Clinical trial NCT00295932
Conditions: Leukemia Lymphoma
Keywords: recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma recurrent small lymphocytic lymphoma recurrent marginal zone lymphoma Waldenstrom macroglobulinemia recurrent mantle cell lymphoma refractory chronic lymphocytic leukemia B-cell chronic lymphocytic leukemia extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue nodal marginal zone B-cell lymphoma splenic marginal zone lymphoma
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2005-12-13; Completion date: 2018-03-11
Enrollment: 79 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving bortezomib together with cyclophosphamide, prednisone, and rituximab may be an effective treatment for non-Hodgkin's lymphoma.

PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of bortezomib when given together with cyclophosphamide, prednisone, and rituximab and to see how well it works in treating patients with relapsed or refractory indolent B-cell non-Hodgkin's lymphoma.

Detailed description:
OBJECTIVES:

Primary

* Determine the maximum tolerated dose of bortezomib when given in combination with rituximab, cyclophosphamide, and prednisone (R-CP) in patients with relapsed or refractory indolent B-cell lymphoproliferative disorders or mantle cell lymphoma. (phase I)
* Determine the frequency and duration of complete and partial responses in patients treated with two different treatment regimes. (phase II)

Secondary

* Evaluate the progression-free survival, event-free survival, and overall survival of patients treated with this regimen. (phase II)
* Evaluate the toxicity profile of this regimen.

OUTLINE: This is a phase I dose-escalation study of bortezomib followed by a phase II randomized, multicenter study. Patients in phase II are stratified according to disease (mantle cell lymphoma vs indolent B-cell lymphoproliferative disorder vs transformed lymphoma).

* Phase I: Patients receive cyclophosphamide IV and rituximab IV on day 1, oral prednisone on days 2-6, and bortezomib IV on days 2 and 7. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 1 of 3 or 2 of 6 patients experience dose-limiting toxicity.

* Phase II: Patients are randomized to 1 of 2 treatment arms.

  * Arm I: Patients receive cyclophosphamide IV and rituximab IV on day 1, oral prednisone on days 2-6, and bortezomib IV (at the MTD determined in phase I) on days 2, 5, 9, and 12. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
  * Arm II: Patients receive cyclophosphamide IV and rituximab IV on day 1, oral prednisone on days 2-6, and bortezomib IV (at the MTD determined in phase I) on days 2 and 8. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 1 month, every 4 months for 2 years, and then every 6 months thereafter.

Arms: arm 1: Patients receive cyclophosphamide IV and rituximab IV on day 1, oral prednisone on days 2-6, and bortezomib IV (at the MTD determined in phase I) on days 2, 5, 9, and 12. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive cyclophosphamide IV and rituximab IV on day 1, oral prednisone on days 2-6, and bortezomib IV (at the MTD determined in phase I) on days 2 and 8. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: rituximab intervention 2: bortezomib intervention 3: cyclophosphamide intervention 4: prednisone
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given orally

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
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Amended: 07/25/12 
 
 
 
A Phase II Study of the Novel Proteasome Inhibitor Bortezomib in Combination with 
Rituximab, Cyclophosphamide and Prednisone in Patients with Relapsed/Refractory 
Indolent B-cell Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL)I 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
 
Principal Investigator: 
John Gerecitano, M.D., Ph.D. 
 
 
 
Co-Principal 
Investigator(s): 
Carol Portlock, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IFormerly: A Phase I/II Study of the Novel Proteasome Inhibitor Bortezomib in Combination with 
Rituximab, Cyclophosphamide and Prednisone in Patients with Relapsed/Refractory Indolent B-cell 
Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL) 


Memorial Sloan-Kettering Cancer Center 
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Amended: 07/25/12 
 
 
 
Investigator(s): 
Paul Hamlin, M.D. 
Steven B. Horwitz, M.D. 
Alison Moskowitz, M.D. 
Craig H. Moskowitz, M.D. 
Ariela Noy, M.D. 
M. Lia Palomba, M.D., Ph.D. 
Jonathan Schatz, M.D. 
David Straus, M.D. 
Andrew D. Zelenetz, M.D., Ph.D. 
Matthew Matasar, M.D 
Mark L. Heaney, M.D., Ph.D. 
Nicole Lamanna, M.D. 
 
Radiology 
Otilia Dumitrescu, M.D. 
Andrei Holodny, M.D. 
 
Nuclear Medicine 
Heiko Schoder, M.D. 
 
Pathology 
Julie Feldstein, M.D. 
 
Basking Ridge, NJ Audrey 
Hamilton, M.D Deena 
Atieh-Graham, M.D. 
Ephraim Casper, M.D. 
Mila Gorsky, M.D. 
Han Xiao, M.D. 
Tina Passalaris, M.D 
Shilen Patel, M.D. 
Commack, NY 
Philip Schulman, M.D. 
Stuart Lichtman, M.D 
Stefan Berger, M.D. 
Julie Fasano, M.D. 
John Fiore, M.D. 
Steven Sugarman, M.D 
Frank Y. Tsai, M.D. 
 
Rockville Center, NY 
Pamela Drullinksy, M.D 
Arlyn Apollo, M.D. 
Zoe Goldberg, M.D. 
Kenneth Ng, M.D. 
Tiffany Troso-Sandoval, M.D. 
 
Sleepy Hollow, NY 
Philip Caron, M.D. 
Michelle Boyar, M.D. 
Nancy Mills, M.D. 
Stephanie Smith-Marrone, M.D. 
Carolyn Wasserheit-Lieblich, M.D. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
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Consenting 
Professional(s): 
John Gerecitano, M.D., Ph.D. 
Carol Portlock, M.D. 
Paul Hamlin, M.D. Steven 
B. Horwitz, M.D. Alison 
Moskowitz, M.D. Craig H. 
Moskowitz, M.D. Ariela 
Noy, M.D. 
M. Lia Palomba, M.D., Ph.D. 
David Straus, M.D. 
Andrew D. Zelenetz, M.D., Ph.D. 
Matthew Matasar, M.D 
Jonathan Schatz, M.D. 
Mark L. Heaney, M.D., Ph.D. 
Nicole Lamanna, M.D. 
Philip Schulman, M.D. 
Stuart Lichtman, M.D 
Audrey Hamilton, M.D 
Pamela Drullinksy, M.D 
Philip Caron, M.D 


Memorial Sloan-Kettering Cancer Center 
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Collaborating institution(s): 
PI Name and Contact Info 
Site Role 
The Cancer Institute of New 
Jersey 
Kevin David, MD 
Site Principal Investigator 
Assistant Professor of 
Medicine 
Department of Medical 
Oncology 
Robert Wood Johnson 
Medical School 
Ph: 732-235-2045 
Email: davidka@umdnj.edu 
Data Collection 
Columbia University Medical 
Center 
Owen O’Connor, MD PhD 
Site Principal Investigator 
Associate Professor of 
Medicine 
Columbia University Medical 
Center, Center for Lymphoid 
Malignancies 
Ph: 212-326-5720 
Email: oo2130@columbia.edu 
Data Collection 
Winship Cancer Institute, 
Emory University 
Christopher Flowers, MD 
Site Principal Investigator 
Assistant Professor 
Hematology and Medical 
Oncology 
Clinical Director of Medical 
Informatics 
Winship Cancer Institute, 
Emory University 
Ph: 404-778-3942 
Email: crflowe@emory.edu 
Data Collection 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. New 
York, NY 10021 


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Table of Contents 
1.0 
SCHEMA ............................................................................................................................ 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .......................................................................... 7 
2.1 
PRIMARY OBJECTIVES...................................................................................... 7 
2.2 
SECONDARY OBJECTIVES................................................................................ 7 
3.0 
BACKGROUND AND RATIONALE ............................................................................... 7 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .................................................. 19 
4.1 
AGENT ADMINISTRATION ............................................................................. 19 
4.2 
SUPPORTIVE CARE GUIDELINES .................................................................. 20 
4.3 
DURATION OF THERAPY ................................................................................ 21 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ..................................................................... 22 
5.1 
BORTEZOMIB PS-341 (NSC # 681239) ............................................................ 22 
5.2 
RITUXIMAB (RITUXAN®) ............................................................................... 30 
5.3 
CYCLOPHOSPHAMIDE..................................................................................... 31 
5.4 
PREDNISONE...................................................................................................... 32 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ..................................................................... 32 
6.1 
SUBJECT INCLUSION CRITERIA.................................................................... 32 
6.2 
SUBJECT EXCLUSION CRITERIA................................................................... 34 
7.0 
RECRUITMENT PLAN................................................................................................... 36 
8.0 
PRETREATMENT EVALUATION ................................................................................ 36 
9.0 
TREATMENT/INTERVENTION PLAN ........................................................................ 38 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ........................................ 41 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................... 41 
12.0 
DOSING DELAYS/DOSE MODIFICATIONS .............................................................. 41 
13.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT............... 44 
14.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................ 51 
15.0 
BIOSTATISTICS ............................................................................................................. 51 
16.0 
RESEARCH PARTICIPANT REGISTRATION PROCEDURES.................................. 53 
16.1 
RESEARCH PARTICIPANT REGISTRATION................................................. 53 
17.0 
PROTECTION OF HUMAN SUBJECTS ....................................................................... 54 
18.0 
DATA  MANAGEMENT ISSUES .................................................................................. 61 
19.0 
RANDOMIZATION......................................................................................................... 67 
20.0 
INFORMED CONSENT PROCEDURES ....................................................................... 67 
21.0 
CORRELATIVE STUDIES ............................................................................................. 68 
22.0 
ADMINISTRATIVE REQUIREMENTS ........................................................................ 69 
23.0 
APPENDICES .................................................................................................................. 72 
APPENDIX A ................................................................................................................... 72 
APPENDIX C: .................................................................................................................. 73 
APPENDIX D:.................................................................................................................. 74 
APPENDIX E: .................................................................................................................. 74 
APPENDIX F.................................................................................................................... 75 
APPENDIX G ................................................ ERROR! BOOKMARK NOT DEFINED. 
APPENDIX H ................................................................................................................... 77 
24.0 
REFERENCES ................................................................................................................. 78 


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1.0 
SCHEMA 
 
 
ELIGIBLE PATIENTS (Phase II)  Relapsed/Refractory (no more than 3 prior cytotoxic 
therapies): Indolent B-cell Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL) 
 
Weekly Dosing Schedule 
Week 1 
Week 2 
Week 3 
|__--------_|  
|  
| 
▲ ∆ 
∆ 
OFF 
Day 
1  2 
8 
▲: Rituximab, cyclophosphamide 
∆ :  Bortezomib 
---: Prednisone (Days 2 – 6) 
 
Day 1: Cyclophosphamide 1000 mg/m2 IVPB+ Rituximab 375 mg/m2 IVPB 
Days 2 and 8: Bortezomib 1.8 mg/m2 SC 
Days 2 through 6: Prednisone 100 mg PO 
Twice-weekly Dosing Schedule 
 
Week 1 
Week 2 
Week 3 
|__--------_|  
|  
| 
▲ ◊ 
∆ 
∆ 
∆ 
OFF 
Day 
1  2 
5 
9 
12 
 
▲: Rituximab, cyclophosphamide 
◊ :  Bortezomib, pegfilgrastim 
∆ :  Bortezomib 
---: Prednisone (Days 2 – 6) 
 
Day 1: Cyclophosphamide 1000 mg/m2 IVPB + Rituximab 375 mg/m2 IVPB 
Days 2, 5, 9, 12: Bortezomib 1.3 mg/m2 SC 
Days 2 through 6: Prednisone 100 mg PO 
Day 2: Pegfilgrastim, 6 mg SC 
 
Both Dosing Schedules 
 
Re-stage after 4 Cycles* 
 
 
Complete/Partial Response 
or Stable Disease 
Therapy not 
Tolerated/ PD 
Remove from 
Study 
 
 
If interim restaging CT shows CR: 2 Additional Cycles; If PR or SD: 4 Additional Cycles, 
Re-staging with PET and CT at the end of treatment 
 
 
First two years after completion of treatment: evaluate with CT and visit, no less than every 6 months. Beginning 
two years post completion of treatment: evaluate with CT and visit, no less than every 12 months. 
 
*One cycle is defined as 21 days.  Up to a 2 week delay will be allowed for recovery from any toxicity, and dose reductions will be allowed 
to the next lower dose level of cyclophosphamide or bortezomib at the discretion of the treating MD. 


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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 
Primary Objectives 
 
 
 
To determine the frequency and duration of complete and partial responses in patients treated 
with bortezomib + R-CP (R-CBorP) administered every 21 days for a total of 6-8 cycles. 
Patients will be treated on two different treatment schedules in a randomized phase II design. 
 
2.2 
Secondary Objectives 
 
 
 
To evaluate the progression-free survival, event-free survival and overall survival of patients 
treated with R-CBorP on two different treatment schedules. 
 
To further evaluate the toxicity profile of these two dosing schedules. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Bortezomib for Injection 
 
Scientific Background 
Bortezomib for Injection is a small molecule proteasome inhibitor developed by Millennium 
Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies. 
Bortezomib is currently approved by the United States Food and Drug Administration (US 
FDA) and it is registered in Europe for the treatment of multiple myeloma patients who have 
received at least one prior therapy. 
 
By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling 
pathways.  The anti-neoplastic effect of bortezomib likely involves several distinct 
mechanisms, including inhibition of cell growth and survival pathways, induction of 
apoptosis, and inhibition of expression of genes that control cellular adhesion, migration and 
angiogenesis.  Thus, the mechanisms by which bortezomib elicits its antitumor activity may 
vary among tumor types, and the extent to which each affected pathway is critical to the 
inhibition of tumor growth could also differ.  Bortezomib has a novel pattern of cytotoxicity 
in National Cancer Institute (NCI) in vitro and in vivo assays (Adams, Palombella et al. 
1999).  In addition, bortezomib has cytotoxic activity in a variety of xenograft tumor models, 
both as a single agent and in combination with chemotherapy and radiation (Teicher, Ara et al. 
1999; Cusack, Liu et al. 2001; Steiner, Neumeier et al. 2001; LeBlanc, Catley et al. 2002; 
Pink, Pien et al. 2002).  Notably, bortezomib induces apoptosis in cells that over express bcl- 
2, a genetic trait that confers unregulated growth and resistance to conventional 
chemotherapeutics (McConkey, Pettaway et al. 1999). 


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Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear 
factor κB (NF-κB) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a 
direct apoptotic effect, and possibly anti-angiogenic and other effects (Hideshima, Richardson 
et al. 2001). 
 
Clinical Pharmacokinetics and Pharmacodynamics 
The clinical pharmacology characterization of bortezomib has been determined from phase 1 
studies in subjects with solid tumors and hematological malignancies, and confirmed in 
phase 2 studies in subjects with multiple myeloma. 
 
Bortezomib demonstrates multi-compartmental pharmacokinetics. Following intravenous 
administration of 1.0 mg/m2 and 1.3 mg/m2 dose, the mean first-dose maximum observed 
plasma concentrations of bortezomib were 57 and 112 ng/mL, respectively in 11 patients with 
multiple myeloma and creatinine clearance values >50 mL/min participating in a 
pharmacokinetics study.  In subsequent doses, mean maximum observed plasma 
concentrations ranged from 67 to 106 ng/mL for the 1.0 mg/m2 dose and 89 to 120 ng/mL for 
the 1.3 mg/m2 dose.  The mean elimination half-life of bortezomib upon multiple dosing 
ranged from 40 to 193 hours.  Bortezomib is eliminated more rapidly following the first dose. 
Mean Total Body Clearances were 102 and 112 L/h following the first dose for doses of 1.0 
mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses 
for doses of 1.0 and 1.3 mg/m2, respectively.  Clinical experience has shown that the change 
in clearance does not result in overt toxicity from accumulation in this multidose regimen in 
humans. 
 
In subjects with advanced malignancies, the maximum pharmacodynamic effect (inhibition of 
20S activity) occurred within 1-hour post dose.  At the therapeutic dose of 1.3 mg/m2 in 
subjects with multiple myeloma, the mean proteasome inhibition at 1-hour post dose was 
approximately 61%. 
 
The time course of proteasome inhibition in subjects is characterized by maximum inhibition 
observed within the first hour after administration, followed by partial recovery of proteasome 
activity over the next 6 to 24 hours to within 50% of the pretreatment activity.  On the Day 1, 
4, 8, and 11 schedule, variable (10%–30%) levels of proteasome inhibition have been 
observed at next scheduled dosing.  In theory, this advantage allows cells to recover 
proteasome activity for normal cellular housekeeping functions between doses. 
The relationship between bortezomib plasma concentrations and proteasome inhibition can be 
described by a maximum effect (Emax) model.  The Emax curve is initially very steep, with 
small changes in plasma bortezomib concentration over the range of 0.5 to 2.0 ng/mL relating 
to large increases in the percent inhibition (0–60%).  After that, a plateau occurs where 
marginal increases of proteasome inhibition are observed in spite of large changes in plasma 
bortezomib concentrations. 
 
Clinical Experience 
It is estimated that more than 100,000 patients have been treated with bortezomib, including 
patients treated through Millennium-sponsored clinical trials, Investigator-Initiated Studies, 


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the US NCI Cancer Therapy Evaluation Program (CTEP), and with commercially available 
drug.  Bortezomib has been commercially available since 13 May 2003. 
 
The overall goal of the Millennium phase 1 program was to determine the MTD and dose- 
limiting toxicity (DLT) of bortezomib in a number of therapeutic settings involving subjects 
with various advanced malignancies.  In a Phase I trial in patients with refractory hematologic 
malignancies, the MTD for a twice weekly for 4 weeks of a 42 day cycle was 1.04 
mg/m2/dose, with DLTs of thrombocytopenia, hyponatremia, hypokalemia, fatigue, and 
malaise (Orlowski, Stinchcombe et al. 2002).  The toxicity was greatest during the third and 
fourth weeks of therapy. In the 3-week schedule of bortezomib monotherapy (4 doses, given 
on Days 1, 4, 8, and 11 of a 21-day treatment cycle), the DLT occurred at 1.56 mg/m2/dose (3 
subjects with Grade 3 diarrhea and 1 with peripheral sensory neuropathy).  Therefore, the 
MTD at this schedule was 1.3 mg/m2/dose.  In a 35-day treatment cycle with 4 weekly doses 
of bortezomib monotherapy, the MTD was 1.6 mg/m2/dose and DLT included hypotension, 
tachycardia, diarrhea, and syncope. 
 
In phase 1 clinical studies, anti-tumor activity was reported in subjects with NHL, multiple 
myeloma, Waldenström’s Macroglobulinemia, squamous cell carcinoma of the nasopharynx, 
bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate cancer. 
 
Studies using bortezomib as monotherapy and in combination with other chemotherapy agents 
are continuing. 
 
3.2 
Biology of Proteasome Inhibition 
The ubiquitin-proteasome pathway plays an essential role in the degradation of most short- 
and long-lived intracellular proteins in eukaryotic cells.  At the heart of this degradative 
pathway is the 26S proteasome, an ATP dependent, multicatalytic protease.  The 26S 
proteasome plays a vital role in degrading regulatory proteins that govern cell cycle, 
transcription factor activation, apoptosis and metastasis.  Some of the targets of ubiquitin- 
proteasome mediated degradation include p53, p21, p27, NF-
B, and Bcl-2.  Preclinical 
observations suggest that inhibitors of the proteasome can act through multiple mechanisms to 
arrest tumor growth, induce apoptosis, prevent tumor spread and inhibit angiogenesis. Phase I 
trials have confirmed tolerability of the proteasome inhibitor bortezomib and have suggested 
possible clinical activity. 
 
A number of key regulatory proteins are temporally degraded during the cell cycle by the 
ubiquitin-proteasome pathway, and the ordered degradation of these proteins is required for 
the cell to progress through the cell cycle and to undergo mitosis (King, Deshaies et al. 1996). 
One of the targets of ubiquitin-proteasome mediated degradation is the tumor suppressor p53, 
which acts as a negative regulator of cell growth.  P53 is required for the transcription of a 
number of genes involved in cell cycle control and DNA synthesis and also plays an important 
function in apoptosis induced by cellular damage including ionizing radiation (Sherr 1996). 
Cyclins and the cyclin-dependent kinase inhibitors p21 and p27 Kip1 are another set of 
growth regulatory proteins that are regulated by proteasome-dependent proteolysis (King, 


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Deshaies et al. 1996).   Both p21 and p27 can induce cell cycle arrest by inhibiting the cyclin 
D-, E- and A-dependent kinases (Sherr 1996). 
 
 
In addition, the ubiquitin-proteasome pathway is required for transcriptional regulation. 
Nuclear factor-
B (NF-
B) is a key transcription factor, whose activation is regulated by 
proteasome-mediated degradation of the inhibitor protein I
B (Palombella, Rando et al. 1994; 
Read, Neish et al. 1995).  Cell adhesion molecules (CAM) such as E-selectin, ICAM-1, and 
VCAM-1 are regulated by NF-
B and are involved in tumor metastasis and angiogenesis in 
vivo (Zetter 1993).  During metastasis, these molecules direct the adhesion and extravasation 
of tumor cells to and from the vasculature to distant tissue sites.  As such, tumor cell 
metastasis will be limited by the down-regulation of NF-
B dependent cell adhesion 
molecule expression.  NF-
B is also required in a number of cell types to maintain cell 
viability as an anti-apoptotic controlling factor (Beg and Baltimore 1996). Inhibiting NF-
B 
activation by stabilizing the I
B protein makes cells more sensitive to environmental stress 
and cytotoxic agents, ultimately leading to apoptosis. 
 
Altered degradation of cell cycle control proteins can result in accelerated and uncontrolled 
cell division, and thereby promote cancer growth and spread.  Interfering with the temporal 
degradation of these regulatory molecules by blocking proteasome function can lead to the 
inhibition of cell growth and the initiation of programmed cell death, thereby arresting 
malignant cell growth.  In addition, inhibition of proteasome-mediated degradation of I
B 
will inhibit NF-
B activation and should make tumor cells more sensitive to 
chemotherapeutic agents that activate NF-B. 
 
Collectively, these observations suggest that inhibitors of the proteasome can act through 
multiple mechanisms to arrest tumor growth, tumor spread and angiogenesis.  The 
combination of these mechanisms offers a novel approach to treating human malignancies. 
Consistent with this hypothesis, tumor cells that bear multiple genetic defects, including 
impaired DNA repair mechanisms and aberrant cell cycle checkpoint controls, are sensitive to 
the growth inhibitory actions of proteasome inhibitors both in vitro and in vivo. 
 
Bortezomib is a dipeptidyl boronic acid inhibitor with high specificity for the proteasome, 
which is being developed by Millennium, Inc. to treat human malignancies.  It is the first 
member of this new class of anti-tumor agents to come to human trials.  Phase I clinical 
studies have demonstrated that bortezomib is a well-tolerated agent with minimal adverse 
effects.  In addition, it has been shown that bortezomib is capable of producing a dose related 
effect on proteasome inhibition when analyzed one-hour post infusion.  There is little inter- 
patient variability, with responses at the lowest doses studied to date (Papandreou, Daliani et 
al. 2001; Aghajanian, Soignet et al. 2002). 
 
3.3 
Study Disease and Rationale 
 
Non-Hodgkin’s lymphomas (NHL) are presently the fifth most common cause of cancer 
related death in the United States.  Collectively, they account for approximately 4 to 5% of all 
cancer-related deaths in Caucasian and Hispanic populations, and about 2% in African- 


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American populations (Cunningham, Zalcberg et al. 1996).  However, because NHL tends to 
afflict a younger population (the average age of all lymphoma patients is about 42 years), the 
years of life lost is greater than in most other malignancies.  This ranks NHL fourth among all 
cancers with regard to their economic impact in the United States.  In 1997, there were 
approximately 53,600 new cases of NHL, with over 23,800 deaths attributed to the disease 
(Cunningham, Zalcberg et al. 1996).  Thus, the case-fatality rate for non-Hodgkin’s 
lymphoma (ie. the number of deaths attributed to the disease expressed as a percentage of the 
incidence of the disease) is approximately 44%.  As with most hematologic malignancies, 
there is a slight male predominance, with about 57% of all cases developing in males. 
 
The indolent non-Hodgkin’s lymphomas comprise approximately one-third of all NHLs. 
Indolent lymphoproliferative disorders (including chronic lymphocytic leukemia (CLL), small 
lymphocytic lymphoma (SLL), the follicular lymphomas (FL), marginal zone lymphomas 
(MZL), and lymphoplasmacytoid lymphoma (ie. Waldenstrom Macroglobulinemia (WM)), 
represent a class of diseases that are characterized by slow, progressive tumor growth that 
typically responds to alkylating agents.  While complete and partial remissions can be 
obtained in most patients, over time, the disease becomes increasingly more refractory to 
chemotherapy, prompting the need for additional, non-cross-resistant treatment approaches. 
 
A review of 204 patients treated over a 19 year time span has helped to characterize the 
natural history of indolent lymphomas (Johnson, Rohatiner et al. 1995).  With a median 
follow-up duration of 12.2 
years, the median survival of this mostly conservatively treated group was 9.2 years.  The 
study starkly illustrates the relapsing/recurring nature of the disease, with response rates and 
duration of response decreasing with subsequent relapses (see table below).  Sixty five percent 
of patients in this study relapsed after initial treatment, with a total of 37 patients ultimately 
receiving a total of four or more courses of therapy. 


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Comparison of Response Rates, Response Durations and Survival Times After 
Treatment of Consecutive Recurrences of Follicular Lymphoma 
 
Treatment 
# Treated 
RR (%) 
Duration (years) 
Survival (years) 
First 
204 
88 
2.6 
9.2 
Second 
110 
78 
1.1 
4.6 
Third 
63 
76 
1.1 
3.5 
Fourth 
37 
68 
0.5 
1.2 
 
An important finding of this study was that the durations of first and second remission and 
subsequent survival were heavily influenced by the degree of response to treatment.  Of the 77 
patients who achieved CR with their first treatment, 5-year disease-free survival (DFS) was 
54%, whereas 5-year DFS was about half of that (28%) for patients achieving only a PR. 
Similarly, median duration of response was 25 months for the 31 patients who achieved a CR 
after treatment for second relapse, but was only 9 months for those patients achieving PR.  It 
is therefore important to identify new treatment combinations that not only increase response 
rates, but that have the potential to increase the quality of response. 
 
 
 
3.4 
Phase II Experience with Bortezomib in NHL 
 
Our group has had a longstanding interest in the development of novel proteasome 
inhibitors dating back to our conduct of the phase I clinical trial of bortezomib in patients 
with hematologic and solid tumor malignancies (Aghajanian, Soignet et al. 2002).  This 
and another phase I study (Orlowski, Stinchcombe et al. 2002) demonstrated not only 
tolerability of the agent, with important pharmacologic endpoints, but also revealed 
significant activity in patients with multiple myeloma, mantle cell lymphoma, and 
follicular lymphoma.  These observations spawned a single-agent phase II study with 
bortezomib in patients with indolent lymphoproliferative disorders at MSKCC (protocol 
01-049).  Based on the promising activity of bortezomib in indolent lymphoma, we 
expanded this trial to a large, multicenter study.  The current protocol seeks to exploit the 
marked single-agent activity of bortezomib in non-Hodgkin’s lymphoma by integrating it 
into a standard conventional regimen for the treatment of these diseases. 
 
The phase II study of single-agent bortezomib (IRB # 01-049) in patients with predominantly 
relapsed or refractory indolent non-Hodgkin’s lymphoma (NHL) conducted by our group has 
recently been reported (O'Connor 2004; O'Connor 2005; O'Connor, Moskowitz et al. 2009). 
Bortezomib was administered at a dose of 1.5 mg/m2 on a day 1, 4, 8 and 11 schedule every 21 
days.  The patients were heavily pre-treated with a median of 3 prior therapies (2 prior therapies 
in MCL patients).  Overall the drug was very well tolerated, with most patients experiencing 
toxicities well known to be associated with the drug, including thrombocytopenia, sensory 


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neuropathy, diarrhea, and asthenia.  Among 18 assessable patients with FL, the overall response 
rate (ORR) was 50%, including 5 partial responses (PR) and 4 patients meeting criteria for 
complete remission (CR)/complete response unconfirmed (CRu).  Of 8 assessable patients with 
marginal zone lymphoma (MZL), 3 achieved a PR, while only 1 of the 6 patients with SLL 
showed any response to therapy (PR) (O’Connor et al., Clinical Cancer Research 2009, in 
press).  Among 36 assessable patients with MCL, the ORR was 50%, including 12PR and 6 
CR/Cru (O'Connor, Moskowitz et al. 2009).  Overall, the median progression free survival 
(PFS) for responding patients with MCL and all other non-MCL patients has been 7.8 and 12.3 
months respectively.  The median time to response is also significantly different among the 
different sub-groups, with MCL and FL lymphoma patients demonstrating a median time to 
response (TTR) of 5 and 11 weeks, respectively.  This particular difference has potentially 
significant ramifications regarding how much therapy to give before one can adequately assess 
drug activity in follicular lymphoma. 
 
Goy et al. at M.D. Anderson Cancer Center began a broader single-agent, single-institution 
study of bortezomib in patients with any B-cell neoplasm, regardless of their prior number of 
treatments (Goy, Younes et al. 2005).  Otherwise, this and the MSKCC studies were similar in 
design.  Of 60 registered patients, 33 had mantle cell lymphoma, 12 had diffuse large B-cell 
lymphoma, and the remainder had a variety of other subtypes, including small lymphocytic 
lymphoma, follicular lymphoma, Waldenstrom’s Macroglobulinemia, and a transformed 
lymphoma.  Overall, this population of patients was more heavily pretreated, with a median 
number of prior therapies of 3 in the MCL group and 4 in the other NHL patients.  The 
overwhelming majority of patients had markedly elevated LDH and Beta-2-microglobulin 
prior to study enrollment. Of 29 assessable patients with mantle cell lymphoma, 12 (41%) 
achieved a major response, with 6 (20.5%) of them attaining a complete remission, and 6 
(20.5%) attaining a partial remission.  Overall, the duration of response was approximately 6 
months.  Among the patients with diffuse large B-cell lymphoma, only one of the 12 
assessable patients achieved a partial remission, with the other patients demonstrating either 
stable or progressive disease.  No activity was seen in patients with small lymphocytic 
lymphoma or in the one assessable patient with transformed lymphoma.  While the numbers 
of patients with other sub-types of NHL were small, the collective experience suggests that 
there may be significant differences among the different sub-types of lymphoma. 
 
In addition to the above studies, two other phase II studies have treated patients with 
bortezomib at a dose of 1.3 mg/m2, using the twice weekly dosing schedule outlined above. 
The National Cancer Institute of Canada (NCIC) reported on a study in patients with, both 
treated and untreated, mantle cell lymphoma (Belch, Kouroukis et al. 2004).  A total of 30 
patients were accrued, of whom 28 were assessable for response at the time of reporting.  The 
number of prior treatments was limited to 2.  Interestingly, there was no difference in ORR 
between chemonaïve and chemotherapy refractory patients.  Among the 13 patients who had 
no prior therapy, 6 achieved a PR (ORR 46.2%), while among the 15 previously treated 
patients, 6 achieved PR and 1 achieved a CRu (ORR 46.7%).  Most adverse events were grade 
1 or 2, although there was an unusual vascular leak syndrome that occurred in some patients 
treated early in the study that may have been attributed to the fact that many of these patients 
had pre-existing effusions.  Interestingly, this toxicity was not seen in other trials.  Straus et 


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al. have enrolled 45 patients with NHL (21 MCL, 12 FL, 5 Waldenstrom’s macroglobulinemia 
(WM), 4 Hodgkin’s disease and 3 other) (Strauss, Maharaj et al. 2004). Responses were seen 
in 7 of 18 MCL patients (1 CR/CRu, 6 PR), 2 of 11 FL patients (both PR with late responses, 3 
months after initiation of treatment), and 2 of 5 WM patients (both PR). No responses were 
seen in patients with aggressive lymphomas.  Again, the most common toxicities were grade 3-
4 thrombocytopenia, fatigue, and peripheral neuropathy (along with 
the additional toxicity of grade 3-4 anemia). 
 
The consistent results in MCL prompted the PINNACLE trial - a multicenter phase II 
registration study of single agent bortezomib in MCL.  The centrally reviewed response rate in 
this trial was 32% (8% CR/CRu), with a median time to progression (TTP) and duration of 
response (DOR) of 6.7 and 9.2 months, respectively (Goy, Bernstein et al. 2009). 
 
Collectively, these data demonstrate that bortezomib has meaningful activity in select sub- 
types of lymphoma, and perhaps more importantly, that the duration of response can be 
clinically significant.  The future challenge, of course, is trying to figure out how best to 
integrate this promising new class of molecules into the present standards of care for 
lymphoma. 
 
Rationale for R-CBorP 
 
Preclinical data in a SCID-beige lymphoma xenograft model suggest that the efficacy of 
bortezomib with cytotoxic therapy is schedule dependent. Data from our laboratory (O'Connor 
2003) have revealed that bortezomib and cyclophosphamide are at least additive in their ability 
to delay and reverse xenograft tumor growth.  The optimal therapeutic effects are seen when 
bortezomib is given following cytotoxic therapy. Simultaneous administration is inferior to 
sequential administration. 
 
The addition of rituximab to bortezomib in a SCID xenograft model of lymphoma also shows 
at least an additive benefit (De Vos, McBride et al. 2004) (figure below). In other experiments 
(data not shown), bortezomib has shown cooperative activity with steroids, as well.  These 
data support the hypothesis that integrating bortezomib in a schedule-dependent manner into 
certain standard therapies is likely to be at least additive, if not synergistic, in the treatment of 
non-Hodgkin’s lymphoma. 


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Fo 
ld 
ch 
an 
ge 
in 
Ini 
tia 
l 
Tu 
m 
or 
V 
ol 
u 
Fold change in tumor volume 
 
 
In-vivo SUDHL-16 tumor growth after treatment with 
RTX and/or Bortezomib 
 
1 30. 0 
1 20. 0 
1 10. 0 
1 00. 0 
9 0.0 
8 0.0 
7 0.0 
6 0.0 
5 0.0 
4 0.0 
3 0.0 
2 0.0 
1 0.0 
0.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
5 
1 
1 
2 
 
Da y  
 
 
 
 
 
 
 
Control 
Rituxan 
Bortezomib 
Ritux/Bortez 
 
The importance of vincristine, a cell-cycle dependent antimitotic agent, in the treatment of 
slowly growing lymphomas is questionable.  Single-agent efficacy of vincristine in indolent 
lymphomas has not been shown in the modern literature.  Furthermore, vincristine and 
bortezomib both incur the potential for neurotoxic adverse effects.  Replacing vincristine with 
bortezomib, a known active agent in indolent lymphomas, in combination with 
cyclophosphamide, rituximab and prednisone therefore offers the potential for greater activity 
in patients with relapsed/refractory indolent NHL, and exploits the cooperative interactions of 
bortezomib with cyclophosphamide, rituximab and steroids. 
 
3.5 
Phase I Results 
 
To determine the (MTD) of bortezomib in combination with R-CP, we employed a modified 
Fibonacci dose escalation schema. We initially sought to explore a weekly dosing schedule of 
bortezomib, based on promising results from a phase II trial of bortezomib combined with 
rituximab comparing weekly with twice-weekly administration (Saleh, Dakhil et al. 2005). 
During this portion of the trial, the starting doses of bortezomib and cyclophosphamide were 
1.3 mg/m2 and 750mg/m2, respectively.  On the second cohort (bortezomib 1.6mg/m2 and 
cyclophosphamide 750mg/m2), one patient experienced a grade 3 diarrhea.  There were no 
further DLTs and the maximum pre-planned doses of bortezomib (1.8mg/m2) and 
cyclophosphamide (1000mg/m2) were therefore considered to be the MTD and Maximum 
Administered Dose (MAD).  However, as we neared the completion of dose escalation using 
weekly administration, new reports from the bortezomib + rituximab trial cast doubt about 
whether weekly dosing is the most potent mode of administration.  We therefore amended the 
Phase I trial to allow for dose escalation with a twice-weekly schedule of bortezomib 
administration in our combination regimen.  A minimum of three patients were followed for at 
least one complete cycle (ie. 3 weeks) of therapy before the trial entered patients at the next 


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dose level. Three patients were initially entered in the twice-weekly schedule at a dose of 1.0 
mg/m2 bortezomib and 750 mg/m2 of cyclophosphamide (with a constant dose of rituximab, 
375 mg/m2 and prednisone, 100 mg/day). Cyclophosphamide dose was increased to 1000 
mg/m2, and bortezomib was increased to 1.3 mg/m2 and 1.5 mg/m2.  As reported at the 2008 
Annual Meeting of the American Society of Clinical Oncology (Gerecitano, Portlock et al. 
2008), the second cohort (1.3 mg/m2 bortezomib, 750 mg/m2 cyclophosphamide) required one 
expansion due to neutropenic fevers.   When a second neutropenic fever was seen, the 
protocol was amended to include filgrastim support, and six additional patients were added at 
this dose level to assess safety.  One of these patients experienced two DLTs (a grade 4 
thrombocytopenia and a grade 4 neuropathy) and the cohort was again expanded, with no 
further DLTs.  Doses were further escalated to the highest pre-planned dose levels (1.5 mg/m2 
bortezomib, 1000 mg/m2 cyclophosphamide) without further DLTs. Although this highest 
dose level is the MTD as defined by our protocol, we have decided to bring the penultimate 
dose level (1.3 mg/m2 bortezomib, 1000 mg/m2 cyclophosphamide) forward into the phase II 
portion of the study.  This decision was made after considerations regarding our phase II 
experience with single-agent bortezomib and discussions with the attendings on the 
lymphoma service at MSKCC and Columbia University.  In order to allow for maximum 
dosing flexibility and patient convenience, we investigated the safety and efficacy of using 
pegylated G-CSF (Neulasta) during bortezomib administration in an expanded cohort at the 
MTD of the phase I study. A separate cohort of 10 patients was added at the twice-weekly 
bortezomib (Bor) 1.3 mg/m2 + cyclophosphamide (C) 1000 mg/m2 level to assess the safety of 
administering overlapping pegfilgrastim (PegG) instead of filgrastim (G). In this cohort, PegG 
was given with bortezomib on day 2.  To evaluate the safety of pegfilgrastim overlapping with 
4 doses of bortezomib, toxicities and CBCs for patients in the PegG group were compared 
with those of patients treated at identical doses of R-CBorP given non-overlapping G support. 
All toxicities and CBC trends were similar, with the exception of a significant but mild 
decline in platelets in the PegG group.  Final results of the phase I trial have been recently 
published (Gerecitano, Portlock et al.). 
 
 
 
3.6 
Rationale for Subcutaneous Dosing of Bortezomib 
 
In 2008, Moreau et al. first described the subcutaneous administration of bortezomib in a 
group of patients with multiple myeloma (MM).  At the 2010 annual meeting of the American 
Society of Hematology (ASH), this group presented data from a phase III randomized 
controlled trial comparing intravenous and subcutaneous routes of administration of 
bortezomib with or without dexamethasone in patients with MM (Moreau, Pylypenko et al. 
2010).  As expected, pharmacokinetic parameters were different in the two arms, with peak 
serum levels greater in the 74 patients in the IV arm (223 ng/ml) compared with the 148 
patients in the SC arm (20.4 ng/ml).  Interestingly, the area under the curve for both routes of 
administration was identical.  During this trial, it was found that several toxicities, most 
impressively sensory peripheral neuropathy, was markedly and significantly lower in patients 
given bortezomib subcutaneously: grade 3-4 toxicity rate was 70% for the IV arm and 57% 
for the SC arm; any grade peripheral neuropathy was seen in 53% of IV patients and 38% of 
SC patients, p = 0.04).  Efficacy of the SC route was indistinguishable from that of the IV 


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route of administration, with an overall response rate of 52% in both arms.  Based on this 
randomized trial, the SC mode of administration appears to increase the safety profile of 
bortezomib while maintaining identical efficacy.  We have therefore chosen to incorporate 
this mode of delivery into the current protocol. 
 
3.7 
Design of Phase II 
 
In the phase I portion of this study, both dosing schedules were well tolerated. The phase II 
portion of this study utilizes a randomized enrollment to further assess these two schedules in 
a larger number of patients.  Both arms will utilize a subcutaneous route of administration for 
bortezomib. 
 
The weekly dose schedule (Arm A) chosen for phase II was the MTD (see sections 3.5 and 
4.1.1). The decision for the phase II dose in the twice-weekly arm (Arm B) was based on 
several factors:  The phase I dose escalation of this schedule proceeded to the highest pre- 
planned level with filgrastim support without any DLTs. However, our phase II experience 
with single-agent bortezomib at this dose and schedule showed clinically important adverse 
effects, especially with respect to neuropathy.  Although this highest dose level is the MTD as 
defined by our protocol, the phase I investigators decided to bring the penultimate dose level 
(1.3 mg/m2 bortezomib, 1000 mg/m2 cyclophosphamide) forward into the phase II portion of 
the study. 
 
Because of the need for a randomized phase II design to assess the optimal dosing schedule, 
twice the number of patients is required (for two randomized arms). 
 
Interim Safety Analysis 
 
Although the SC route of administration seems to increase the safety of bortezomib 
administration, it has not been explored in combination with other agents.  For this reason, an 
interim safety analysis is planned after the enrollment of 6 patients in each treatment arm.  If 
any 2 of the first 6 patients enrolled to each arm experiences a dose limiting toxicity (DLT, as 
defined below), 6 further patients will be enrolled in that arm at a lower dose of bortezomib 
(see table under section 12.2).  One further dose reduction will be allowed in each arm if 
necessary.  The dose level at which < 2/6 patients in each arm experience a DLT will be used 
for the remainder of the study.  If > 2/6 patients experience a DLT even after 2 dose 
reductions in either arm, that arm will be terminated, and an amendment to the protocol will 
be planned to revert to IV treatment in that arm. 
 
Definition of Dose Limiting Toxicity 
 
The definition of DLT used in the phase 1 portion of this trial will be used for the interim 
safety analysis. 
 
DLT will be defined as any of the following events that are attributed to the study drug 
combination and occur during the first cycle of drug administration: 


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Grade 4 neutropenia (i.e., absolute neutrophil count (ANC) < 500 cells/mm3) for 7 
or more consecutive days or febrile neutropenia (i.e., fever > 38.5º C with an 
ANC < 1000 cells/mm3); 
 
Grade 4 thrombocytopenia (platelets <25,000 lasting for 7 consecutive days), 
platelets < 10,000 x 1 day, or platelets < 25,000 associated with a bleeding 
episode requiring transfusions. 
 
Neurosensory toxicity of Grade 2 with pain or any neurosensory toxicity higher 
than grade 2 (by Common Toxicity Criteria 4.0 defined as “a disorder 
characterized by functional disturbances of sensory neurons resulting in 
abnormal cutaneous sensations of tingling, numbness, pressure, cold, and 
warmth that are experienced in the absence of a stimulus” with “moderate 
symptoms; limiting instrumental ADL”); 
 
Grade 3 or greater nausea and/or vomiting despite the use of adequate/maximal 
medical intervention and/or prophylaxis; 
 
Any Grade 3 or greater non-hematological, non-neurosensory toxicity (except 
Grade 3 injection site reaction, alopecia, fatigue); 
 
Re-treatment delay of more than 3 weeks due to delayed recovery from a toxicity 
related to treatment with the study drug combination. 
 
In patients with advanced CLL, it may be difficult to evaluate hematologic toxicity. 
Deterioration in the platelet count, hemoglobin, or granulocyte count may represent either drug 
toxicity or progression of disease.  Therefore, frequent CBCs should be obtained while the 
patient is on study.  If a significant decline in peripheral counts occurs, drug therapy should be 
stopped and bone marrow examination should be performed to document the mechanism of the 
deterioration in the blood counts. Hematologic toxicity will be graded according to the following 
table: 


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NCI SPONSORED WORKING GROUP GRADING SCALE FOR 
HEMATOLOGIC TOXICITY 
 
Decrease from 
Pretreatment Value (%) 
Toxicity Grade 
(Platelets/Hemoglobin) 
0-10 
0 
11-24 
1 
25-49 
2 
50-74 
3 
>75 
4 
 
A decrease in circulating granulocytes is not considered as it is not a reliable 
index in CLL 
 
A platelet count decreasing to < 10,000 ml will be considered Grade 4 toxicity 
regardless of the pretreatment level 
 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Agent Administration 
 
4.1.1 On day 1 of both treatment arms A and B, cyclophosphamide will be dosed at 
1000 mg/m2 and rituximab will be dosed at 375mg/m2.  Prednisone will be given 
orally at a dose of 100 mg per day on days 2 through 6.  Each treatment cycle will 
last 21 days. 
 
 
4.1.1.1 Arm A (weekly bortezomib): Bortezomib will be administered at a dose 
of 1.8 mg/m2 on days 2 and 8 in the weekly dosing group. 
 
 
 
4.1.1.2 Arm B (twice-weekly bortezomib): Bortezomib will be administered at a 
dose of 1.3 mg/m2 on days 2, 5, 9 and 12 in the twice-weekly dosing group. 
Pegfilgrastim, 6 mg, will be injected subcutaneously on day 2. 
 
 
4.1.2 Bortezomib will be administered as a subcutaneous (SC) injection administered at 
a concentration of 2.5 mg/mL normal [0.9%] saline.  SC injection sites are the 
thighs or abdomen. Injection sites will be rotated for subsequent injections within 
a cycle. See figure below for suggested rotation of injections. 


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4.1.3 Pre-treatment parameters: On day 1 of each cycle, platelets must be ≥ 50,000/µl 
and ANC must be ≥ 1,000/µl.  On bortezomib-only treatment days, platelets must 
be ≥ 25,000/µl, and ANC must be ≥ 100/µl. 
 
4.1.4 Treatment will be administered on an outpatient basis.  Expected adverse events 
and appropriate dose modifications for bortezomib are described in Section 12.0. 
No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient’s malignancy. 
 
4.1.5 Up to a 2 week delay will be allowed for recovery from any toxicity, and dose 
reductions will be allowed to the next lower dose level of cyclophosphamide or 
bortezomib at the discretion of the treating MD.  Please refer to the protocol 
section on dosing delays and dose modification for more details (Section 12.0). 
 
4.2 
Supportive Care Guidelines 
 
4.2.1 Antiemetic treatment and precautions for cyclophosphamide will be based on 
current institutional guidelines. 
 
4.2.2 On the weekly dosing schedule, filgrastim or pegfilgrastim may be used in the 
setting of neutropenic fever (NTPF), or if the patient has experienced NTPF or 
neutropenia with prior administrations of the study drug combination. 
 
4.2.3 The use of pegylated G-CSF (Neulasta) will be mandated for all patients on the 
twice-weekly dosing schedule. 
 
4.2.4 Platelet and red blood cell transfusions are allowed, and erythropoiesis- 
stimulating agents may be given at the treating physician’s discretion for anemia 
with hemoglobin <11 g/dl. 


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4.2.5 Treatment and precautions for rituximab infusion reactions will be based on the 
current institutional guidelines. Steroid treatment for infusional reactions is 
allowed, but should not routinely be used for prophylaxis. 
 
4.2.6 Acyclovir and sulfamethoxazole/trimethoprim or equivalent substitutions should 
be uniformly recommended for all patients, administered prophylactically during 
treatment. Other prophylactic antibiotics will be allowed at the discretion of the 
treating physician. Prophylactics will continue for up to 4 months post treatment 
at the investigator’s discretion. 
 
4.2.7 Pain management will be addressed promptly by either the Attending Physician 
managing the patient, or through a consultation with the Pain and Palliative Care 
Service or similar services at each institution. 
 
4.2.8 Additional intravenous normal saline may be given with each injection of 
bortezomib as deemed necessary by the treating physician. 
 
4.2.9 Patients may be allowed treatment with corticosteroids as long as corticosteroids 
are discontinued at least seven days prior to starting study treatment. Otherwise, 
the regular use of corticosteroids is prohibited during the treatment phase unless 
used at physiologic doses (≤ 20 mg prednisone equivalent per day) for conditions 
not related to lymphoma (e.g. adrenal insufficiency, etc.). 
 
4.2.10  Any patient with a baseline neuropathy should be evaluated by a physician in 
rehabilitation or neurology prior to beginning treatment, and again if symptoms 
worsen during treatment. 
 
4.3 
Duration of Therapy 
 
 
 
4.3.1 A total of up to 8 cycles will be allowed, depending on response: 
 
4.3.1.1 If, after the initial 4 cycles, the patient has achieved a CR based on interim 
CT and PET scan, then 2 additional cycles will be administered, with re- 
staging CT at the completion of treatment. 
 
4.3.1.2 If, after the initial 4 cycles, the patient has achieved a PR or SD based on 
interim CT and PET scan, then 4 additional cycles will be administered, 
with re-staging CT and PET at the completion of treatment. 
 
4.3.1.3 If, at any point, the patient is deemed to have progressive disease (PD) 
based on radiologic study or physical examination, then he or she will be 
removed from the study. 


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5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
Bortezomib PS-341 (NSC # 681239) 
 
Bortezomib for Injection is a sterile lyophilized powder for reconstitution and is supplied in 
vials containing bortezomib and mannitol at a 1:10 ratio.  For example, vials containing 3.5 
mg of bortezomib contain 35 mg of mannitol. 
 
5.1.1 Availability: Bortezomib is a proteasome inhibitor supplied to investigators by 
Millennium Pharmaceuticals, Inc. 
 
5.1.2 How Supplied and Preparation: Drug is available in sterile, single-use vials 
containing 3.5 mg of bortezomib.  For SC administration, each vial of 
bortezomib for Injection should be reconstituted under a laminar flow biological 
cabinet (hood), within 8 hours before dosing, with 1.4 mL of normal (0.9%) 
saline, sodium chloride injection, so that the reconstituted solution contains 
bortezomib at a concentration of 2.5 mg/mL. The reconstituted solution is clear 
and colorless, with a final pH of approximately 5 to 6. Dissolution is completed in 
approximately 10 seconds. Reconstituted bortezomib should be administered 
promptly and in no case more than 8 hours after reconstitution. 
 
Dosage and Administration 
 
Bortezomib may be administered intravenously (IV) at a concentration of 1 
mg/mL, or subcutaneously at a concentration of 2.5 mg/ml.  When administered 
intravenously, bortezomib is administered as a 3 to 5 second bolus IV injection. 
 
Because each route of administration has a different reconstituted concentration, 
caution should be used when calculating the volume to be administered. 
 
Administration Precautions 
 
The drug quantity contained in one vial (3.5 mg) may exceed the usual dose 
required.  Caution should be used in calculating the dose to prevent overdose. 
 
When administered subcutaneously, sites for each injection (thigh or abdomen) 
should be rotated.  New injections should be given at least one inch from an old 
site and never into areas where the site is tender, bruised, erythematous, or 
indurated. 
 
If local injection site reactions occur following bortezomib administration 
subcutaneously, a less concentrated bortezomib solution (1 mg/mL instead of 2.5 
mg/mL) may be administered subcutaneously.  Alternatively, the IV route of 
administration should be considered. 
 
Bortezomib is an antineoplastic.  Procedures for proper handling and disposal 
should be considered. 


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In clinical trials of bortezomib IV, local skin irritation was reported in 5% of 
patients, but extravasation of bortezomib was not associated with tissue 
damage. In a clinical trial of subcutaneous bortezomib, a local reaction was 
reported in 6% of patients as an adverse event, mostly redness. 
 
 
5.1.3 Bortezomib is cytotoxic: As with all cytotoxic drugs, caution is required when 
preparing and handling bortezomib solutions. Cytotoxic drugs should only be 
handled by staff specially trained in the safe handling of such preparations. The 
use of gloves and other appropriate protective clothing is recommended.  In case 
of skin contact, wash the affected area immediately and thoroughly with soap and 
water for at least 15 minutes.  If product contacts eye, immediately flush eye 
thoroughly with water for at least 15 minutes.  Always contact a physician after 
any form of body contact. All materials that have been used for preparation 
should be disposed of according to standard practices. A log must be kept of all 
disposed materials. 
 
5.1.4 Storage and Stability: Vials containing lyophilized bortezomib for Injection 
should be stored according to the label requirements.  For the United States, store 
at USP Controlled Room Temperature which is 25ºC (77ºF); excursions permitted 
from 15 to 30ºC (59 to 86ºF).  To date, stability data indicate that the lyophilized 
drug product is stable for at least 18 months when stored under the recommended 
conditions. Stability studies are ongoing, and Millennium Pharmaceuticals, Inc. 
will notify the investigator should this information be revised during the conduct 
of the study. 
 
5.1.5 Schedule and Route of Administration.  Drug will be administered only to 
eligible patients under the supervision of the investigator or identified sub- 
investigator(s).  Patients may be treated on an out-patient basis, if possible. 
The pharmacist will prepare the drug under aseptic conditions.  The amount (in 
mg) of drug to be administered will be determined based on body surface area. 
Body surface area is to be calculated based on body weight using a standard 
nomogram (See Appendix C).  The dose should be calculated on Day 1 of each 
cycle; the dose administered should remain the same throughout each cycle but 
should be recalculated at the start of the next cycle.  If a patient experiences a 
notable change in weight within a cycle, as determined by an unscheduled weight 
assessment, then the patient’s dose should be recalculated at that time based on 
clinical judgment. The appropriate amount of bortezomib will be drawn from the 
injection vial and administered as a subcutaneous injection.  Vials are for single 
use administration. 
 
Patients randomized to the weekly dosing schedule (Arm A) will receive 
bortezomib as a subcutaneous injection on days 2 and 8, followed by a one week 
rest period.  Patients randomized to the twice-weekly dosing schedule (Arm B) 
will receive bortezomib as a subcutaneous injection on days 2, 5, 9, 12, followed 
by a one week rest period. 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
There must be at least 72 hours between each dose of bortezomib. 
 
Bortezomib Return 
 
For commercially-labeled bortezomib for IND-exempt studies, please contact 
Millennium to arrange for study drug return procedures.  Any unused or expired 
bortezomib must be returned to Millennium.  Drug return activity must be 
documented in the drug accountability log. 
 
Millennium Study Drug Product Complaints 
 
A product complaint is a verbal, written, or electronic expression which implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a 
drug product.  Individuals who identify a potential product complaint situation 
should immediately contact MedComm Solutions (see the following contact 
information below) and report the event.  Whenever possible, the associated 
product should be maintained in accordance with the label instructions pending 
further guidance from a Millennium quality representative. 
 
 
For Product Complaints, call MedComm Solutions at 
+1-866-835-2233 
 
5.1.6 Reported Adverse Events and Potential Risks. To date, more than 100,000 
patients have been treated with bortezomib in both clinical trials investigating its 
use in hematological malignancies and solid tumors, and in patients who were 
treated with commercially available bortezomib. 
 
Prescribing physicians and health care practitioners are referred to their locally 
approved product label for bortezomib regarding Indications and Usage, 
Contraindications, Warnings, and Precautions. 
 
The known anticipated risks of bortezomib therapy are presented in Table 5-1 and 
Table 5-2.  These risks are grouped according to the combined frequency 
observed in an integrated analysis of AEs in sponsored clinical studies of single- 
agent bortezomib dosed at 1.3 mg/m2 twice weekly on a 21-day schedule, in 
patients with multiple myeloma and mantle cell lymphoma. 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
 
Table 5-1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Blood and Lymphatic System Disorders 
Most common 
Thrombocytopenia*, anaemia* 
Very common 
Neutropenia* 
Common 
Lymphopenia, pancytopenia*, leukopenia*, febrile 
neutropenia 
Cardiac Disorders 
Common 
Tachycardia, atrial fibrillation, palpitations, cardiac 
failure congestive* 
Uncommon 
Cardiogenic shock*, atrial flutter, cardiac tamponad e*±, 
bradycardia, atrioventricular block complete, arrhythmia, 
cardiac arrest∗, cardiac failure, arrhythmia, pericardial 
effusion, pericarditis, pericardial diseas e±, 
cardiopulmonary failure± 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impaired 
Eye Disorders 
Common 
Blurred vision, conjunctivitis, conjunctival haemorrhage 
Gastrointestinal Disorders 
Most common 
Constipation, diarrhoea*, nausea, vomiting* 
Very common 
abdominal pain (excluding oral and throat) 
Common 
Dyspepsia, pharyngolaryngeal pain, gastroesophageal 
reflux, abdominal distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal haemorrhage*, 
lower gastrointestinal haemorrhage*± rectal 
haemorrhage 
Uncommon 
Eructation, gastrointestinal pain, tongue ulceration, 
retching, upper gastrointestinal haemorrhage*, 
haematemesis*, oral mucosal petechiae, ileus paralytic*, 
ileus, odynophagia, enteritis, colitis, oesophagitis, 
enterocolitis, diarrhoea haemorrhagic, acute 
pancreatitis*, intestinal obstruction 
General Disorders and Administration Site Conditions 
Most common 
Fatigue, pyrexia 
Very common 
Chills, oedema peripheral, asthenia 
Common 
Neuralgia, lethargy, malaise, chest pain, mucosal 
inflammation* 
Uncommon 
Injection site pain, injection site irritation, injection site 
phlebitis, general physical health deterioration*, 
catheter-related complication 
Hepatobiliary Disorders 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
 
Table 5-1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
 
System Organ Class 
Observed Incidence 
Preferred Term 
Uncommon 
Hyperbilirubinaemia, hepatitis*± 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 
Infections and Infestations 
Very common 
Upper respiratory tract infection, nasopharyngitis, 
pneumonia*, Herpes zoster* 
 
Common 
Lower respiratory tract infection*, sinusitis, pharyngitis, 
oral candidiasis, urinary tract infection*, sepsis∗, 
bactaeremia*, cellulitis∗, Herpes simplex, bronchitis, 
gastroenteritis*, infection 
Uncommon 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung infection∗, 
infusion site cellulitis, catheter site cellulitis, infusion 
site infection, urosepsis*, Aspergillosis*, tinea infection, 
Herpes zoster ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic±, varicella, empyema±, 
fungal oesophagitis± 
Injury, Poisoning, and Procedural Complications 
Common 
Fall 
Uncommon 
Subdural haematoma 
Investigations 
Common 
Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, 
blood alkaline phosphatase increased, liver function test 
abnormal, blood creatinine increased* 
Uncommon 
Gam ma-glutamyltransferase (GGT) increased, oxygen 
saturation decreased*, blood albumin decreased, ejection 
fraction decreased* 
Metabolism and Nutritional Disorders 
Very common 
Decreased appetite, anorexia, dehydration* 
Common 
Hyperglycaemia, hypoglycaemia, hyponatraemia, 
hypokalaemia, hypercalcaemia* 
Musculoskeletal and Connective Tissue Disorders 
Very common 
Bone pain, myalgia, arthralgia, back pain 
Common 
Muscular weakness 
Uncommon 
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon 
Tumour lysis syndrome* 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
 
Table 5-1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
 
System Organ Class 
Observed Incidence 
Preferred Term 
Nervous System Disorders 
Most common 
Peripheral neuropathy (including all preferred terms 
under the MedDRA High-level term Peripheral 
neuropathy NEC) 
Very common 
Paresthesia, dizziness excluding vertigo, headache 
Common 
Polyneuropathy, syncope, dysesthesia, dysgeusia, 
postherpetic neuralgia 
Uncommon 
Convulsion, loss of consciousness, ageusia, 
encephalopathy, paralysis*,autonomic neuropathy, 
reversible posterior leukoencephalopathy syndrom e± 
Psychiatric Disorders 
Very common 
Anxiety, insomnia 
Common 
Confusional state 
Uncommon 
Delirium 
Renal and Urinary Disorders 
Common 
Renal impairment*, renal failure*, haematuria 
Uncommon 
Micturition disorder 
Respiratory, Thoracic, and Mediastinal Disorders 
Very common 
Cough, dyspnoea 
 
Common 
Epistaxis, dyspnoea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary oedem a∗ 
Uncommon 
Hemoptysis*, acute respiratory distress syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar haemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, pleuritic 
pain 
Skin and Subcutaneous Tissue Disorders 
Very common 
Rash 
Common 
Rash pruritic, rash erythematous, urticaria, petechiae 
Uncommon 
Cutaneous vasculitis, leukocytoclastic vasculitis± 
Vascular Disorders 
Common 
Hypotension*, orthostatic hypotension 
Uncommon 
Cerebral haemorrhage* 
Source: VELCADE® Investigator’s Brochure Edition 14. 
Most common = ≥ 30%, Very common = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%. 
*  Fatal outcomes have been reported. 
±  Indicates a Preferred term not listed in the source table, however the event is deemed medically important 
and so is included. 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
 
 
 
Table 5-2 
Reports of Adverse Reactions From 
Postmarketing Experience 
 
 
 
System Organ Class 
Preferred Term 
 
Blood and lymphatic system disorders 
Observed 
Incidencea 
 
Disseminated intravascular coagulation             Rare 
 
Cardiac Disorders 
 
Atrioventricular block complete                           Rare 
 
Cardiac tamponade                                              Rare 
 
Ear and labyrinth disorders 
 
Deafness bilateral                                                Rare 
 
Eye Disorders 
 
Ophthalmic herpes                                               Rare 
Optic neuropathy                                                  Rare 
Blindness                                                               Rare 
Gastrointestinal Disorders 
 
Acute pancreatitis                                                 Rare 
 
Ischemic colitis                                                     Rare 
 
Hepatobiliary disorders 
 
Hepatitis                                                               Uncommon 
 
Liver failure                                                          Unknown 
 
Infections and infestations 
 
Herpes meningoencephalitis                                Rare 
 
Septic shock                                                          Rare 
 
Immune System Disorders 
 
Angioedema                                                          Rare 
 
Nervous System Disorders 
 
Autonomic neuropathy 
Rare 
Dysautonomia 
Unknown 
Encephalopathy 
Rare 
Respiratory, thoracic and mediastinal disorders: 
Acute diffuse infiltrative pulmonary diseaseb           Rare 
Acute respiratory distress syndrome (ARDS)       Rare 
Interstitial pneumonia                                          Rare 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
Lung infiltration                                                   Rare 
Pneumonitis                                                          Rare 
Pulmonary hypertension                                      Rare 
Skin and subcutaneous system disorders 
 
Acute febrile neutrophilic dermatosis                  Unknown 
 
Toxic epidermal necrolysis                                   Unknown 
Source: VELCADE® Investigator’s Brochure Edition 14. 
a  Incidence is assigned using the following convention: very common 
(≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and 
< 1/100); rare (≥ 1/10,000 and < 1/1000 ); very rare (< 1/10,000, 
including isolated reports). 
b  Acute diffuse infiltrative pulmonary disease is a MedDRA Lower 
Level Term which corresponds to a Preferred Term of Interstitial lung 
disease. 
 
 
Other medical events of interest that are considered not causally related to bortezomib include 
hepatic failure and QT prolongation.  Fatal outcomes have been reported. 
 
Women of childbearing potential should avoid becoming pregnant while being treated with 
bortezomib.  Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames 
assay and in the in vivo micronucleus assay, but it is a clastogen in the in vitro chromosomal 
aberration assay. 
 
Additional details on the potential risks of bortezomib may be found in the Investigator’s 
Brochure. 
 
5.1.7 Agent Ordering: Bortezomib will be supplied by Millennium Pharmaceuticals, 
Inc. free of charge for investigational use only. 
 
5.1.8 Agent Accountability: Accountability for the drug at all study sites is the 
responsibility of the principal investigator.  The investigator will ensure that the 
drug is used only in accordance with this protocol.  Drug accountability records 
indicating the drug’s delivery date to the site (if applicable), inventory at the site 
(if applicable), use by each patient, and return to Millennium or disposal of the 
drug (if applicable and if approved by Millennium) will be maintained by the 
clinical site.  Accountability records will include dates, quantities, lot numbers, 
expiration dates (if applicable), and patient numbers. 
 
All material containing bortezomib will be treated and disposed of as hazardous 
waste in accordance with governing regulations. 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
Precautions and Restrictions 
 
It is not known what effects bortezomib has on human pregnancy or development of 
the embryo or fetus.  Therefore, female patients participating in this study should 
avoid becoming pregnant, and male patients should avoid impregnating a female 
partner.  Nonsterilized female patients of reproductive age and male patients should 
use effective methods of contraception through defined periods during and after 
study treatment as specified below. 
 
Female patients must meet 1 of the following: 
• Postmenopausal for at least 1 year before the screening visit, or 
 
• Surgically sterile, or 
 
• If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing the informed consent form through 30 days 
after the last dose of bortezomib, or agree to completely abstain from heterosexual 
intercourse. 
 
It is strongly recommended that at least 1 of these 2 methods be highly effective (see 
  
examples below).  
 
Highly effective methods 
Other effective methods (barrier methods) 
Intra-uterine devices (IUD) 
Latex condom 
Hormonal contraceptives (birth control pills/oral 
contraceptives, injectable contraceptives, 
contraceptive patches, or contraceptive implants) 
Diaphragm with spermicide 
Cervical cap 
Sponge 
If one of the highly effective methods cannot be used, using 2 effective methods at the same time is 
recommended. 
 
Male patients, even if surgically sterilized (ie, status post vasectomy) must agree to 1 of 
the following: 
• Practice effective barrier contraception during the entire study treatment period and 
through a minimum of 30 days after the last dose of study drug, or completely abstain 
from heterosexual intercourse. 
 
 
5.2 
Rituximab (Rituxan®) 
 
 
 
5.2.1 Mechanism of action: Rituximab binds to the CD20 antigen expressed on B-cells 
and causes cell death by complement mediated lysis and Antibody- Dependent 
Cell-mediated Cytotoxicity (ADCC). 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
5.2.2 Formulation: Rituximab is supplied as 100 mg and 500 mg sterile, preservative- 
free, single use vials. 
 
5.2.3 Preparation: The appropriate dose is withdrawn and diluted to a final 
concentration of 1-4 mg/ml in either 0.9% sodium chloride or 5% dextrose 
solution. The solution is then stable at 2o to 8oC for 24 hours and at room 
temperature for an additional 12 hours. 
 
5.2.4 Storage: Vials can be stored at 2o to 8oC. They should be protected from sunlight. 
 
5.2.5 Administration: The first infusion should be administered at an initial rate of 50 
mg/hr. If hypersensitivity or infusion-related events do not occur, the rate may be 
increased by 50 mg/hr every 30 minutes up to a maximum of 400 mg/hr. 
Subsequent infusions may be started at 100 mg/hr and the rate increased by 100 
mg/hr every 30 minutes to a maximum of 400 mg/hr, as tolerated. Patients will be 
premedicated with acetaminophen 650-mg orally and diphenhydramine 50 mg IV 
30 minutes prior to beginning the rituximab infusion. For severe reactions, the 
infusion will be stopped and can be resumed at 50% of the prior rate once the 
reactions are treated and symptoms resolved. If infusion interruption is required, 
the administration of steroids (the equivalent of 50-100 mg hydrocortisone) prior 
to restarting the infusion is allowed at the investigator’s discretion. 
 
5.2.6 Reported Adverse Events and Potential Risks: Weakness, dizziness, hypo- or 
hypertension, peripheral edema, anxiety, flushing, headache, nausea or vomiting, 
diarrhea, rash, pruritus, angioedema, anaphylaxis, chest pain, cardiac arrhythmias, 
cough, throat irritation, bronchospasm, dyspnea, sinusitis, rhinitis, night sweats, 
lymphopenia, leukopenia, neutropenia, anemia, thrombocytopenia, infection, 
nephrotoxicity, hyperglycemia, urticaria, arthralgia, back pain PML 
 
5.2.7 Supplier: Genentech, Inc. 
 
5.3 
Cyclophosphamide 
 
5.3.1 Mechanism of action: Activation by hepatic microsomal enzymes forming two 
major intermediates, aldophosphamide and 4-hydroxycylophosphamide, which 
act as powerful alkylating agents and prevent cross linking of DNA strands. 
 
5.3.2 Formulation: Available in both oral and parenteral forms. The parenteral 
formulation is available as white crystals with sodium chloride as an excipient. 
The 100 mg dose is provided in a 10 mL vial and a 500 mg dose in a 30 mL vial. 
For high dose intravenous therapy there are 1 and 2 gram vials which are 
reconstituted in 50-100 mL of sterile water containing a solution of 20 mg/mL. 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
5.3.3 Preparation: The drug may be given by intravenous push or as a slow infusion. 
Adequate hydration of the patient before and 72 hours after high-dose therapy is 
recommended to reduce the incidence of hemorrhagic cystitis. 
5.3.4 Storage: Solutions reconstituted as described have a 24 hour stability at room 
temperature. 
5.3.5 Toxicity: myelosuppression (predominantly leukopenia), acute sterile 
hemorrhagic cystitis, SIADH, bladder carcinomas and cellular dysplasia, alopecia, 
nausea and vomiting, Rare: pneumonitis, infertility, and secondary leukemia. 
5.3.6 Supplier: Mead Johnson 
5.4 
Pred isone 
5.4.1 Mechanism of action: Decreases inflammation by suppression of migration of 
polymorphonuclear leukocytes and reversal of increased capillary permeability; 
suppresses the immune system by reducing activity and volume of the lymphatic 
system; suppresses adrenal function at high doses. Antitumor effects may be 
related to inhibition of glucose transport, phosphorylation, or induction of cell 
death in immature lymphocytes. Antiemetic effects are thought to occur due to 
blockade of cerebral innervation of the emetic center via inhibition of 
prostaglandin synthesis. 
5.4.2 Preparation:  1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 50 mg tablet 
5.4.3 Toxicities: euphoria/depression, GI distress, growth depression, hypertension, 
sodium and fluid retention, impaired skin healing, increased risk of infection, 
osteoporosis, skin atrophy, adrenocortical insufficiency , cataracts, glaucoma, 
Cushing's syndrome, hyperglycemia, tuberculosis reactivation 
5.4.4 Supplier: The Upjohn Company 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
6.1.1 Patients with B-cell small lymphocytic lymphoma, marginal zone lymphoma 
(including lymphoplasmacytic lymphoma), follicular lymphoma, grade I, II, IIIa, 
Waldenstrom’s macroglobulinemia or mantle cell lymphoma.  Patients with 
transformed indolent lymphomas will not be eligible for this study.  Patients 
relapsed or refractory after at least one prior chemo or immunotherapeutic 
modality will be eligible.  Pathology should be confirmed at local participating 
institution. 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
 
6.1.2 All patients must have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension (longest diameter to be recorded 
as >2 cm with conventional techniques or as >1 cm with spiral CT scan).  Lymph 
nodes measuring < 1 cm in the short axis are considered normal. Patients with 
WM and no measurable lymphadenopathy are allowed, and will be assessed using 
the criteria of the Forth International Workshop on WM. 
 
6.1.3 Patients must have received at least one prior chemo or immunotherapeutic 
regimen of any kind, but no more than three prior regimens of conventional 
cytotoxic therapy, and must be off all cytotoxic chemotherapy for at least four 
weeks prior to study enrollment (6 weeks for BCNU or mitomycin C, 12 weeks 
with recovery to baseline counts for radioimmunotherapy).  Patients are allowed 
to have received one course of prior radioimmunotherapy (RIT: either 
tositumomab or ibritumomab).  Prior recipients of stem cell transplantation will 
be included, with the preparative cytoreductive and high-dose therapies counted 
collectively as one prior therapy. 
 
6.1.4 Patients must not have received any therapeutic monoclonal antibodies (e.g. 
rituximab, tositumomab, ibritumomab, alemtuzumab, etc.) within 3 months of 
enrollment.  Patients who have been treated with monoclonal antibodies within 3 
months may be enrolled if they show progression of disease on this therapy, as 
long as they have not received the treatment within 7 days of enrollment. 
 
6.1.5 Age greater than or equal to 18 years. Because no dosing or adverse event data are 
currently available on the use of bortezomib in patients <18 years of age, children 
are excluded from this study but will be eligible for future pediatric single-agent 
trials, if applicable. 
 
6.1.6 Karnofsky Performance Status >50%
 (see Appendix B). 
 
6.1.7 Patients must have adequate organ and marrow function as defined below (within 
14 days of study drug administration): 
 
• Absolute Neutrophil Count (ANC) > 1,000/mcL at enrollment and on day 1 of 
each cycle (If known lymphomatous involvement of the bone marrow, then 
ANC  >  500/mcl). 
• Platelets > 50,000/mcL at enrollment and on day 1 of each cycle 
• Total bilirubin < 1.5 times institutional upper limit of normal 
• AST (SGOT) and ALT (SGPT) ≤ 2.5 times institutional upper limit of normal 
(4x ULN if liver involvement) 
• Creatinine < 1.5 times institutional upper limit or creatinine clearance ≥50 
 
6.1.8 Patients may have febrile episodes up to 38.5 oC without evidence of active 
infection. 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
 
6.1.9 The effects of bortezomib on the developing human fetus at the recommended 
therapeutic dose are unknown.  For this reason, and because bortezomib belongs 
to a new class of antineoplastic agents that may be teratogenic, women of child- 
bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control) prior to study entry and for the duration of study 
participation. Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
 
6.1.10  Patients must have no signs of congestive heart failure class III/IV according the 
New York Heart Failure Guidelines (see Appendix D) uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities. Prior to study entry, any 
ECG abnormality at screening must be documented by the investigator as not 
medically relevant. 
 
6.1.11  Patients must have the ability to understand ramifications of the study, and the 
willingness to sign a written informed consent document. 
 
6.1.12  Voluntary written informed consent must be obtained before performance of any 
study-related procedure not part of normal medical care, with the understanding 
that consent may be withdrawn by the subject at any time without prejudice to 
future medical care. 
 
6.1.13  Female subject is either postmenopausal for at least 1 year before the screening 
visit, is surgically sterilized or if they are of childbearing potential, agree to 
practice 2 effective methods of contraception from the time of signing the 
informed consent form through 30 days after the last dose of bortezomib, or agree 
to completely abstain from heterosexual intercourse. 
 
6.1.14  Male subjects, even if surgically sterilized (ie, status postvasectomy) must agree 
to 1 of the following:  practice effective barrier contraception during the entire 
study treatment period and through a minimum of 30 days after the last dose of 
study drug, or completely abstain from heterosexual intercourse. 
 
 
6.2 
Subject Exclusion Criteria 
 
6.2.1 Patients without prior therapeutic regimen of any kind, or patients who have had 
more than three prior regimens of conventional cytotoxic therapy will be excluded 
from this clinical trial.  Patients who have had chemotherapy or radiotherapy 
within 4 weeks (6 weeks for nitrosoureas or mitomycin C, 12 weeks or lack of 
recovery to baseline counts for RIT) prior to entering the study or those who have 
not recovered from adverse events due to agents administered more than 4 weeks 
earlier, and patients who have received a therapeutic monoclonal antibody within 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
3 months (except those with objective evidence of PD) will be excluded from this 
clinical trial. 
 
6.2.2 Patients receiving palliative steroids for the purpose of treating NHL within 7 
days of starting the study treatment will be excluded from this clinical trial. 
 
6.2.3 Participation in clinical trials with other investigational agents not included in this 
trial, within 14 days of the start of this trial and throughout the duration of this 
trial. 
 
6.2.4 Patients with known brain metastases or meningeal disease will be excluded from 
this clinical trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events. 
 
6.2.5 Patients who have had any major surgery within four weeks of study entry will be 
excluded from this clinical trial. 
 
6.2.6 Patients with uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, cerebrovascular 
accident (CVA) or transient ischemic attack within 6 months of study enrollment, 
unstable angina pectoris, cardiac arrhythmia, EKG evidence of acute ischemia, or 
psychiatric illness/social situations that would limit compliance with study 
requirements will be excluded from this clinical trial. 
 
6.2.7 Pregnant and breast-feeding women are excluded from this study because 
bortezomib is a novel agent that may have the potential for teratogenic or 
abortifacient effects.  Confirmation that the subject is not pregnant must be 
established by a negative serum β-human chorionic gonadotropin (β-hCG) 
pregnancy test result obtained during screening.  Pregnancy testing is not required 
for post-menopausal or surgically sterilized women. 
 
6.2.8 Patients with uncontrolled hypertension requiring active manipulation of 
antihypertensive medications will be excluded from this clinical trial. 
 
6.2.9 HIV-positive patients on combination antiretroviral therapy are eligible if their 
HIV is under adequate control with an antiretroviral regimen that has been stable 
for > 4 weeks, as long as the CD4 count is > 300.  Appropriate studies will be 
undertaken in patients receiving combination antiretroviral therapy when 
indicated. 
 
6.2.10  Patients with a history of hypersensitivity to bortezomib, boron or mannitol will 
be excluded from this clinical trial. 


Amended: 07/25/12 
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IRB#: 05-103 A(14) 
 
 
 
6.2.11  Patients who had experienced myocardial infarction within 6 months prior to 
enrollment will be excluded from this clinical trial.  Prior to study entry, any ECG 
abnormality at Screening has to be documented by the investigator as not 
medically relevant. 
 
6.2.12  Patients diagnosed or treated for another malignancy within 3 years prior to study 
enrollment (with the exception of complete resection of basal cell carcinoma or 
squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate 
cancer after curative therapy) will be excluded from this clinical trial. 
 
6.2.13  Patients with peripheral neuropathy > grade 1 with pain or grade ≥2 will be 
excluded from this clinical trial. If the patient has baseline neuropathy grade 1 or 
2, it is recommended that the patient be referred for evaluation for rehabilitation 
medicine or neurology prior to beginning treatment, and again if symptoms 
worsen during treatment. 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Subjects will be recruited and treated from Memorial Sloan Kettering Cancer Center, The 
Cancer Institute of New Jersey at Robert Wood Johnson Medical School, Columbia 
University Medical Center, and the Winship Cancer Institute at Emory University.  Adult 
men and women of all ethnic groups are eligible for this trial.  60 patients total will take 
part in this Phase II subcutaneous portion of the study.  About 42 patients are expected to 
be treated at MSKCC; the remainder are to be accrued by the subsites. The proposed 
study population is illustrated in the table below. 
 
Race/Ethnicity 
Gender 
White, not 
of 
Hispanic 
Origin 
Black, not 
of 
Hispanic 
Origin 
Hispanic 
Asian or 
Pacific 
Islander 
Unknown 
Total 
Male 
~46% 
1-2% 
2-3% 
1-2% 
- 
~53% 
Female 
~40% 
1-2% 
2-3% 
1-2% 
- 
~43% 
Total 
~86% 
~3.3% 
~5% 
~3% 
2.7% 
100% 
 
8.0 
PRETREATMENT EVALUATION 
 
8.1 
Pre-Treatment Evaluation must be performed within 14 days of study drug 
administration unless otherwise noted. 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
8.1.1 History and physical examination, including height, weight, vital signs, and a 
comprehensive neurologic examination. 
 
8.1.2 Karnofsky Performance status 
 
8.1.3 CBC with automated differential and platelet count. 
 
8.1.4 Serum chemistries including electrolytes, glucose, BUN, creatinine, magnesium, 
calcium, phosphorous, albumin, SGOT (AST)/SGPT (ALT), alkaline 
phosphatase, total bilirubin, LDH, serum cryoglobulins. 
 
8.1.5 Beta-2 microglobulins and protein electrophoresis (serum) should be performed 
pre-study. 
 
8.1.6 Documentation of known measurable or assessable disease parameters including 
radiographic imaging procedures (CT and PET scan) within 6 weeks. If the 
patient has a history of measurable disease in the neck, a CT of the neck should 
also be performed at baseline. 
 
8.1.7 Urine or serum pregnancy test for woman with childbearing potential. 
 
8.1.8 Unilateral bone marrow aspirate and biopsy (within 4 months). 
 
8.1.9 EKG 
 
8.1.10  Pretreatment paraffin-embedded histologic samples will be obtained from all 
patients for tissue microarray. Unstained slides (preferably > 20) may be 
substituted when block is not available. 


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9.0 
TREATMENT/INTERVENTION PLAN 
 
STUDY CALENDAR 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycles 5-8 D 
Final 
VisitN 
Follow Up 
Pre-Study K 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
6, 12, 18, 24, 36, 
48, etc., months 
post final visit E 
Bortezomib 
D(2,8) –Arm A 
D(2,5,9,12)-Arm B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cyclophosphamide (D1) 
X 
X 
X 
X 
X 
Rituximab (D1) 
X 
X 
X 
X 
X 
Prednisone (D2-6) 
X 
X 
X 
X 
X 
Neulasta® (D2 of Arm B only) 
X 
X 
X 
X 
X 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
Physical ExamA 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Urinalysis 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status (per RN) 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cryoglobulins L 
X 
X 
X 
X 
X 
X 
X 
X 
Bone Marrow Aspirate and biopsy 
X 
XI 
XI 
Serum chemistry and LDH L 
X 
X 
X 
X 
X 
X 
X 
X 
Beta-2-microglobulins 
X 
X 
Protein Electrophoresis (serum) 
X 
XJ 
XJ 
EKG 
X 


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Adverse event evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
Immunofixation (serum)M 
X 
X 
X 
Immunoglobulin, quantitative M 
X 
X 
X 
Tumor measurements H 
XG 
XF 
XG 
X 
Radiologic evaluation G 
XG 
XF 
XG 
X 
B-HCG (serum) C 
X 


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A:  Patients will be seen on or within 7 days prior to day 1 of each cycle, more frequently at treating MD’s discretion. 
B:  With the exception of screening, CBCs should be performed within a 24 hour window prior to treatment.  Day 2 CBCs of each cycle are optional. A CBC should be performed and resulted 
within 24 hours of all Bortezomib treatments. 
C:  Serum pregnancy test (women of childbearing potential only). 
D:  Continued treatment follows the same pattern of follow-up examination as cycles 3 and 4. Treatment continues for up to 6 or 8 cycles in total, depending on response.  Please see the 
duration of therapy section in protocol for details (Section 4.3). 
E:  Radiologic evaluation and follow up visits will continue after treatment, starting 6 months after the final visit, and continue every 6 months for the first two years, and every 12 months 
thereafter (or more frequently at discretion of treating MD) until the patient begins another treatment regimen. 
F:  Radiologic studies at the end of cycle 4 will include CT: CA , PET scan, and, if the patient had a history of disease in neck, a CT: Neck.  CT measurements should be performed during the 
3rd week of cycle 4. 
G:  Baseline, restaging, and post-treatment radiologic studies will include a CT: CAP, PET scan, and CT: Neck (only if history of disease in neck). All patients on study will have PET and CT 
scans performed during the Cycle 4 radiologic evaluation. Thereafter, once a patient enters complete remission (CR), then only CT’s (chest/abdomen/pelvis and neck, if necessary) should be 
obtained. End-of treatment restaging radiologic studies should be performed 3-4 weeks after the last dose of bortezomib. Radiologic documentation must also be provided for patients 
removed from study for progressive disease. 
H: Tumor measurements should be documented after each radiologic assessment that occurs while the patient is on the study (including unscheduled scans ordered at the discretion of the 
treating physician, scans that require patient to go off study, and any scan ordered per protocol.) 
I:   Bone marrow biopsy and aspirate will be included as part of the end of treatment evaluation (final visit)  in all patients who achieve a radiologic CR and in whom bone marrow involvement 
was documented in the pre-study evaluation.  If there is radiologic evidence of a CR at interim restaging in patients with documented bone marrow involvement at baseline, a bone marrow 
biopsy and aspirate should be performed prior to Cycle 6 Day 1 to confirm radiologic CR. 
J:   Serum Protein Electrophoresis should be performed at baseline, at restaging, and repeated at end of treatment, if baseline value was abnormal or the patient has Waldenström’s 
Macroglobulinemia. 
K:  Baseline laboratory evaluations and physical examination are to be conducted within 14 days prior to administration of study agent.  Scans must be done within 6 weeks prior to enrollment. 
Bone marrow biopsy must be done within 4 months prior to enrollment. 
L. With the exception of screening, serum chemistries should be performed within 7 days prior to treatment. Serum Chemistry includes: Albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT[AST], SGPT[ALT], sodium, serum cryoglobulins (quantitative), magnesium, phosphorus, uric 
acid. Serum chemistries do not need to be resulted prior to treatment on Day 1. 
M. Patients with Waldenström’s Macroglobulinemia must have these labs performed at screening, restaging and at 6 week follow up from first negative values in CR is achieved.  These tests 
are    strongly encouraged for all patients but only required for Waldenström’s Macroglobulinemia patients. 
N. Final visit evaluation will take place 30 days +/- one week after the last dose of bortezomib. While every attempt will be made to collect this final visit data, it is understood that medical 
and/or logistical reasons may arise that could potentially interfere with the ability of the patient to attend the final visit. If any patient is unable to comply wih the final visit, the reason(s) for 
this will be documented in the medical records and this would not be considered a protocol violation. 


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10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
See the Study Calendar (Section 9.0) for scheduled evaluations during treatment.  For the 
purposes of this study, patients will be reevaluated for response with a CT and PET scan after 4 
cycles and 3-4 weeks after the last dose of bortezomib.  A follow-up visit will be scheduled 1 
month after completion of treatment, with repeat CT scans every 6 months in the first two years. 
Two years post completion of treatment, patients should be re-imaged at least every 12 months, 
with interim imaging at the discretion of the treating physician. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 Expected Adverse Events Associated with Bortezomib 
 
Toxicity will be described according to NCI Common Toxicity Criteria for Adverse Events 
(CTCAE) Version 4.0.  Toxicity will be evaluated on day 1 of each cycle.  Expected 
toxicities are described in the information supplied by Millennium Pharmaceuticals, Inc. 
For the list of potential risks and adverse events refer to the section detailing Reported 
Adverse Events and Potential Risks (section 5.1.6).  Further details on the potential risks of 
bortezomib may be found in the Investigator Brochure. 
 
11.2 Expected Adverse Events Associated with Other Study Drugs 
 
11.2.1  Rituximab: Fever, chills, nausea, asthenia, hypotension, angioedema, respiratory 
distress, tumor lysis syndrome, and neutropenia. 
 
11.2.2  Cyclophosphamide: myelosuppression (predominantly leukopenia) acute sterile 
hemorrhagic cystitis, SIADH, bladder carcinomas and cellular dysplasia, alopecia, 
nausea and vomiting.  Rare: cardiomyopathy, pneumonitis, infertility, and 
secondary leukemia. 
 
11.2.3  Prednisone: euphoria/depression, GI distress, growth depression, hypertension, 
sodium and fluid retention, impaired skin healing, increased risk of infection, 
osteoporosis, skin atrophy, adrenocortical insufficiency , cataracts, glaucoma, 
Cushing's syndrome, hyperglycemia, tuberculosis reactivation 
 
12.0 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Before each drug dose, the patient will be evaluated for possible toxicities that may have 
occurred after the previous dose(s).  Toxicities are to be assessed according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 
Neuropathic pain and peripheral sensory neuropathy are to be managed as described in Table 
12.2. 


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Before day 1 of each cycle, platelets must be ≥ 50,000/µl and Absolute Neutrophile Count 
(ANC) must be ≥ 1,000/µl. On bortezomib-only treatment days, platelets must be ≥ 25,000/µl, 
and ANC must be ≥ 100/µl. 
 
Dose escalation will not be allowed in any patient, and there must be at least 72 hours between 
each dose of Bortezomib. Skipped doses of bortezomib will not be made up. 
 
12.1 Previously established or new toxicities observed at any time, with the exception of 
neuropathic pain and peripheral sensory neuropathy, are to be managed as follows: 
 
12.1.1  Patients who develop a febrile neutropenia or Grade 4 hematologic toxicity can be 
treated with a repeat cycle after holding the dose for up to two weeks and 
allowing blood count recovery to either the pre-treatment criteria (dose 1 of any 
cycle – see section 6.1.7), or 25,000/mcl for platelets and 100/mcl for absolute 
neutrophil count (on days when bortezomib is given alone within each cycle). 
Cytokine support can be given as outlined in “Supportive Care,” section 4.2. 
Should the patient develop a second Grade 4 neutropenia or neutropenic fever, 
then the dose of cyclophosphamide should be reduced to 750 mg/m2. 
 
12.1.2  If, after treatment has been held, the toxicity does not resolve, as defined above, 
treatment must be discontinued. 
 
12.1.3  Dose interruption or study discontinuation is not required for lymphopenia of any 
grade. 
 
12.1.4  Should the patient develop a second Grade 4 thrombocytopenia, then after 
resolution as above, the dose of bortezomib should be reduced by one dose level 
(see table below under section 12.2).  A second dose reduction will be allowed if 
grade 4 thrombocytopenia persists. 
 
12.1.5  Drug should be held in patients who develop any treatment-related Grade 3-4 
non-hematologic toxicity (except Grade 3 alopecia, injection site reaction, fatigue, 
or grade 3-4 lab values related to underlying baseline conditions),  grade 1 
neuropathy with pain or any toxicity that is deemed intolerable by the patient or 
investigator until symptoms resolve to baseline.  Such patients can be re-treated 
with a reduced dose of bortezomib and/or cyclophosphamide as outlined above. 
Should the Grade 3-4 toxicity recur after dose reduction, that patient will be 
removed from study.  If a grade 3-4 toxicity is based solely on laboratory 
abnormalities that are thought to be clinically insignificant by the treating 
physician, the lab values should be discussed with the principle investigator to 
decide if dose interruption or reduction is necessary. 


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Patients who experience bortezomib-related neuropathic pain or peripheral sensory 
neuropathy are to be managed as presented in Table 12.2.  Once the dose is reduced for 
peripheral neuropathy, the dose may not be re-escalated. 
 
Table 12.2 Management of Patients with Bortezomib-Related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy 
 
Recommended Dose Modification for Bortezomib related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy 
 
Severity of Peripheral Neuropathy 
Signs and Symptoms 
Modification of Dose and Regimen 
 
Grade 1 (asymptomatic; loss of deep tendon 
reflexes or paresthesia)  without pain or loss 
of function 
No action 
 
Grade 1 with pain or Grade 2 (moderate 
symptoms; limiting instrumental ADL) 
Reduce bortezomib to -1 level 
 
 
 
Grade 2 with pain or Grade 3 (severe 
symptoms; limiting self care ADL) 
 
Grade 4 (Life-threatening consequences; 
urgent intervention indicated) 
Discontinue bortezomib and remove patient 
from study 
 
Discontinue bortezomib and remove patient 
from study 
 
Grading based on NCI Common Terminology Criteria CTCAE v 4.0 
NCI Common Terminology Criteria website - http://ctep.info.nih.gov/reporting/ctc.html 
 
 
 
Table: Bortezomib Dose Reduction Schema 
Weekly dosing 
group 
Twice-Weekly 
dosing group 
Starting dose 
1.8 mg/m2 
1.3 mg/m2 
-1 
1.6.mg/m2 
1.0 mg/m2 
-2 
1.3 mg/m2 
0.7 mg/m2 
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 -3.0 X ULN) while on study, the investigator should hold 
bortezomib until the toxicity returns to < Grade 2. Restarting bortezomib at the next lower 
dosed level could be considered at the Investigator’s discretion and following exclusion of 


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bortezomib-induced liver impairment and careful consideration of liver disease due to other 
causes, such as, but not limited to active infection and multiple myeloma-related liver disease. 
 
The neurotoxicity-directed questionnaire (see Appendix F) is a useful tool for determining the 
presence and intensity of neuropathic pain and/or peripheral neuropathy from the patient’s 
perspective.  Neuropathic symptoms are more prominent than abnormalities on the clinical 
examination.  After the patient completes the neurotoxicity-directed questionnaire, the 
questionnaire should be reviewed to assist with the evaluation of the onset and intensity of 
peripheral neuropathy and other neurotoxicities that may possibly require intervention or dose 
modification. 
 
13.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
13.1 Definitions 
Response and progression of disease will be evaluated in this study using the international 
criteria proposed by the Cheson et al. (Cheson, Pfistner et al. 2007) for patients with 
lymphoma, and the Forth International Workshop on Waldenstrom’s Macroglobulinemia 
(Dimopaulos et al, 2009) for patients with Waldenstrom’s Macroglobulinemia..  Note: 
Lesions are either measurable or non-measurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
 
13.1.1  Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as >20 mm with conventional 
techniques (PET, CT) or as >10 mm with spiral CT scan.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
13.1.2  Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter 
<20 mm with conventional techniques or <10 mm using spiral CT scan), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions 
are all non-measurable. 
 
13.1.3  Target Lesions 
All measurable lesions up to a maximum of six lesions representative of all 
involved organs should be identified as target lesions and recorded and measured 
at baseline.  Target lesions should be selected on the basis of their size 
(determining the product obtained from the longest diameter of two perpendicular 
measurements) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). 


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13.1.4  Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline.  Non-target lesions include measurable 
lesions that exceed the maximum numbers per organ or total of all involved 
organs as well as non-measurable lesions.  Measurements of these lesions are not 
required, but the presence or absence of each should be noted throughout follow- 
up. 
 
13.2 Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations (CT, PET, superficial clinical lesion measurements) should be 
performed as closely as possible to the beginning of treatment and never more than 6 weeks 
before the beginning of the treatment.  A CT:CAP and PET should be performed at baseline, 
restaging, and at end of treatment.  Post treatment follow-up will be performed with CT 
scans.  A CT:Neck should be performed along with each scheduled CT:CAP if the patient 
has a history of disease in the neck. Tumor lesions that are situated in a previously irradiated 
area are considered measurable. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow- up.  Imaging-based evaluation 
is preferred to evaluation by clinical examination when both methods have been used to 
assess the antitumor effect of a treatment. 
 
13.2.1  Clinical lesions.  Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes).  In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended. 
 
13.2.2  Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable. 
 
13.2.3  Conventional CT and MRI.  These techniques should be performed with cuts of 
10 mm or less in slice thickness contiguously.  Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm.  This applies to tumors of the 
chest, abdomen, and pelvis.  Head and neck tumors and those of extremities 
usually require specific protocols. 
 
13.2.4  Ultrasound (US).  When the primary endpoint of the study is objective response 
evaluation, US should not be used to measure tumor lesions.  It is, however, a 
possible alternative to clinical measurements of superficial palpable lymph nodes, 
subcutaneous lesions, and thyroid nodules.  US might also be useful to confirm 
the complete disappearance of superficial lesions usually assessed by clinical 
examination. 


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13.2.5  Endoscopy, Laparoscopy.  The utilization of these techniques for objective 
tumor evaluation has not yet been fully and widely validated.  Their uses in this 
specific context require sophisticated equipment and a high level of expertise that 
may only be available in some centers.  Therefore, the utilization of such 
techniques for objective tumor response should be restricted to validation 
purposes in reference centers. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained. 
 
13.2.6  Tumor markers.  Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.  For patients with low- 
grade lymphomas, quantification and monitoring of any pre-existing monoclonal 
gammopathy (via serum protein electrophoresis) and Beta-2-microglobulin will 
be followed if there is an abnormal baseline value. 
 
13.2.7  Cytology, Histology.  These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions where known residual benign tumors can remain). 
 
13.2.7.1  The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate 
between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
13.3 Response Criteria 
 
13.3.1  Response Criteria for patients with NHL 
Response criteria are determined through evaluation of target lesions.  Response criteria 
for patients with NHL will follow the guidelines previously reported by Cheson et al., 
2007 (Cheson, Pfistner et al. 2007) and are described below.  The criteria for NHL are as 
follows (GTD = Greatest Transverse Diameter; SPD = Sum of the Products of the 
Greatest Diameter): 
 
13.3.1.1  Complete Remission (CR): 
  Disappearance of all evidence of disease. 
  No disease related symptoms. 
  Lymph nodes, nodal masses regressed to “normal” size: 
o If >1.5 cm before treatment, regressed to ≤ 1.5 cm in GTD. 
o If 1.1 to 1.5 cm before treatment, regressed to ≤ 1 cm in GTD (or >75% in 
SPD). If PET scan was positive before therapy, a post-treatment residual 
mass of any size is permitted as long as it is PET negative. PET is 
considered negative if target lesions all have uptake values below the level 
of average uptake in the liver. 


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  Spleen and all previously enlarged organs decreased to normal in size. 
  If the Bone marrow was involved prior to treatment, it is clear on repeat 
aspirate and biopsy at the same site. 
 
13.3.1.2  Partial Remission (PR): 
  ≥ 50% decrease in SPD of six largest dominant nodes/nodal masses. 
  No increase in size of other nodes, liver or spleen. 
  Splenic and hepatic nodes regressed at least 50% in SPD 
  No new sites of disease. 
  If the PET scan was positive before therapy, the post-treatment PET is 
positive in at least one previously involved site. 
  Patients who achieve a CR by the above criteria, but who have persistent bone 
marrow involvement (or those in whom pre-treatment bone marrow was 
involved and post-treatment bone marrow involvement was not assessed). 
 
13.3.1.3  Relapsed Disease (RD): 
  In patients previously CR : 
  New lesion > 1.5 cm in any axis 
  Size of previously involved site has increase ≥ 50% in GTD. 
  ≥ 50% increase in either: 
o GTD of any previously identified node that was >1 cm in its short axis, or 
o SPD of any node or other lesion. 
 
13.3.1.4  Stable Disease (SD): 
  Patients who have achieved less than a partial remission but who have not 
developed findings consistent with progressive disease. 
 
13.3.1.5  Progressive Disease (PD): 
  In patients previously PR or SD. 
  ≥ 50% increase from nadir or baseline in SPD or any node or lesion 
  ≥ 50% increase from nadir in GTD of any node previously >1cm in shortest 
diameter 
  Appearance of any new lesion during or at the end of therapy. 
 
13.3.1.6  Evaluation of non-target lesions 
 
13.3.1.6.1 
Complete Response (CR*): Disappearance of all non- 
target lesions and normalization of any tumor markers (i.e. 
IgM levels in WM).  Any post-treatment masses still 
present that were PET positive prior to treatment must be 
PET negative at the completion of therapy. 


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13.3.1.6.2 
Incomplete Response/Stable Disease (SD): Persistence of 
one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits 
 
13.3.1.6.3 
Progressive Disease (PD):  Appearance of one or more 
new lesions and/or unequivocal progression of existing 
non-target lesions 
 
***Although a clear progression of “non-target” lesions only is exceptional, 
in such circumstances the opinion of the treating physician should prevail, and 
the progression status should be confirmed at a later time by the review panel 
(or study chair).*** 
 
*Note:  If tumor markers (i.e. IgM levels in WM) are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete 
clinical response. 
 
13.3.2Response Criteria for patients with Waldenström’s Macroglobulinemia 
 
The response criteria used for patients with Waldenström’s Macroglobulinemia (WM) 
in this study are the criteria from the Forth International Workshop on Waldenström’s 
Macroglobulinemia (Dimopaulos, et al 2009).  These specific criteria are defined 
below: 
 
13.3.2.1  Complete Response (CR): 
  Disappearance of monoclonal protein by immunofixation. 
  No histologic evidence of bone marrow involvement. 
  Resolution of any adenopathy/organomegaly (confirmed by CT scan). 
  Resolution of any signs or symptoms attributable to WM. 
  Reconfirmation of the CR status is required at least 6 weeks apart with a 
second immunofixation. 
 
13.3.2.2  Partial Response (PR): 
  At least 50% reduction of serum monoclonal IgM concentration on protein 
electrophoresis. 
  At least 50% decrease in adenopathy/organomegaly on physical examination 
or on CT scan. 
  No new symptoms or signs of active disease. 
13.3.2.3  Minor Response (MR): 
  At least 25% but less than 50% reduction of serum monoclonal IgM by 
protein electrophoresis. 
  No new symptoms or signs of active disease. 


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13.3.2.4  Stable Disease (SD): 
  A less-than-25% reduction and less-than-25% increase of serum monoclonal 
IgM by electrophoresis without progression of adenopathy/organomegaly, 
cytopenias, or clinically significant symptoms due to disease and/or signs of 
WM. 
 
13.3.2.5  Progressive Disease (SD): 
  At least 25% increase in serum monoclonal IgM by protein electrophoresis 
confirmed by a second measurement or progression of clinically significant 
findings due to disease (ie, anemia, thrombocytopenia, leukopenia, bulky 
adenopathy/organomegaly) or symptoms (unexplained recurrent fever of at 
least 38.4°C, drenching night sweats, at least 10% body weight loss, or 
hyperviscosity, neuropathy, symptomatic cryoglobulinemia, or amyloidosis) 
attributable to WM. 
 
13.4 Evaluation of the best overall response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of their health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration.”  Every effort should be made to 
document objective progression, even after discontinuation of treatment. 


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In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
 
13.5  Duration of response 
 
13.5.1  Duration of overall response 
The duration of overall response is measured from the time measurement criteria 
are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented.  If stem cell transplant is planned after achieving CR, these patients 
will be censored at the time of beginning the preparative regimen for transplant. 
 
13.5.2  Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since 
the treatment started. 
 
13.5.3  Progression-Free Survival 
Mean and median durations of response, progression-free survival, event-free 
survival and overall survival will be calculated from the observed study durations. 
If the study evaluation is performed before all data have reached their respective 
end-points, right-censored data for all duration estimates will be treated as 
independent censoring and Kaplan-Meier survival estimates will be employed. 
Time-to-progression analyses will treat patient withdrawals and interventions for 
reasons other than progression or death as independent censoring. If stem cell 
transplant is planned after achieving a response, these patients will be censored at 
the time of beginning the preparative regimen for transplant. 
 
13.5.4  Time to progression is defined as the start of treatment to the first documented 
progression or death. 
 
13.5.5  Event free survival is defined as the time of enrollment to the first documented 
event, with events defined as: death, relapse, progressive disease, secondary 
malignancy, or toxicity attributed to therapy and requiring removal from study. 
 
13.5.6  Time to death is defined from of the start of treatment to the date of death. 


Memorial Sloan-Kettering Cancer Center 
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IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
14.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Termination of Treatment and/or Study Participation 
 
Patients must be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care.  The investigator also has the right to 
withdraw, and in some cases is required to withdraw patients from the study. 
 
The investigator or Millennium Pharmacovigilance may discontinue the clinical research 
study if they determine that the study or treatment offers little or no future benefit, or the 
supply of medication ceases to be available, or other causes prevent continuation of the 
clinical research study. If at any time the treating physician feels that continuing in the study 
is not beneficial for a given patient, or if a patient is unable to follow the treatment plan, 
treatment may be stopped. If there is progression of disease despite this therapy, it will be 
stopped.  If the investigator is in doubt as to whether progression has occurred, particularly 
with respect to non target lesions and the appearance of a new lesion, it is advisable to 
continue treatment for up to one additional cycle until formal evaluation of response has been 
completed. Every effort should be made to complete this evaluation before the end of the next 
cycle. 
 
15.0 
BIOSTATISTICS 
 
15.1  Study Design/Endpoints 
For the weekly schedule, the MTD doses of bortezomib (1.8 mg/m2) and cyclophosphamide 
(1000 mg/m2) will be brought forward to the phase II portion.  For the twice-weekly 
schedule, the 1.3 mg/m2 dose of bortezomib will be used.  Each treatment arm will be 
evaluated separately.  The study will employ a Simon two stage design in the analysis of the 
Phase II portion in each arm separately. For indolent lymphomas and MCL, a 60% response 
rate is considered promising, whereas, a 40% is considered not promising. Assuming Type I 
and Type II errors are 0.10 and 0.20 respectively, then 17 patients will be accrued to the first 
stage of each arm. If 7 or fewer patients in either treatment arm respond, no additional 
patients will be enrolled in that treatment arm and the regimen will be considered not 
promising in this cohort of patients. If 8 or more patients respond in either treatment arm, 
then an additional 13 patients (for a total of 30) will be enrolled in that arm. 
 
We will use the “pick the winner” format based on the randomized phase II clinical trials 
approach proposed by Simon et al.(Simon, Wittes et al. 1985).  If both regimens are 
efficacious without significant differences in toxicity, then we plan to pick the winner as 
follows:  If the number of patients who respond in one arm is at least 16 and it exceeds by at 
least 1 patient the number of responders in the other arm, then the arm with the higher 
response rate (RR) would be declared the winner. If neither arm had at least 16 responses, the 
regimens in both arms would be considered unworthy of further evaluation. No formal 
statistical comparison between the two arms is planned. 


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Amended: 07/25/12 
 
 
 
Upon completion of the trial, if objective responses are observed in 16 patients or more in 
either arm, this new regimen will be declared to have promising activity. Based on this two 
stage design, the probability of completing the trial and declaring the new regimen effective 
is 80% when the true response rate is at least 60% Although this sample size will not allow 
for statistical comparisons between arms, differences between the arms (such as toxicity or 
convenience, in addition to response) may generate hypotheses that can be tested in future 
studies. 
 
15.2  Sample Size/Accrual Rate 
Approximately 1 to 2 patients will be accrued per month. It is expected that the duration of the 
entire study should be approximately 30-60 months. 60 patients total will take part in Phase II of 
this study at Memorial Sloan-Kettering Cancer Center, The Cancer Institute of New Jersey, 
Robert Wood Johnson Medical School, Columbia University Medical Center, and the Winship 
Cancer Institute at Emory University. About 42 patients are expected to be treated at MSKCC; 
the remainder will be accrued by the subsites. 
 
15.3  Stratification Factors 
Patients will be randomized between the twice-weekly and weekly bortezomib treatment 
schedules at the time of enrollment. Each treatment arm will be analyzed independently from 
the other. As such, each treatment arm will accrue patients following the Simon two stage 
design. 
 
15.4  Analysis of Secondary Endpoints 
The following secondary endpoints will also be investigated in the phase II portion of 
the trial: 
 
15.4.1  Progression-free survival, mean and median durations of response, event-free 
survival, and overall survival will be calculated from the observed durations. The 
Kaplan-Meier curves will be generated. 
 
15.4.2  The primary safety endpoint is to determine toxicity based on NCI Common 
Terminology Criteria for Adverse Events version 4.0. The frequencies of 
toxicities will be tabulated for each arm separately. 
 
15.5  Reporting and Exclusions 
 
 
15.5.1  Evaluation of toxicity.  All patients will be assessable for toxicity from the time 
of their first treatment with bortezomib.  Patients who do not receive at least one 
dose of bortezomib will be excluded from this analysis and replaced. 
 
15.5.2  Evaluation of response. All patients who meet eligibility criteria and are 
included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  (1) complete response, (2) partial 


Memorial Sloan-Kettering Cancer Center 
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IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
response, (3) stable disease, (4) progressive disease, (5) early death from 
malignant disease, (6) early death from toxicity, (7) early death because of other 
cause, or (9) unknown (not assessable, insufficient data). 
 
15.5.3  An incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate. 
 
All conclusions should be based on all eligible patients except as outlined above.  Sub- 
analyses may then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.).  However, 
these sub-analyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported. The 95% confidence intervals should also be provided. 
 
16.0 
RESEARCH PARTICIPANT REGISTRATION PROCEDURES 
 
16.1 
Research Participant Registration 
 
Only individuals designated as consenting professionals on the facesheet of this protocol 
may obtain patient informed consent. 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject 
Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled “Informed 
Consent Procedures.” 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center.  PPR is available Monday through 
Friday from 8:30am - 5:30pm at (646) 735-8000. The PPR fax numbers are (646) 735- 
0008 and  (646) 735-0003.  Registrations can be phoned in or faxed by MSKCC staff 
only.  The completed signature page of the written consent/verbal script and a completed 
Eligibility Checklist must be faxed to PPR. 
 
Patient registration must be initiated at Memorial Sloan Kettering Cancer Center within 
48 hours of the patient signing the informed consent. 
 
 
 
16.1.1  For Participating Sites 
 
Central registration for this study will take place at Memorial Sloan Kettering Cancer 
Center (MSKCC). 


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IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
To complete registration and enroll a patient from another institution, the study staff at 
that site must contact the designated research staff at MSKCC to notify him/her of the 
participant registration. The site staff then needs to fax registration/eligibility 
documents to the Multicenter Trials Core at MSKCC at 646-227-2482. 
 
The following documents must be sent for each enrollment within 24 hours of the 
informed consent being signed: 
• The completed or partially completed MSKCC eligibility checklist 
• The signed informed consent and signed HIPAA Authorization form (Research 
Authorization) 
• Supporting source documentation for eligibility questions (laboratory results, 
pathology report, radiology reports, MD notes, Physical exam sheets, medical 
history, prior treatment records, and EKG report) 
 
Upon receipt, the research staff at MSKCC will conduct an interim review to confirm 
documents are received to complete registration. 
 
If the eligibility checklist is not complete, the patient will be registered PENDING and 
the site is responsible for sending a completed form within 30 days of the consent. 
 
If the eligibility checklist is complete, the patient meets all criteria, all source 
documentation is received, the participating site IRB has granted approval for the 
protocol, and the site is in good standing with MSKCC, the MSKCC research staff will 
send the completed registration documents to the MSKCC Protocol Participant 
Registration (PPR) Office to be enrolled as stated in section 16.1.  The participant will 
be registered. 
 
Once eligibility has been established and the participant is registered, the participant 
will be assigned an MSKCC Clinical Research Database (CRDB) number (protocol 
participant number).  This number is unique to the participant and must be written on 
all data and correspondence for the participant.  This protocol participant number will 
be relayed back to study staff at the registering site via e-mail and will serve as the 
enrollment confirmation. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Three copies of the MSKCC informed consent will be signed and dated by the patient or the 
patient’s legally authorized representative, and by the physician obtaining informed consent 
before drug will be administered. Physicians qualified to obtain informed consent are the 
Investigators listed on the cover page of the protocol. One copy will be given to the patient, one 
copy will be filed in the patient's medical record, and one copy will be retained in the Protocol 
Participant Registration Office, Office of Clinical Research. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
Risks in Relation to Anticipated Benefit:  All four drugs used in this protocol are active in B- 
cell lymphoproliferative disorders, and it is anticipated that the benefit derived from disease 
suppression will outweigh the risks of toxicity. 
 
Provisions for Adverse Events:  Anti-emetics will be prescribed to all patients in order to 
minimize nausea and vomiting.  Infections will be treated with appropriate antimicrobial therapy. 
Blood and platelet transfusions will be given as clinically indicated. 
 
Protocol Amendments and Study Termination:  All protocol amendments will be reviewed 
and approved by Millennium Pharmaceuticals, Inc. before they are submitted to the Institutional 
Review Board of Memorial Hospital for approval and implementation. 
 
Alternative Treatments:  Patients with B-cell lymphoproliferative disorders not treated on this 
protocol could be treated with a conventional approach, or offered participation in another study, 
as appropriate.  Many different chemotherapeutic regimens, radioimmunotherapies and stem cell 
transplant modalities have shown activity in these diseases. 
 
Incentives:  No incentives will be offered to patient/subjects for participation in this study. 
Participation is voluntary. 
 
Costs:  Most costs associated with the procedures specified in this protocol reflect those 
associated with the typical care provided to patients with B-cell lymphoproliferative disorders. 
Bortezomib will be provided free of charge, as will any other costs related to the protocol that are 
not considered standard of care.  The patient will be responsible for the costs of standard medical 
care, including complications of treatment. 
 
Eligibility Exceptions: There will be no exceptions to the eligibility requirements for this 
protocol without the authorization of the Institutional Review Board and the Privacy Board of 
Memorial Sloan-Kettering Cancer Center. 
 
17.1 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form.  The use and disclosure 
of protected health information will be limited to the individuals described in the Research 
Authorization form.  A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
 
 
 
17.2 
Serious Adverse Event (SAE) Reporting 
From the time the patient signs consent until he or she is 30 days post treatment, all SAEs 
must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. The 
IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org containing the following information: 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
Fields populated from the CRDB: 
• Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
 
17.3 Adverse events, regulatory and reporting requirements 
 
17.3.1 Definitions 
 
Adverse Event definition 
An adverse event (AE) is any untoward medical occurrence in a patient 
administered a pharmaceutical product, which does not necessarily have a causal 
relationship with the treatment.  An adverse event can be any unfavorable and 
unintended sign (eg, including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of the drug, whether or not it is 
considered to be drug related.  This includes any newly occurring event or 
previous condition that has increased in severity or frequency since the 
administration of drug. 
 
Serious Adverse Event definition 
 
A Serious Adverse (SAE) is any adverse event, occurring at any dose and 
regardless of causality that: 
 Results in death. 


Memorial Sloan-Kettering Cancer Center 
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Amended: 07/25/12 
 
 
 
 Is life-threatening.  Life-threatening means that the patient was at immediate 
risk of death from the reaction as it occurred, ie, it does not include a reaction 
which hypothetically might have caused death had it occurred in a more 
severe form. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospital admissions and/or surgical operations scheduled to occur during the 
study period but planned prior to study entry are not considered AEs if the 
illness or disease existed before the patient was enrolled in the trial, provided 
that it did not deteriorate in an unexpected manner during the trial (eg, 
surgery performed earlier than planned). 
 Results in persistent or significant disability/incapacity.  Disability is defined 
as a substantial disruption of a persons’ ability to conduct normal life 
functions. 
 Is a congenital anomaly/birth defect. 
 Is an important medical event.  An important medical event is an event that 
may not result in death, be life-threatening, or require hospitalization but may 
be considered an SAE when, based upon appropriate medical judgment, it 
may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definitions for 
SAEs.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Clarification should be made between the terms “serious” and “severe” since they are not 
synonymous.  The term “severe” is often used to describe the intensity (severity) of a 
specific event (as in mild, moderate, or severe myocardial infarction); the event itself, 
however, may be of relatively minor medical significance (such as a severe headache). 
This is not the same as “serious,” which is based on patient/event outcome or action 
criteria described above and are usually associated with events that pose a threat to a 
patient’s life or functioning.  A severe adverse event does not necessarily need to be 
considered serious.  For example, persistent nausea of several hours duration may be 
considered severe nausea but not an SAE.  On the other hand, a stroke resulting in only a 
minor degree of disability may be considered mild, but would be defined as an SAE 
based on the above noted criteria.  Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
 
17.3.2 Procedures for AE and SAE reporting 
 
17.3.2.1     It is the responsibility of the principal investigator and his/her research 
team to identify, review and report all necessary adverse events to the institutional 
IRB, Millennium Pharmacovigilance and governmental agencies (i.e., NCI and/or 
FDA) as appropriate. Adverse events should be identified through standard, 
routine protocol review and clinical assessment of each subject participating in the 


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clinical trial. This review should be timely in order to meet the requirements for 
adverse event reporting defined below. All unexpected or serious adverse events 
(SAE), regardless of the type of research study, phase or sponsor must be reported 
to the MSKCC IRB (see section 19.2). 
17.3.2.2 
All serious adverse events (SAEs) (regardless of expectedness, causality, and 
whether commercial or investigational bortezomib is used) must be reported to 
Millennium Pharmacovigilance.  See Section 19.3.5 for the reporting of SAEs. The 
sponsor-investigator is responsible to meet all regulations and requirements applicable to 
the sponsor-investigator. 
 
17.3.3 Millennium Reporting Guidelines 
Adverse events (AEs) may be spontaneously reported by the patient and/or in response to an open 
question from study personnel or revealed by observation, physical examination, or other diagnostic 
procedures.  AEs which are serious must be reported to Millennium Pharmacovigilance from first dose 
of bortezomib up to and including 30 days after administration of the last dose of bortezomib. 
 
When possible, signs and symptoms indicating a common underlying pathology should be noted as 
one comprehensive event. Any SAE that occurs at any time after completion of bortezomib treatment 
or after the designated follow-up period that the investigator and/or sub-investigator considers to be 
related to any study drug must be reported to the Millennium Pharmacovigilance. Planned hospital 
admissions or surgical procedures for an illness or disease that existed before the patient was enrolled 
in the trial are not to be considered AEs unless the condition deteriorated in an unexpected manner 
during the trial (e.g., surgery was performed earlier or later than planned). All SAEs should be 
monitored until they are resolved or are clearly determined to be due to a patient’s stable or chronic 
condition or intercurrent illness(es). 
 
This is an investigator-initiated study.  The principal investigator, Dr. John Gerecitano, MD, PhD, 
(who may also sometimes be referred to as the sponsor-investigator), is conducting the study and 
acting as the sponsor. Therefore, the legal/ethical obligations of the principal investigator include both 
those of a sponsor and those of an investigator. 
Sponsor-investigator must report all SAEs, regardless of expectedness or relationship with any study 
drug, to Millennium Pharmacovigilance as soon as possible, but no later than 5 calendar days of the 
sponsor-investigator’s observation or awareness of the event.   For external sites, the sponsor- 
investigator is responsible to ensure that the SAE reports are sent to Millennium Pharmacovigilance 
from all sites participating in the study. Subinvestigators must report all SAEs to the sponsor- 
investigator so that the sponsor-investigator can meet his/her foregoing reporting obligations to 
Millennium Pharmacovigilance, unless otherwise agreed between the sponsor-investigator and 
subinvestigator(s). Millennium Pharmacovigilance may request follow-up information to a reported 
SAE, which the sponsor-investigator will be responsible for providing to Millennium 
Pharmacovigilance. 
 
The SAE report must include event term(s), serious criteria, and the sponsor-investigator’s or sub- 
investigator’s determination of both the intensity of the event(s) and the relationship of the event(s) to 
study drug administration. 
 
Intensity for each SAE, including any lab abnormality, will be determined by using the NCI CTCAE, 
version 4.0, as a guideline, whenever possible. The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 


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Amended: 07/25/12 
 
 
 
 
Relationship to all study drugs for each SAE will be determined by the sponsor-investigator or sub- 
investigator by responding yes or no to the question: Is there a reasonable possibility that the AE is 
associated with the study drug(s)? 
 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study or study drug(s), including, 
but not limited to, telephone conversation logs, as soon as possible but no later than 5 calendar days of 
such communication. 
 
 
 
Millennium Pharmacovigilance 
SAE and Pregnancy Reporting Contact Information: 
North America 
PPD, Inc. 
Safety and Medical Management, US 
Fax:  +1 888-488-9697 
Hotline number (available 24/7):  1-800-201-8725 
 
Millennium Pharmaceuticals will send to the sponsor-investigator VELCADE safety letters (real-time 
safety letters and/or the quarterly safety updates). All safety letters pertaining to the VELCADE 
program will be sent to the Investigator-Sponsor via an electronic distribution using Mercury, the 
Millennium Secure File Transfer (MFT) system. For each safety letter distributed, Sponsor- 
Investigator will receive an e-mail inviting to download the Adobe/PDF document from Mercury. 
 
To meet GCP requirements, Millennium is required to send Sponsor-Investigators the safety letters 
within 15 days after the world-wide receipt date of the safety event.  Sponsor-Investigators 
responsibility is to read the safety letter, and provide the safety letter to the Institutional Review Board 
or Ethics Committee per institution’s policy. Sponsor-investigator will be responsible for forwarding 
such reports to any sub-investigator(s). 
 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and must permanently discontinue study drug(s). All 
pregnancies and suspected pregnancies must be reported to Millennium Pharmacovigilance 
immediately.  The pregnancy must be followed for the final pregnancy outcome (ie, delivery, still 
birth, miscarriage) and Millennium Pharmacovigilance will request this information from the sponsor- 
investigator. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in this 
study, this must be reported to Millennium Pharmacovigilance immediately.  Every effort should be 
made to follow the pregnancy for the final pregnancy outcome 


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Amended: 07/25/12 
 
 
 
17.3.4 Serious Adverse Event (SAE) Reporting for Participating Sites 
 
Responsibility of Participating Sites 
• Participating sites are responsible for reporting all SAEs to the MSKCC PI via fax or e- 
mail within 3 calendar days of learning of the event. 
• Participating sites should notify the MSKCC PI of any grade 5 event immediately 
• Participating sites should use the SAE Report Template (Appendix A) to report SAEs to 
MSKCC. 
 
SAE contact information for the Coordinating Center is listed below: 
Multicenter Trials Core 
Study Coordinator 
e-Fax: 646-227-2482 
 
Responsibility of MSKCC 
• The MSKCC Research Staff is responsible for submitting all SAEs to the MSKCC 
IRB/PB as specified in 19.2 (and to the funding entity as described in 19.3.3) 
• The MSKCC PI is responsible for informing all participating sites about unexpected 
SAEs as they occur within 30 days of receiving the stamped SAE from the MSKCC 
IRB/PB. 
• Any report pertaining to a grade 5 event will be distributed to the participating sites as 
soon as possible 
 
17.4 Safety Reports 
• MSKCC will distribute outside safety reports to the participating sites 
immediately upon receipt. 
• MSKCC must submit safety reports to the MSKCC IRB/PB according to 
institutional guidelines. 
• Participating sites must submit safety reports to their institution’s IRBs within 30 
days of receipt from MSKCC or per participating site guidelines. 
 
17.5 
Monitoring of adverse events and period of observation 
Adverse events, both serious and non-serious, and deaths that occur during the patient’s 
study participation will be recorded in the source documents.  All SAEs should be 
monitored until they are resolved or are clearly determined to be due to a patient’s stable 
or chronic condition or intercurrent illness(es). 
 
17.6 
Procedures for reporting drug exposure during pregnancy and birth events 
If a woman becomes pregnant or suspects she is pregnant while participating in this 
study, she must inform her treating physician immediately and permanently discontinue 
drug. Millennium Pharmaceuticals, Inc. must also be contacted immediately by faxing a 
completed pregnancy form to either millennium product safety for North America or 
PRA safety management services for Europe.  The pregnancy must be followed through 
delivery for SAEs. 


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17.7 
Inclusion of Children in Research 
This protocol/project does not include children because the number of children is limited 
and because the majority are already accessed by a nationwide pediatric cancer research 
network.  This statement is based on exclusion 4b of the NIH Policy and Guidelines on 
the Inclusion of Children as Participants in Research Involving Human Subjects. 
 
18.0 
DATA  MANAGEMENT ISSUES 
 
18.1 Data Management 
 
Data 
Standardized Case Report Forms (CRFs), directions for use and sign off requirements 
have been generated for this study. Blank case report forms will be sent to the study staff 
at each participating site for use. The participating Site PI is responsible for ensuring 
these forms are completed accurately, legibly and in a timely manner. 
 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should be 
consistent with data entered into CRFs. Relevant source documentation to be submitted 
throughout the study includes: 
o Baseline measures to assess pre–protocol disease status (ex. CT, bone marrow) 
o Treatment records 
o Grade 3-5 toxicities/adverse events not previously submitted with SAE Reports 
o Response designation 
 
Data and Source Documentation Submission for Participating Sites 
Participating sites should fax CRFs and source documentation to MSKCC to the contact 
provided below. Submissions should include a cover page listing all CRFs enclosed per 
participant. 
 
FAX to the attention of: 
Multicenter Trials Core 
e-Fax: 646-227-2482 
 
Data Review and Queries for Participating Site Data 
 
Data and source documentation to support data should be transmitted to MSKCC according to 
chart below. Research staff at MSKCC will review data and source documentation as it is 
submitted. Data will be monitored against source documentation and discrepancies will be sent 
as queries to the participating sites. Queries will be sent by MSKCC Research staff twice a 
month. 
Participating sites should respond to data queries within 14 days of receipt. 


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Amended: 07/25/12 
 
 
 
Data and Source Submission Requirements and Timelines for Therapeutic Studies 
 
 
Baseline 
Cycle 
1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
SAE 
Off Study 
SUBMISSION SCHEDULE 
Source Documentation 
Within 24 hours 
within 14 days of end of cycle 
(until Cycle 8 if needed) 
Within 3 days of event; 
updates to be submitted 
as available 
Within 
14 days 
of visit 
CRFs 
Within 7 days of 
visit 
Required Forms 
Demographics Form 
X 
Medical History Form 
X 
Concomitant 
Medications 
Form 
X 
X 
X 
X 
X 
X 
Physical Exam Form 
X 
X 
X 
X 
X 
X 
Treatment Form 
X 
X 
X 
X 
X 
Laboratory Form 
X 
X 
X 
X 
X 
X 
Lesion/EOD Form 
X1 
X 
Adverse Event Form 
X 
X 
X 
X 
X 
X 
Serious Adverse Event 
Form 
X 
Off Study Form 
X 
 
 
 
 
 
1Lesion/EOD form should be provided after 4 cycles, and every restaging point thereafter. 


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18.2 Quality Assurance 
Registration reports will be generated to monitor patient accruals and completeness of 
registration data.  Routine data quality reports will be generated to assess missing data and 
inconsistencies.  Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of once a year or more frequently if indicated. 
 
18.2.1 Quality Assurance for Participating Sites 
 
Each site participating in the accrual of participants to this protocol will be audited by the 
staff of the MSKCC study team for protocol and regulatory compliance, data verification 
and source documentation.  Audits may be accomplished in one of two ways: (1) selected 
participant records can be audited on-site at participating sites or (2) source documents 
for selected participants will be sent to MSKCC for audit. Audits will usually be 
determined by participant accrual numbers and rate of accrual, but can also be prompted 
by reported SAEs or request of MSKCC PI. 
 
Audits will be conducted at least once shortly after initiation of participant recruitment at 
a site, annually during the study (or more frequently if indicated), and at the end or 
closeout of the trial. The number of participants audited will be determined by available 
time and the complexity of the protocol. 
 
The audit will include a review of source documentation to evaluate compliance for: 
 
• Informed consent documents and procedures 
• Adherence to eligibility criteria 
• Protocol defined treatment 
• Required baseline, on study and follow-up protocol testing 
• IRB documents (submitted amendments, annual continuing review reports, SAEs) 
• Required specimen submission 
• Pharmacy review, if applicable 
• Case Report Form submissions to MSKCC: timing and accuracy 
 
A wrap-up session will be conducted at the participating site and preliminary findings 
will be discussed with the participating site PI and research team. The preliminary results 
will be sent to the MSKCC PI. 
 
Each audit will be summarized and a final report will be sent to the PI at the audited 
participating site within 30 days of the audit. The report will include a summary of 
findings, participant by participant case review, specific recommendations on any 
performance and/or shortcomings and request for corrective action, when necessary. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
When corrective action is required, the participating site must reply within 45 days of 
receipt of audit report with their corrective action plan. 
 
A copy of the audit report and corrective action plan (if applicable) submitted by the 
participating site must be sent to the MSKCC IRB/PB, CRQA and maintained in the 
department’s protocol regulatory binder. 
 
18.2.2  Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer 
Center were approved by the National Cancer Institute in September 2001.  The plans 
address the new policies set forth by the NCI in the document entitled “Policy of the 
National Cancer Institute for Data and Safety Monitoring of Clinical Trials” which can be 
found at:  http://cancertrials.nci.nih.gov/researchers/dsm/index.html.   The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research.  The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality.  There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for monitoring the 
activities of our clinical trials programs.  The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required.  Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) Will 
be addressed and the monitoring procedures will be established at the time of protocol 
activation. 
 
18.2.3  Response Review 
 
Since therapeutic efficacy is a stated primary objective, all sites patient’s responses are 
subject to review by MSKCC’s Therapeutic Response Review Committee (TRRC). 
Radiology, additional lab reports and possibly bone marrow biopsies and/or aspirates 
will need to be obtained from the participating sites for MSKCC TRRC review and 
confirmation of response assessment. These materials must be sent to MSKCC promptly 
upon request. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
18.3 Regulatory Documentation 
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be 
approved by the MSKCC Institutional Review Board/Privacy Board (IRB/PB). Prior to 
implementing this protocol at the participating sites, approval for the MSKCC IRB/PB 
approved protocol must be obtained from the participating site’s IRB. 
 
The following documents must be provided to MSKCC before the participating site can 
be initiated and begin enrolling participants: 
 
• Participating Site IRB approval(s) for the protocol, appendices, informed consent 
form and HIPAA authorization 
• Participating Site IRB approved consent form 
• Participating Site IRB membership list 
• Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 
• Curriculum vitae and medical license for each investigator and consenting 
professional 
• Documentation of Human Subject Research Certification training for investigators 
and key staff members at the Participating Site 
• Participating site laboratory certifications and normals 
 
Upon receipt of the required documents, MSKCC will formally contact the site and grant 
permission to proceed with enrollment. 
 
18.4 Amendments 
 
Each change to the protocol document must be organized and documented by MSKCC 
and first approved by the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, 
MSKCC will immediately distribute amendments to the participating sites, for 
submission to their local IRBs. 
 
Participating sites must obtain approval for all non expedited amendments from their IRB 
within 90 calendar days of MSKCC IRB/PB approval. If the amendment is the result of a 
safety issue, sites will not be permitted to continuing enrolling new participants until the 
participating site IRB approval has been granted. 
 
The following documents must be provided to MSKCC for each amendment within 
the stated timelines: 
• 
Participating Site IRB approval 
• 
Participating Site IRB approved informed consent form and HIPAA  authorization 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
18.5 Additional IRB Correspondence 
 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most 
current approved version of the informed consent form should be submitted to MSKCC 
within 7 days of expiration. Failure to submit the re-approval in the stated timeline will 
result in suspension of study activities. 
 
Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant 
who does not meet all the eligibility criteria, pretreatment evaluation, or who requires 
alteration in their study plan. If a deviation from this protocol is proposed for a potential 
or existing participant at MSKCC or a participating site, approval from the MSKCC 
IRB/PB is required prior to the action. Participating sites should contact the MSKCC PI 
who will in turn seek approval from the MSKCC IRB/PB. 
 
A protocol violation is anything that occurs with a participant, which deviated from the 
protocol without prior approval from the MSKCC IRB/PB. For protocol violations that 
are identified after they occur, the participating site should report to MSKCC as soon as 
possible. The MSKCC PI will in turn report the violation to the MSKCC IRB/PB. 
 
Participating sites should report deviations and violations to their institution’s IRBs as 
soon as possible per that site’s institutional guidelines. Approvals/acknowledgments from 
the participating site IRB for protocol deviations and violations should be submitted to 
MSKCC as received. 
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB 
according to local guidelines, and submit copies of that correspondence to MSKCC. 
 
Document maintenance 
The MSKCC PI and the Participating Site PI will maintain adequate and accurate records 
to enable the implementation of the protocol to be fully documented and the data to be 
subsequently verified. 
 
The participating sites will ensure that all participating site IRB correspondence (IRB 
approval letters referencing protocol version date and amendment number, IRB approved 
protocol, appendices, informed consent forms, deviations, violations, and approval of 
continuing reviews) is maintained in the regulatory binder on site and sent to MSKCC. 
 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be 
paper or electronic. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
After study closure, the participating site will maintain all source documents, study 
related documents and CRFs for 7 years. 
 
18.6 Noncompliance 
 
If a participating site is noncompliant with the data and regulatory requirements set forth 
in section 18.0-18.2, accrual privileges may be suspended and/or contract payments may 
be withheld (if applicable), until the outstanding issues have been resolved. 
 
 
 
19.0 
RANDOMIZATION 
 
19.1 
Randomization for MSKCC 
Patients will be randomized to a treatment schedule with bortezomib given on a weekly 
(Arm A) vs. twice-weekly (Arm B) schedule. After eligibility is established and 
immediately after consent is obtained, patients will be registered in the Protocol Patient 
Registrar (PPR) system and randomized using the Clinical Research Database (CRDB). 
To register and randomize, MSKCC staff will call PPR at (646) 735-8000 between the 
hours of 8:30 am and 5:30 pm, Monday – Friday. Randomization will be accomplished 
by the method of random permuted block. 
 
 
 
19.2 
Randomization for Non-MSKCC Participating Sites 
Randomization to a treatment schedule with bortezomib given on a weekly (Arm A) vs. 
twice-weekly (Arm B) schedule for this study will take place at Memorial Sloan 
Kettering Cancer Center (MSKCC) immediately following registration.  Protocol Patient 
Registrar (PPR) system should only be contacted by MSKCC research staff, and 
randomization results will be promptly reported to the participating site staff by MSKCC 
research staff via e-mail, along with the patient registration number. 
 
20.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
 
1.   The nature and objectives, potential risks and benefits of the intended study. 
2.   The length of study and the likely follow-up required. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
3.   Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4.   The name of the investigator(s) responsible for the protocol. 
5.   The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
20.1For Participating Sites 
The investigators listed on the protocol cover page and their qualified designees at each 
participating site may obtain informed consent and care for the participants according to 
good clinical practice and protocol guidelines. 
 
Signed copies of the informed consent should be distributed as follows: One copy will be 
given to the participant to be retained for their personal records. One copy will be 
maintained on file at the MSKCC. The third copy will be confidentially maintained by 
the participating institution. 
 
A note will be placed in the medical record documenting that informed consent was 
obtained for this study, and that the participant acknowledges the risk of participation. 
 
21.0 
CORRELATIVE STUDIES 
 
 
 
21.1 Tissue Microarray: Pretreatment paraffin-embedded histologic samples will be obtained 
from all MSKCC patients, when possible. TMA blocks will be subjected to 
immunohistochemical staining targeting cell markers that will give insight into biological 
features predicted to relate to prognosis or response to treatment. TMA staining will be 
correlated with treatment outcome in each patient. We will then look for trends that 
would suggest baseline biological characteristics that correlate with ultimate response to 
bortezomib treatment. This correlative study will not require the harvesting of any 
additional tissue samples from the patients enrolled. Participating outside sites will not be 
asked to partake in these correlative studies. 
 
21.2 DNA Sequencing, real-time PCR, and Gene Expression Studies: Funding is being 
sought for genetic studies.  Once funding is obtained the informed consent will be revised 
to request patient permission for fine needle aspirate.  DNA and RNA will be isolated 
from FNA samples collected from consenting patients to understand the roles of specific 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
genes in disease pathogenesis and response to the treatment protocol. Genomic DNA will 
be subjected to sequencing to detect mutations and loss of heterozygosity, and to real- 
time PCR to detect gene amplifications and deletions. RNA will be used to generate 
cDNA through RT-PCR for analysis of gene expression. Samples for these studies will 
require additional FNA procedures but will not require any additional biopsy procedures 
than what’s outlined in the other sections. Patients who participate will undergo 2 FNA 
procedures. Both will be Research Non-Billable and funded by Geoffrey A. Beene 
Cancer Center Grant and start-up funds from Sloan Kettering Institute. This optional 
correlative study will only be open to follicular lymphoma patients. Participating outside 
sites will not be asked to partake in these correlative studies. 
 
22.0 
ADMINISTRATIVE REQUIREMENTS 
 
22.1 Good Clinical Practice 
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory 
requirement(s).  The sponsor-investigator will be thoroughly familiar with the appropriate 
use of the drug as described in the protocol and Investigator’s Brochure.  Essential 
clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected.  Master files should be established at the beginning of the 
study, maintained for the duration of the study and retained according to the appropriate 
regulations. This is the responsibility of the sponsor-investigator. 
 
22.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki.  The IRB/IEC will review all appropriate study documentation in 
order to safeguard the rights, safety and well-being of the patients.  The study will only 
be conducted at sites where IRB/IEC approval has been obtained.  The protocol, 
Investigator’s Brochure, informed consent, advertisements (if applicable), written 
information given to the patients (including diary cards), safety updates, annual progress 
reports, and any revisions to these documents will be provided to the IRB/IEC by the 
investigator.  Millennium requests that the protocol and informed consent documents be 
reviewed by Millennium prior to IRB/IEC submission. 
 
22.3 Patient Information and Informed Consent 
The principles of informed consent are described by Federal Regulatory Guidelines 
(Federal Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for 
Protection from Research Risk Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR46).  They must be followed to comply with FDA regulations for the 
conduct and monitoring of clinical investigations. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
22.4 Institutional Review 
This study must be approved by an appropriate institutional review committee as defined 
by Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, 17, January 27, 1981, 
part 56) and the Office for Protection from Research Risks Reports:  Protection of Human 
Subjects (Code of Federal Regulations 45 CFR 46). 
 
 
 
22.5 Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, 
study reports and communications will identify the patient by initials and the assigned 
patient number.  The sponsor-investigator will grant monitor(s) and auditor(s) from 
Millennium and regulatory authority(ies) access to the patient’s original medical records 
for verification of data gathered on the data capture records and to audit the data 
collection process.  The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations. 
 
22.6 Protocol Compliance 
The sponsor-investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies). 
Changes to the protocol will require approval from Millennium and written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is 
needed to eliminate an immediate hazard(s) to patients.  The IRB/IEC may provide, if 
applicable regulatory authority(ies) permit, expedited review and approval/favorable 
opinion for minor change(s) in ongoing studies that have the approval /favorable opinion 
of the IRB/IEC.  The sponsor-investigator will submit all protocol modifications to 
Millennium and the regulatory authority(ies) in accordance with the governing 
regulations. Any departures from the protocol must be fully documented in the source 
documents. 
 
22. 7On-site Audits 
Regulatory authorities, the IEC/IRB and/or Millennium may request access to all source 
documents, data capture records, and other study documentation for on-site audit or 
inspection.  Direct access to these documents must be guaranteed by the investigator, 
who must provide support at all times for these activities. 
 
22.8 Drug Accountability 
Accountability for the drug at all study sites (including all subsites, if applicable) is the 
responsibility of the sponsor-investigator.  The sponsor-investigator will ensure that the 
drug is used only in accordance with this protocol.  Drug accountability records 
indicating the drug’s delivery date to the site (if applicable), inventory at the site (if 
applicable), use by each patient, and return to Millennium will be maintained by the site 
and/or subsites.  Accountability records will include drug receipt, quantities, lot numbers, 
expiration dates (if applicable), and corresponding registered patient numbers. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
Any unused or expired commercially labeled bortezomib must be returned to 
Millennium.  Bortezomib destruction at any study site is not allowed for commercially 
labeled product that is associated with this Investigator Initiated Study. 
 
All material containing bortezomib will be treated and disposed of as hazardous waste in 
accordance with governing regulations. 
 
22.9 Premature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the sponsor-investigator or 
Millennium, there is sufficient reasonable cause.  Written notification documenting the 
reason for study termination will be provided to the sponsor-investigator or Millennium 
by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient complete and/or evaluable data 
• Plans to modify, suspend or discontinue the development of the drug 
 
22.10 Record Retention 
The sponsor-investigator will maintain all study records according to ICH-GCP and 
applicable regulatory requirement(s). 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
23.0 
APPENDICES 
 
APPENDIX A: SAE Template (attached as a separate protocol document) 
 
APPENDIX B: Karnofsky Performance Status Scale 
 
The following table presents the Karnofsky performance status scale: 
 
 
 
Points 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or to do active work 
60 
Requires occasional assistance but is able to care for most of his/her needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization indicated.  Death not imminent 
20 
Very sick; hospitalization necessary; active support treatment necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
Sources: Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky Performance Status Scale: an examination 
of its reliability and validity in a research setting. Cancer 1984;53:2002-2007. 
Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the palliative treatment 
of cancer. Cancer1948; 1(4):634-656. 
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM, ed. 
Evaluation of Chemotherapeutic Agents. New York: Columbia University Press, 1949, I9 1-205. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
Amended: 07/25/12 
 
 
 
APPENDIX C: Body Surface Area and Creatinine Clearance Calculations 
 
 
 
Body surface area (BSA) should be calculated using a standard nomogram that yields the 
following results in meters squared (m2): 
 
 
BSA = 
Ht(inches) ×Wt(lbs) 
3131 
 
or 
 
 
BSA = 
 
 
Ht (cm) × Wt(kg ) 
3600 
 
 
 
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as follows: 
CrCl (ml/min) = (140-age) (actual wt in kg) 
72 x serum creatinine (mg/dl) 
For females use 85% of calculated CrCl value. 
Note: In markedly obese patients, the Cockroft-Gault formula will tend to overestimate 
the creatinine clearance. (Adipose tissue tends to contribute little creatinine requiring 
renal clearance.) 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14)
APPENDIX D: NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION OF 
 
 
CARDIAC DISEASE 
 
The following table presents the NYHA classification of cardiac disease: 
 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal 
syndrome may be present even at rest. If any physical activity is undertaken, 
discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & 
Co; 1994:253-256. 
 
 
 
 
APPENDIX E: Common Terminology Criteria for Adverse Events Version 4.0 
 
http://ctep.cancer.gov/reporting/ctc.html 


Amended: 07/25/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14) 
 
 
 
APPENDIX F: FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14)
 
- -- ----
 
 
NEUROTOXICIT.Y ASSESSMENT TOOL 
 
 
Patient Name -- - - - -- - -- - - - - -- - - - 
Visit  Date -   ----
-- 
 
Instructions for Patientsu 
By circling one (1) number per line,please indicate how true each statement has been for you during the past 7 days. 
- 
 
 
Ihave numbness or tingling in my hands 
Not at all   A little bit 
 
0 
2 
ite a bit  Very much 
 
3 
4 
-----4-----+-------+-- 
1 have numb ness or tingling in my feet  
0 
 
Ifeel di scomfort in my  hands  
0 
 
1 feel discom fort in my feet  
0 
2 
3 
4 
 
2 
3 
4 
- 
2 
3 
4 
--------------+------- 
I have joint pain or muscl e cramps 
0 
 
Ifeel weak all over  
0 
 
0 
 
0 
 
0 
 
0 
 
0 
2 
3 
4 
 
3 
4 
 
3 
4 
 
3 
4 
 
3 
4 
 
2 
3 
4 
 
2 
3 
4 
 
Instructions for Health Care Professionals 
This asse ssment tool is provided to help you eval uate peripheral neuropathy in patients receiving chemotherapy. 
Health c re professionals may find discussion of patient responses helpful in determining the grade of neuropathy 
as defined by the NCI CommonToxicity Criteria listed below;there is no direct correlation between assessment 
scores and toxicity grades. 
 
NCI Common Toxicity Criteria for Peripheral  Neuropathy and Neuropathic Pain 
3
 
PeripheralSensory Neuropathy 1(NCIC T C Grade) 
1  Normal 
2  Loss of deep tendon reflexes or paresthesia but not interfering with function 
3  Objective sensory loss or paresthesia, interfering with function,but not with ADLs 
(Activities of Daily Living) 
4  Sensoryloss or paresthesia interfering with ADLs 
5 Permanent sensory loss that interferes with function 
 
Neuropathic Pain (N CIC T C Grade} 
0  None 
1 Mild pain not interfering with function 
2 Moderate pain:pain or analgesics interfering with function, but not ADLs 
3  Severe pain:pain or analgesics severely interfering with ADLs 
4  Disabling 
 
Ref er eo ees :1. Cela O F,Tu blty O S, Gr oy G,S ero lien 8 ,llo y d  S .U M E . et a l Th elu n c...,alass eu m en to f  can cer  th o <apy iFA tTlsc al e d...lop lnen lan tlv alitlao o n of the g en eral.,.•sure. 
J Clin Oncoi1!193;111Jl:5/0on.2. 'ltoun EA . F tsllman A. Roland  PY.lur u il JR. Ch lnf ll CH· , Ita  0 VtoidiV alld stlt eliv t stWoJVily ot1M FACT /GDG·Nt.. Absltactll!il.3 6 lh A nn u al Meetin g 
of m.A mer ican S o ciety of  Cfi<1 cal Oncology ,Ma y2000 , Ntw O eo n s,lA 3. No tion al Can etr  mstr tu te Cln cer  Tb tr ap y Enluanon Pro g  HCommon l01t1Coly Cro ..,ia,V ersio n 2 .0. June1 999 . 
 
MillENNIUM' 
NV0085 
 
 
 
rpf Amended: 07/25/12 
8/03_) 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14)
Amended: 07/25/12 
 
 
To Be Completed By Nurse 
Date 
Cycle Number 
Day Number 
Previous Site of Injection (#) 
Today’s Site of Injection (#) 
 
APPENDIX H: BORTEZOMIB INJECTION SITE TOOL 
 
Bortezomib S for IRB #05-103: A Phase II Study of the Novel Proteasome Inhibitor 
Bortezomib in Combination with Rituximab, Cyclophosphamide and Prednisone in 
Patients with Relapsed/Refractory Indolent B-Cell Lymphoproliferative Disorders and 
Mantle Cell Lymphoma (MCL) 
 
 
 
Instructions (Per Protocol section 4.1.2):  Bortezomib will be administered as a subcutaneous 
(SC) injection administered at a concentration of 2.5 mg/mL normal [0.9%] saline. SC injection 
sites are the thighs or abdomen. Injection sites will be rotated for subsequent injections within a 
cycle (see figure below). 
 
 
 
RN Signature:   
 
Date:_  
 
 
 
Comments:  
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-103 A(14)
Amended: 07/25/12 
 
 
 
24.0 
REFERENCES 
 
 
Adams, J., V. J. Palombella, et al. (1999). "Proteasome inhibition: a new strategy in cancer 
treatment." Invest New Drugs 18(2): 109-21. 
 
 
Aghajanian, C., S. Soignet, et al. (2002). "A phase I trial of the novel proteasome inhibitor 
PS341 in advanced solid tumor malignancies." Clin Cancer Res 8(8): 2505-11. 
 
 
Beg, A. A. and D. Baltimore (1996). "An essential role for NF-kappaB in preventing TNF-alpha- 
induced cell death." Science 274(5288): 782-4. 
 
 
Belch, A., C. T. Kouroukis, et al. (2004). "Phase II Trial of Bortezomib in Mantle Cell 
Lymphoma." Blood 104(11): Abstract #608. 
 
 
Cheson, B. D., B. Pfistner, et al. (2007). "Revised Response Criteria for Malignant Lymphoma." 
J Clin Oncol 25(5): 579-586. 
 
 
Cunningham, D., J. R. Zalcberg, et al. (1996). "Final results of a randomised trial comparing 
'Tomudex' (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. 
"Tomudex" Colorectal Cancer Study Group." Ann Oncol 7(9): 961-5. 
 
 
Cusack, J. C., Jr., R. Liu, et al. (2001). "Enhanced chemosensitivity to CPT-11 with proteasome 
inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition." Cancer Res 61(9): 
3535-40. 
 
 
De Vos, S., W. H. McBride, et al. (2004). "Active combination therapy of Bortezomib and 
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Amended: 07/25/12 
 
 
 
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Memorial Sloan-Kettering Cancer Center 
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IRB#: 05-103 A(14)
Amended: 07/25/12 
 
 
 
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Memorial Sloan-Kettering Cancer Center 
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IRB#: 05-103 A(14)
Amended: 07/25/12 
 
 
 
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