of a new lesion(s) > 
1.5 cm in any axis, ≥ 50% increase 
in SPD of more than one node, or 
≥ 50% increase in longest diameter 
of a previously identified node > 1 
cm in short axis 
 
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior to 
therapy 
> 50% increase 
from nadir in the 
SPD of any 
previous lesions 
New or recurrent 
involvement 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; 
CT, computed tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable 
disease; PD, progressive disease. 


 
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Recommended Timing of PET (PET/CT) Scans 
Histology 
Pretreatment 
Mid-Treatment 
Response 
Assessment 
Post-Treatment 
Surveillance 
DLBCL 
Yes* 
Optional 
Yes§ 
No 
MCL 
Yes* 
Optional 
Yes* § 
No 
Abbreviations: PET, positron emission tomography; CT, computed tomography; FDG, 
[18F]fluorodeoxyglucose; DLBCL, diffuse large B-cell lymphoma; HL, Hodgkin's lymphoma; NHL, non-
Hodgkin's lymphoma; MCL, mantle-cell lymphoma; ORR, overall response rate; CR, complete remission.  
* Recommended but not required. 
§ Not recommended if pretreatment study negative. 
Centralized Radiology Review 
Radiologic images to determine response status (baseline and subsequent exams) will be 
transmitted to the Study Chair’s site for centralized review and confirmation of response assessment 
when a subject goes off treatment. 
Images should be copied onto CDs in Dicom format. 
All CDs should be anonymized, i.e., patient-specific information will be removed - site information 
and date/type of image can remain, at the treating site prior to submission. 
Site personnel should use a soft-tipped permanent marker to note the following information on each 
CD submitted: 
 
Study: NCI 8064/MCC 15428 
 
Subject Initials 
 
Subject’s Sequence Number 
Each CD may contain multiple exams for a single study subject, but must not contain exams for 
multiple subjects. 
Each CD submitted must be accompanied by a completed Radiology Exam Transmission 
Notification form (Appendix A). 
Submit CDs and completed Radiology Exam Transmission Notification forms to: 
 
VCU Massey Cancer Center 
 
 
 
 
 
Send CDs and forms via traceable mechanism (Federal Express, DHL, other). 


 
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12 SUBMISSION OF MATERIALS FOR CORRELATIVE STUDIES, CENTRAL 
PATHOLOGICAL REVIEW, DATA REPORTING, AND REGULATORY 
REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 (Adverse 
Events: List and Reporting Requirements). 
12.1 Submission of Materials for Correlative Studies and Pathological Review 
Submission of slides or blocks is acceptable. If slides are submitted, send at least 10 unstained 
tissue sections on positively-charged glass slides. Slides will NOT be returned to the send; tissue 
blocks will be returned if requested. 
Choice of material for submission: 
 
If the patient’s disease process has been known to undergo histological transformation in the 
past, the submitted tissue should be obtained relatively recently and must be obtained 
subsequent to the most recent systemic treatment. In some cases this may necessitate a 
repeat biopsy. 
 
If the patient’s disease has NOT been known to undergo histological transformation in the past, 
any archival tissue suffices. If there are multiple archival samples, the most recent (not the 
initial diagnostic) sample should be submitted. The rationale for this is that the purpose of the 
biopsy is to correlate NF-κB expression with response. If NF-κB is variable within the lifespan 
of a tumor, the most recent tissue sample is more likely to reflect the on-study status of NF-κB 
expression. 
At least 24 hours PRIOR to tissue sample submission, email the following individuals to alert them 
to sample submission: 
  
 
 
 
 
Samples should be shipped Monday through Thursday and not the day before a holiday. 
Samples must be shipped by a traceable mechanism, e.g., Federal Express, UPS, DHL. Phone 
contact for shipping: 
 
The Tissue Notification Form (Appendix B) must accompany all sample submissions. 
Material must be submitted to 
 of the Moffitt Cancer Center Department of 
Pathology for correlative studies and central pathological review at the address below. 
 
 
 
 
 
 
Be sure to mark on the package: “ATTENTION: 
, STUDY SPECIMEN.” 


 
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12.2 Data Reporting 
12.2.1 Method 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports 
are due January 31, April 30, July 31, and October 31. Instructions for submitting data using 
CDS application can be found on the CTEP web site (http://ctep.cancer.gov). Note: All 
adverse events that have occurred on the study, including those reported through CTEP 
AERS, must be reported via CDS. 
12.2.2 Responsibility for Data Submission 
Study sites are responsible for entering data at least monthly in the Coordinating Center’s 
Oncore™ database to allow time for Coordinating Center compilation and Study Chair 
review prior to monthly safety teleconferences. 
The Southeast Phase Two Consortium (SEP2C) leadership committee has identified that 
the Study Chair is the appropriate individual to be responsible for compiling and submitting 
CDUS data to CTEP for all participants on his study, as he is actively monitoring the 
protocol and evaluating the data. The Study Chair and related staff will work closely with the 
coordinating center (Moffitt Cancer Center) to ensure that logistical barriers related to CTEP 
reporting are removed. 
12.3 Data and Safety Monitoring 
12.3.1 Safety Updates 
The SEP2C Coordinating Center is responsible for distributing all IND Action Letters or 
Safety Reports received from CTEP to all participating institutions for submission to their 
individual IRBs for action as required. 
12.3.2 Monitoring 
The Study Chair and the Massey research team will monitor the data and submit reports to 
the SEP2C Steering Committee at least monthly. 
12.3.3 Auditing 
The trial will be audited in a manner consistent with the SEP2C guidelines. 
12.4 CTEP Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines. The 
specific responsibilities of the Protocol Chair and the Coordinating Center (Study Coordinator) and 
the procedures for auditing are found in CTEP’s Investigator Handbook 
(http://ctep.cancer.gov/handbook/index.html). 
 
The Coordinating Center is responsible for distributing all IND Action Letters or Safety Reports 
received from CTEP to all participating institutions for submission to their individual IRBs for 
action as required. 


 
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 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP. Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) (except for Group studies). 
12.5 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) 
The agents supplied by CTEP, DCTD, NCI in this protocol are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the NCI Division of Cancer Treatment and 
Diagnosis and Merck and Company and Millennium Pharmaceuticals, Inc (herein referred to as 
Collaborator(s)). The agents that will be supplied in this protocol are vorinostat and bortezomib, 
respectively. Therefore, the following obligations/guidelines, in addition to the provisions in the 
Intellectual Property Option to Collaborator (http://ctep.cancer.gov/industry) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing investigational Agents contain 
confidential information and should not be shared or distributed without the permission of the NCI. 
If a copy of this protocol is requested by a patient or patient’s family member participating on the 
study, the individual should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other 
investigational Agent(s), each the subject of different collaborative agreements , the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as “Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data solely 
for development, regulatory approval, and commercialization of its own investigational 
Agent. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be 
made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order. Additionally, all Clinical Data and Results 
and Raw Data will be collected, used, and disclosed consistent with all applicable federal statutes 
and regulations for the protection of human subjects including, if applicable, the Standards for 
Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, 
or PI for other studies) of Collaborator's wish to contact them. 


 
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5. Any data provided to Collaborator(s) for phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for 
this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group 
office for Cooperative Group studies or by the principal investigator for non-Cooperative Group 
studies for immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an additional 30 
days in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at 
least three (3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also be 
forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ 
media presentation should be sent to: 
  
 
 
 
 
 
 
 
 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
13  STATISTICAL CONSIDERATIONS 
13.1 Mantle Cell Lymphoma  
No prior bortezomib (Cohort A): 
Patients will be accrued to the protocol according to a two-stage minimax design (36). Based on 
patient response (CR + PR), we will either conclude that the therapy is effective or ineffective. The 
two-stage design has the smallest sample size with the following two properties: 
(1) if the true response rate is less than or equal to 30%, we will conclude that the therapy is 
ineffective with probability of at least 90% (alpha = .10), and 
(2) if the true response rate is at least 50%, we will conclude that the therapy is effective with 
probability at least 90% (beta = .10). 
At least 8 of 28 patients must respond in the first stage to proceed to the second stage. At any 
point when it is realized that this cannot happen, the study will be stopped and the therapy will be 
considered ineffective. Under the null hypothesis, this would occur with 36% probability. If the 
protocol proceeds to the second stage, at least 16 of 39 patients overall must respond for the 
therapy to be considered effective. 


 
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Prior bortezomib (Cohort B – closed with Protocol Version 8.0, 3/17/10): 
Patients will be accrued to the protocol according to a two-stage minimax design (2). Based on 
patient response (CR + PR), we will either conclude that the therapy is effective or ineffective. The 
two-stage design has the smallest sample size with the following two properties: 
(1) if the true response rate is less than or equal to 10%, we will conclude that the therapy is 
ineffective with probability of at least 90% (alpha = .10), and 
(2) if the true response rate is at least 25%, we will conclude that the therapy is effective with 
probability at least 90% (beta = .10). 
At least 3 of 27 patients must respond in the first stage to proceed to the second stage. At any 
point when it is realized that this cannot happen, the study will be stopped and the therapy will be 
considered ineffective. Under the null hypothesis, this would occur with 48% probability. If the 
protocol proceeds to the second stage, at least 7 of 40 patients overall must respond for the 
therapy to be considered effective. 
13.2 Diffuse Large B-cell Lymphoma  
(Cohort C – closed 6/25/2013) 
Patients will be accrued to the protocol according to a two-stage minimax design. Based on patient 
response (CR + PR), we will either conclude that the therapy is effective or ineffective. The two-
stage design has the smallest sample size with the following two properties: 
(1) if the true response rate is less than or equal to 10%, we will conclude that the therapy is 
ineffective with probability of at least 90% (alpha = .10), and 
(2) if the true response rate is at least 25%, we will conclude that the therapy is effective with 
probability at least 90% (beta = .10). 
At least 3 of 27 patients must respond in the first stage to proceed to the second stage. At any 
point when it is realized that this cannot happen, the study will be stopped and the therapy will be 
considered ineffective. Under the null hypothesis, this would occur with 48% probability. If the 
protocol proceeds to the second stage, at least 7 of 40 patients overall must respond for the 
therapy to be considered effective. 
13.3 Stratification Factors 
For each tumor type, patients will be stratified according to prior or no prior autologous stem cell 
transplant. This stratification will not affect the assessment of the primary aim, treatment response. 
However, it will be used as a variable in the correlative studies logistic regression analysis 
described below, as well as to gauge whether it significantly affect the progression-free survival in 
any of the three treatment arms in Cox regression analysis. 
13.4 Correlative Studies 
The two correlative studies will be conducted by pooling the data across the three treatment arms 
(with the use of dummy variables for two of the treatment arms as offsets); to adjust for multiple 
testing, the Bonferroni-Holm procedure will be used to have an overall alpha of .05. The sample 
size for this protocol was determined for the primary endpoint. It is unclear whether this will be 
sufficient for these secondary aims, especially the second one which requires pre- and post-


 
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treatment biopsies, which may not be performed in all patients. Also, one or more of the treatment 
arms may be terminated early. However, this testing plan provides the possibility of a statistically 
significant result if the hypothesized association is quite strong and could have data from as many 
as 116 patients, if all three treatment arms completely accrue. Prior to analysis with the dependent 
variable, response (and while blinded to its possible association), a power transformation of the 
independent variable (nuclear relA expression) will be considered, with the powers 1 (raw data), ½ 
(square root), and 0 (log transformation) examined. The Anderson-Darling test for normality will be 
the principal measure of ideal transformation, with the lowest value being the best. Slight 
preference will be given to both the raw and log transformations over the square root based upon 
their more facile interpretation (when examining change, a difference in raw values represents an 
additive change, while a difference in log values represents a multiplicative change). After the 
transformation has been determined and agreed upon by the PI and statistician, the main tests will 
be conducted. These will be logistic regression analyses, with three independent variables: nuclear 
relA expression, and dummy variables for the two mantle cell lymphoma groups (with the diffuse 
large cell lymphoma arm arbitrarily selected as the referent group). 


 
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14 REFERENCES 
1. 
VelcadeTM Prescribing Information. Cambridge, MA: Millennium Pharmaceuticals Inc; 2003.; 
December 2006. 
2. 
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, 
Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, 
Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 
study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003; 348:2609-2617. 
3. 
Strauss SJ, Maharaj L, Hoare S, Johnson PW, Radford JA, Vinnecombe S, Millard L, Rohatiner 
A, Boral A, Trehu E, Schenkein D, Balkwill F, Joel SP, Lister TA. Bortezomib therapy in patients 
with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor 
necrosis factor alpha response with clinical activity. J Clin Oncol. 2006; 24:2105-2112. 
4. 
Almond JB, Cohen GM. The proteasome: a novel target for cancer chemotherapy. Leukemia. 
2002; 16:433-443. 
5. 
Cusack JC, Jr., Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, Baldwin AS, Jr. Enhanced 
chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear 
factor-kappaB inhibition. Cancer Res. 2001; 61:3535-3540. 
6. 
Ling YH, Liebes L, Zou Y, Perez-Soler R. Reactive oxygen species generation and mitochondrial 
dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human 
H460 non-small cell lung cancer cells. J Biol Chem. 2003; 278:33714-33723. 
7. 
Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and 
cancer: causes and therapies. Nat Rev Cancer. 2001; 1:194-202. 
8. 
An B, Goldfarb RH, Siman R, Dou QP. Novel dipeptidyl proteasome inhibitors overcome Bcl-2 
protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and 
induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ. 1998; 
5:1062-1075. 
9. 
Zolinza Prescribing Information. Merck & Co. Inc.; 2006. 
10. 
Olsen E, Kim YH, Kuzel T, Pacheco TR, Foss F, Parker S, Wang JG, Frankel SR, Lis J, Duvic 
M. Vorinostat (suberoylanilide hydroxamic acid, SAHA) is clinically active in advanced cutaneous 
T-cell lymphoma (CTCL): Results of a phase IIb trial. Journal of Clinical Oncology. 2006; 
24:422s-422s. 
11. 
O'Connor OA, Heaney ML, Schwartz L, Richardson S, Willim R, MacGregor-Cortelli B, Curly T, 
Moskowitz C, Portlock C, Horwitz S, Zelenetz AD, Frankel S, Richon V, Marks P, Kelly WK. 
Clinical experience with intravenous and oral formulations of the novel histone deacetylase 
inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J 
Clin Oncol. 2006; 24:166-173. 
12. 
Marks PA. Discovery and development of SAHA as an anticancer agent. Oncogene. 2007; 
26:1351-1356. 
13. 
Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-histone 
proteins. Gene. 2005; 363:15-23. 
14. 
Rosato RR, Wang Z, Gopalkrishnan RV, Fisher PB, Grant S. Evidence of a functional role for 
the cyclin-dependent kinase-inhibitor p21WAF1/CIP1/MDA6 in promoting differentiation and 
preventing mitochondrial dysfunction and apoptosis induced by sodium butyrate in human 
myelomonocytic leukemia cells (U937). Int J Oncol. 2001; 19:181-191. 
15. 
Ruefli AA, Ausserlechner MJ, Bernhard D, Sutton VR, Tainton KM, Kofler R, Smyth MJ, 
Johnstone RW. The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide 
hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and 
production of reactive oxygen species. Proc Natl Acad Sci U S A. 2001; 98:10833-10838. 
PMCID: PMC58560. 
16. 
Nimmanapalli R, Fuino L, Bali P, Gasparetto M, Glozak M, Tao J, Moscinski L, Smith C, Wu J, 
Jove R, Atadja P, Bhalla K. Histone deacetylase inhibitor LAQ824 both lowers expression and 
promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-


 
NCI-8064 Version 18 
 
47 
04-10-2014 
sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res. 2003; 
63:5126-5135. 
17. 
Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, 
Boyapalle S, Atadja P, Seto E, Bhalla K. Inhibition of histone deacetylase 6 acetylates and 
disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity 
of histone deacetylase inhibitors. J Biol Chem. 2005; 280:26729-26734. 
18. 
Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP. The deacetylase HDAC6 
regulates aggresome formation and cell viability in response to misfolded protein stress. Cell. 
2003; 115:727-738. 
19. 
Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasome inhibitor bortezomib 
interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells 
sensitive and resistant to STI571. Blood. 2003; 102:3765-3774. 
20. 
Dai Y, Rahmani M, Dent P, Grant S. Blockade of histone deacetylase inhibitor-induced RelA/p65 
acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process 
mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. 
Mol Cell Biol. 2005; 25:5429-5444. PMCID: PMC1156999. 
21. 
Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human multiple 
myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin 
Cancer Res. 2004; 10:3839-3852. 
22. 
Mayo MW, Denlinger CE, Broad RM, Yeung F, Reilly ET, Shi Y, Jones DR. Ineffectiveness of 
histone deacetylase inhibitors to induce apoptosis involves the transcriptional activation of NF-
kappa B through the Akt pathway. J Biol Chem. 2003; 278:18980-18989. 
23. 
Chen LF, Mu Y, Greene WC. Acetylation of RelA at discrete sites regulates distinct nuclear 
functions of NF-kappaB. EMBO J. 2002; 21:6539-6548. PMCID: PMC136963. 
24. 
Chen L, Fischle W, Verdin E, Greene WC. Duration of nuclear NF-kappaB action regulated by 
reversible acetylation. Science. 2001; 293:1653-1657. 
25. 
Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL, Anderson KC. 
Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor 
activity in multiple myeloma. Proc Natl Acad Sci U S A. 2005; 102:8567-8572. PMCID: 
PMC1150844. 
26. 
Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Neri P, Tassone P, Atadja P, Chauhan 
D, Munshi NC, Anderson KC. Aggresome induction by proteasome inhibitor bortezomib and 
alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in 
myeloma cells. Blood. 2006; 108:3441-3449. PMCID: PMC1895432. 
27. 
Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J 
Clin Invest. 2005; 115:2656-2664. PMCID: PMC1236697. 
28. 
Wu J, Kaufman RJ. From acute ER stress to physiological roles of the Unfolded Protein 
Response. Cell Death Differ. 2006; 13:374-384. 
29. 
Nawrocki ST, Carew JS, Pino MS, Highshaw RA, Andtbacka RH, Dunner K, Jr., Pal A, 
Bornmann WG, Chiao PJ, Huang P, Xiong H, Abbruzzese JL, McConkey DJ. Aggresome 
disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. 
Cancer Res. 2006; 66:3773-3781. 
30. 
Badros A. Personal Communication June 6 2007. 
31. 
Grant S. Protocol NCI 6413: Phase I Trial of Bortezomib (PS-341; NSC 681239) and Flavopiridol 
(NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms. 
32. 
Belch A, Kouroukis CT, Crump M, Sehn L, Gascoyne RD, Klasa R, Powers J, Wright J, 
Eisenhauer EA. A phase II study of bortezomib in mantle cell lymphoma: the National Cancer 
Institute of Canada Clinical Trials Group trial IND.150. Ann Oncol. 2007; 18:116-121. 
33. 
Kath R, Blumenstengel K, Fricke HJ, Hoffken K. Bendamustine monotherapy in advanced and 
refractory chronic lymphocytic leukemia. J Cancer Res Clin Oncol. 2001; 127:48-54. 
34. 
Alamdari HS, Pinter-Brown L, Cassarino DS, Chiu MW. Severe cutaneous interface drug 
eruption associated with bendamustine. Dermatol Online J. 2010; 16:1. 


 
NCI-8064 Version 18 
 
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04-10-2014 
35. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, 
Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, 
Vose JM, Connors JM, Federico M, Diehl V. Revised response criteria for malignant lymphoma. 
J Clin Oncol. 2007; 25:579-586. 
36. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989; 10:1-10. 
 
 


Appendix A 
NCI-8064 Version 18 
 
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04-10-2014 
Radiology Exam Transmission Notification Form 
 
Instructions: 
o Send a Radiology Exam Transmission Notification form with each compact disk submitted 
o Send CDs & forms via traceable mechanism (Federal Express, DHL, other) 
o Be sure that exams are DE-IDENTIFIED prior to burning on CD 
o Do NOT send exams on more than 1 subject on the same CD 
o Use soft-tipped permanent marker to note the following on each CD submitted 
o Study: NCI 8064/MCC 15428 
o Subject Initials 
o Subject’s Sequence # 
 
Protocol:NCI 8064 (Moffitt Protocol MCC 15428) 
Subject Initials: 
______________________ 
 
 
 
Subject Sequence #: 
______________________ 
 
 
 
The above patient has been enrolled in an IRB-approved clinical trial. The patient has signed the proper 
Informed Consent and Research Authorization documents. 
 
Radiology Exam Details (note: exams required at baseline & every 9 weeks) 
For each exam burned on enclosed CD, please note the following: 
Study Timepoint 
(circle one) 
Date of 
exam 
Type of exam (circle all that apply) 
Baseline 
 
 
 
CT: 
head 
neck 
chest 
abdomen 
pelvis 
other:______ 
Week 
9 
18 
27 
36 
 
 
Other: 
________ 
PET 
or 
PET/CT 
Baseline 
 
 
 
CT: 
head 
neck 
chest 
abdomen 
pelvis 
other:______ 
Week 
9 
18 
27 
36 
 
 
Other: 
________ 
PET 
or 
PET/CT 
Baseline 
 
 
 
CT: 
head 
neck 
chest 
abdomen 
pelvis 
other:______ 
Week 
9 
18 
27 
36 
 
 
Other: 
________ 
PET 
or 
PET/CT 
Baseline 
 
 
 
CT: 
head 
neck 
chest 
abdomen 
pelvis 
other:______ 
Week 
9 
18 
27 
36 
 
 
Other: 
________ 
PET 
or 
PET/CT 
Baseline 
 
 
 
CT: 
head 
neck 
chest 
abdomen 
pelvis 
other:______ 
Week 
9 
18 
27 
36 
 
 
Other: 
_________ 
PET 
or 
PET/CT 
 
Sender’s Information: 
Name: 
 
Site: 
 
Telephone #: 
 
Email: 
 


APPENDIX B 
NCI-8064 Version 18 
 
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04-10-2014 
Tissue Notification Form 
 
 
Subject Initials:  
Sequence #:  
Collection Date / Time:  
Protocol MCC #: NCI 8064/MCC 15428 
Sample Collection Details:  
 
 
The above patient has been recruited to a research protocol. The 
patient has signed the proper Informed Consent and Research 
Authorization documents. 
 
 
Sender’s Information: 
Name:  
 
Title: 
 
 
Telephone #: