Conditions: Mantle Cell Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 487
Healthy volunteers: no

Brief summary:
This is a randomized, open-label, multicenter, prospective study to compare the efficacy and safety of the combination of VcR-CAP to that of R-CHOP in participants who have newly diagnosed mantle cell lymphoma grade II, III or IV and who are ineligible to undergo bone marrow transplantation.

Detailed description:
The drug being tested in this study were combination of VcR-CAP and R-CHOP. Combination of VcR-CAP and R-CHOP is being tested to treat people who had mantle cell lymphoma (MCL).

The study enrolled 487 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in a 1:1 ratio:

Treatment Group A (VcR-CAP) Treatment Group B (R-CHOP)

The study included a screening phase, a treatment phase, a short-term follow-up phase, and a long-term follow-up phase. The screening phase was up to 28 days (56 days for bone marrow evaluation) prior to randomization.

This multi-center trial was conducted worldwide. The total study duration from randomization of the first patient until the last progression-free survival (PFS) event required for the final analysis was expected to be approximately 42 months (24 months for enrollment and 18 months for follow-up) and survival follow-up every 12 weeks until death.

Arms:
arm 1: Rituximab 375 mg/m\^2, Cyclophosphamide 750 mg/m\^2, Doxorubicin 50 mg/m\^2, Vincristine 1.4 mg/m\^2, and Prednisone 100 mg/m\^2 arm 2: Rituximab 375 mg/m\^2, Cyclophosphamide 750 mg/m\^2, Doxorubicin 50 mg/m\^2, VELCADE 1.3 mg/m\^2, and Prednisone 100 mg/m\^2

Interventions: intervention 1: Rituximab 375 mg/m^2 intervention 2: Cyclophosphamide 750 mg/m^2 intervention 3: Doxorubicin 50 mg/m^2 intervention 4: VELCADE 1.3 mg/m^2 intervention 5: Prednisone 100 mg/m^2 intervention 6: Vincristine 1.4 mg/m^2
Intervention descriptions: intervention 1: Intravenous rituximab 375 mg/m\^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles. intervention 2: Intravenous cyclophosphamide 750 mg/m\^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles intervention 3: Intravenous doxorubicin 50 mg/m\^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles intervention 4: Intravenous VELCADE 1.3 mg/m\^2 on Days 1,4,8, and 11of a 21-day (3 week) cycle for 6 cycles intervention 5: Oral prednisone 100 mg/m\^2 on Day 1 to Day 5 of a 21-day (3 week) cycle for 6 cycles intervention 6: Intravenous vincristine 1.4 mg/m\^2 on Day 1of a 21-day (3 week) cycle for 6 cycles. Maximum of 2 mg. Participants could receive 8 cycles if a response was initially documented at the Cycle 6 assessment.

Protocol document:
Prot_001.pdf: 
FINAL – 3 February 2014
1
Janssen Research & Development*
Millennium Pharmaceuticals, Inc.
Clinical Protocol
A Randomised, Open-Label, Multicentre Phase 3 Study of the Combination of 
Rituximab, Cyclophosphamide, Doxorubicin, VELCADE, and Prednisone 
(VcR-CAP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and 
Prednisone (R-CHOP) in Patients With Newly Diagnosed Mantle Cell 
Lymphoma who are not Eligible for a Bone Marrow Transplant
Protocol 26866138-LYM-3002; Phase 3
JNJ-26866138 (VELCADE** [Bortezomib] for Injection)
EudraCT Number: 2007-005669-37
Amendment INT-6
*Janssen Research & Development is a global organization that operates through different legal 
entities in various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & 
Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; 
Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious Diseases 
BVBA; Janssen R&D Ireland; or Janssen Research & Development, LLC. The term “sponsor” is used 
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact 
Information page that accompanies the protocol.  
**VELCADE is the exclusive trademark of Millennium Pharmaceuticals, Inc., registered in the United 
States and internationally.
This study will be conducted under Food & Drug Administration IND regulations 
(21 CFR Part 312).
Issue/Report Date:
3 February 2014
Prepared by:
Janssen Research & Development, L.L.C.
Department:
Drug Development
Document No.:
EDMS-ERI-13160313:9.0 (Legacy No.: EDMS-PSDB-7480850)
Compliance:  This study will be conducted in compliance with this protocol, Good Clinical Practice, and 
applicable regulatory requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged
or confidential.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
2
INVESTIGATOR AGREEMENT


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
3
TABLE OF CONTENTS
PROTOCOL AMENDMENTS ................................................................................................... 6
SYNOPSIS .............................................................................................................................. 53
TIME AND EVENTS SCHEDULE........................................................................................... 58
ABBREVIATIONS................................................................................................................... 63
1.
INTRODUCTION........................................................................................................ 65
1.1.
Background ................................................................................................................ 65
1.1.1.
VELCADE................................................................................................... 67
1.2.
Overall Rationale for the Study .................................................................................. 68
2.
OBJECTIVES............................................................................................................. 69
3.
OVERVIEW OF STUDY DESIGN.............................................................................. 70
3.1.
Study Design .............................................................................................................. 70
3.2.
Study Design Rationale.............................................................................................. 73
4.
STUDY POPULATION............................................................................................... 75
4.1.
General Considerations.............................................................................................. 75
4.2.
Inclusion Criteria......................................................................................................... 75
4.3.
Exclusion Criteria........................................................................................................ 76
5.
RANDOMIZATION AND BLINDING.......................................................................... 77
5.1.
Overview..................................................................................................................... 77
5.2.
Procedures ................................................................................................................. 77
6.
DOSAGE AND ADMINISTRATION........................................................................... 78
6.1.
Dose Adjustments for VELCADE ............................................................................... 80
6.1.1.
VELCADE Dose Modifications for Neuropathic Pain or Peripheral 
Sensory Neuropathy .................................................................................. 81
6.2.
Dose Adjustments for Rituximab................................................................................ 83
6.3.
Dose Adjustments for Cyclophosphamide ................................................................. 84
6.4.
Dose Adjustments for Doxorubicin............................................................................. 85
6.5.
Dose Adjustment for Vincristine ................................................................................. 85
6.6.
Dose Adjustments for Prednisone.............................................................................. 86
6.7.
Cycle Delay ................................................................................................................ 86
7.
COMPLIANCE ........................................................................................................... 87
8.
CONCOMITANT THERAPY ...................................................................................... 87
8.1.
Therapy for Tumor Lysis Syndrome........................................................................... 88
8.2.
Prophylactic Treatment for Herpes Zoster ................................................................. 88
8.3.
Prophylaxis for Hepatitis B Re-activation ................................................................... 88
8.4.
Permitted Medications and Supportive Therapies ..................................................... 88
8.5.
Excluded Medications ................................................................................................ 89
8.6.
Subsequent Therapies ............................................................................................... 89
9.
STUDY EVALUATIONS ............................................................................................ 90
9.1.
Study Procedures....................................................................................................... 90
9.1.1.
Overview .................................................................................................... 90
9.1.2.
Pretreatment Phase ................................................................................... 91
9.1.3.
Treatment Phase........................................................................................ 92


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9.1.4.
Follow-up.................................................................................................... 93
9.1.4.1.
Short-term Follow-up .............................................................................. 93
9.1.4.2.
Long-term Follow-up for Survival Status (Every 12 Weeks)................... 94
9.2.
Efficacy....................................................................................................................... 95
9.2.1.
Evaluations................................................................................................. 95
9.2.1.1.
Radiographic Image Assessment........................................................... 95
9.2.1.2.
Definitions of Measurable and Assessable Disease............................... 95
9.2.1.3.
Criteria for Response Categories ........................................................... 96
9.2.1.4.
Reappearing Nodes................................................................................ 99
9.2.2.
Efficacy Criteria .......................................................................................... 99
9.2.2.1.
Primary Endpoint .................................................................................... 99
9.2.2.2.
Secondary Endpoints............................................................................ 100
9.3.
Patient-Reported Outcomes..................................................................................... 101
9.4.
Medical Resource Utilization.................................................................................... 103
9.5.
Pharmacogenomics Evaluations .............................................................................. 103
9.5.1.
Analyses Related to the Trial (Part 1) ...................................................... 104
9.5.1.1.
Somatic Mutational Status of Tissue .................................................... 104
9.5.1.2.
Analysis of Whole Blood Samples........................................................ 104
9.5.1.3.
Biomarkers............................................................................................ 105
9.5.2.
Pharmacogenomics and Biomarker Samples.......................................... 106
9.5.3.
DNA Storage for Future Analyses (Part 2)............................................... 106
9.6.
Safety Evaluations.................................................................................................... 107
10.
PATIENT COMPLETION/WITHDRAWAL............................................................... 110
10.1.
Completion ............................................................................................................... 110
10.2.
Discontinuation of Treatment ................................................................................... 110
10.3.
Withdrawal From the Study...................................................................................... 111
11.
STATISTICAL METHODS....................................................................................... 112
11.1.
Sample Size Determination...................................................................................... 112
11.2.
Study Populations..................................................................................................... 112
11.3.
Efficacy Analyses ..................................................................................................... 113
11.4.
Patient-Reported Outcomes Analyses ..................................................................... 113
11.5.
Pharmacogenomics Analyses.................................................................................. 114
11.6.
Medical Resource Utilization Analyses .................................................................... 116
11.7.
Safety Analyses........................................................................................................ 116
11.8.
Interim Analyses....................................................................................................... 117
11.9.
Independent Data Monitoring Committee ................................................................ 118
11.10.
Independent Radiology Review................................................................................ 118
12.
ADVERSE EVENT REPORTING............................................................................. 118
12.1.
Definitions................................................................................................................. 119
12.1.1.
Adverse Event Definitions and Classifications......................................... 119
12.1.2.
Attribution Definitions ............................................................................... 120
12.2.
Procedures ............................................................................................................... 121
12.2.1.
All Adverse Events ................................................................................... 121
12.2.2.
Serious Adverse Events........................................................................... 122
12.2.3.
Pregnancy ................................................................................................ 123
12.3.
Contacting Sponsor Regarding Safety..................................................................... 123
13.
STUDY DRUG INFORMATION ............................................................................... 124
13.1.
Physical Description of Study Drug(s)...................................................................... 124
13.2.
Packaging................................................................................................................. 124
13.3.
Labeling .................................................................................................................... 125


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
5
13.4.
Preparation and Handling......................................................................................... 126
13.5.
Drug Accountability................................................................................................... 128
14.
STUDY-SPECIFIC MATERIALS ............................................................................. 129
15.
ETHICAL ASPECTS................................................................................................ 129
15.1.
Study-Specific Design Considerations ..................................................................... 129
15.2.
Regulatory Ethics Compliance ................................................................................. 130
15.2.1.
Investigator Responsibilities..................................................................... 130
15.2.2.
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB).................................................................................................. 131
15.2.3.
Informed Consent..................................................................................... 133
15.2.4.
Privacy of Personal Data.......................................................................... 134
15.2.5.
Country Selection..................................................................................... 135
16.
ADMINISTRATIVE REQUIREMENTS..................................................................... 135
16.1.
Protocol Amendments .............................................................................................. 135
16.2.
Regulatory Documentation....................................................................................... 136
16.2.1.
Regulatory Approval/Notification.............................................................. 136
16.2.2.
Required Prestudy Documentation .......................................................... 136
16.3.
Patient Identification, Enrollment, and Screening Logs............................................ 137
16.4.
Source Documentation............................................................................................. 138
16.5.
Case Report Form Completion................................................................................. 138
16.6.
Data Quality Assurance............................................................................................ 140
16.7.
Record Retention...................................................................................................... 140
16.8.
Monitoring................................................................................................................. 141
16.9.
Study Completion/Termination................................................................................. 141
16.9.1.
Study Completion..................................................................................... 141
16.9.2.
Study Termination .................................................................................... 142
16.10.
On-Site Audits .......................................................................................................... 142
16.11.
Use of Information and Publication .......................................................................... 142
17.
REFERENCES......................................................................................................... 145
ATTACHMENTS ................................................................................................................... 148
Attachment 1: ECOG Performance Status.......................................................................... 149
Attachment 2: Creatinine Clearance Calculation................................................................. 150
Attachment 3: Body Surface Area Calculation .................................................................... 151
Attachment 4: FACT/GOG-Neurotoxicity Questionnaire, Version 4.0................................. 152
Attachment 5: Pharmacogenomics Sample Collection and Shipment Procedure .............. 153
Attachment 6: Candidate Gene List for Part 1 of Pharmacogenomics................................ 156
Attachment 7: Health Questionnaire.................................................................................... 157
Attachment 8: EORTC QLQ-C30 ........................................................................................ 160
Attachment 9: Brief Fatigue Inventory ................................................................................. 162
Attachment 10: Calculating the International Prognostic Index for MCL............................. 163
Attachment 11: American Joint Committee on Cancer, NHL Staging System.................... 164
Attachment 12: New York Heart Association Classification of Cardiac Disease ................ 165
LAST PAGE .......................................................................................................................... 165


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
6
PROTOCOL AMENDMENTS
The original Protocol was issued 13 December 2007. Amendments are listed 
beginning with the most recent amendment.
Protocol Version 
Issue Date
Original Protocol
13 Dec 2007
Amendment INT-1
1 Oct 2008
Amendment INT-2
26 Feb 2009
Amendment INT-3
16 Sep 2009
Amendment INT-4
23 Sep 2010
Amendment INT-5
9 Aug 2011
Amendment INT-6
3 Feb 2014
Amendment INT-6 (3 February 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to provide 
clarification regarding long-term follow-up once the clinical cutoff has been reached for the primary 
endpoint and to add information regarding collection of second primary malignancy data. 
Applicable Section(s)
Description of Change(s)
Rationale: Clarification is provided directing investigators to stop radiographic assessment of disease 
progression for subjects in short-term follow-up once clinical cutoff for the primary analysis has been 
reached.
Synopsis Overview; 
Time/Events 
Schedule footnote f; 
3.1. Study Design; 
9.1.1. Overview;
9.1.4.1. Short-term 
Follow-up
Clarification added that upon notification by the sponsor that clinical cutoff 
for the primary analysis (295 PFS events) has been reached, radiographic 
assessment of disease progression will stop, and all subjects in short-term 
follow-up will enter the Long-term Follow-up Phase for assessment of 
survival status.
Rationale: Second primary malignancy is a possible risk associated with some chemotherapy 
treatments. Additional guidance is provided to investigators to help ensure that all cases of second 
primary malignancy are identified.
Synopsis Safety
Evaluation;
Time/Events 
Schedule footnote s;
9.1.4.2. Long-term 
Follow-up; 
9.6. Safety 
Evaluations; 
12.2.1. All Adverse 
Events
Clarification added that instances of second primary malignancy will be 
documented for the duration of a subject’s participation in the study, 
regardless of onset date and relationship to study drug.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
7
Applicable Section(s)
Description of Change(s)
Rationale: Additional detail required to specify duration of the Long-term Follow-up Phase.
Synopsis Efficacy 
Evaluations;
Time/Events 
Schedule footnote g;
9.1.1. Overview;
9.1.4.2. Long-term 
Follow-up;
11.3. Efficacy 
Analyses
Long-term follow-up will continue until June 2017. 
Rationale: Alignment with current sponsor requirements. 
Title Page:
1. Introduction
The company name has been updated to Janssen Research & Development. 
The protocol has been prepared by Janssen Research & Development, L.L.C. 
A statement has been added to the title page to explain the relationship 
between Janssen Research & Development and local operating companies.
5.2. Randomization 
and Blinding 
Procedures
Deleted reference to use of subject initials during randomization procedure.
12.2.1. All Adverse 
Events
Added clarification that in addition to reporting to investigators all serious 
adverse events that are unlisted and associated with the use of the drug, the 
sponsor will report this information to the head of the investigational institute 
where required.
12.2.3. Pregnancy
The timing for initial sponsor notification by the investigational staff of 
pregnancies in partners of male subjects is changed from within 1 working day 
of investigational staff  knowledge of the event to within 24 hours of 
investigational staff knowledge of the event.
16.11. Use of 
Information
Alignment of text with current sponsor publication policy.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
8
Amendment INT-5 (09 August 2011)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The reasons for the amendment are to define criteria and 
appropriate boundaries for futility in the third interim analysis and to correct a footnote in the Time 
and Events table that was unintentionally changed in Amendment 3.
Applicable Section(s)
Text Changes
(new text in bold, deleted text in strikeout)
Description of change/
Rationale for Change
Throughout
Correction of minor typographical errors
Time and Events 
Schedule, 
Footnote bb
Hematology samples on Days 1, 4, 8, and 
11 of each cycle are required only for 
patients in Arm A prior to VELCADE 
dosing. For patients randomized to Arm B 
hematology samples will be taken on Day 1 
and 11 of each cycle. No site visits are 
required on Day 4 and Day 8 of each cycle 
for patients randomized to Arm B. Samples 
can be taken up to 24 hours prior to 
dosing day, provided the results are 
available before the dose of study 
medication is given. For pregnancy tests, 
if the pregnancy test during screening is 
within 28 days of Cycle 1 Day 1, it does 
not need to be repeated.
This sentence was 
unintentionally omitted from 
Amendment 3 and is being 
restored as it is applicable to all 
protocol amendments.
Section 11.8, Interim 
Analyses
The third interim analysis has been planned 
for this study after at least 148 events have 
occurred in the ITT population. If, at the 
third interim analysis, pre-specified 
boundaries for PFS are met then the study 
will be terminated and superiority of the 
experimental arm (VcR-CAP) will be 
declared over the comparator arm 
(R-CHOP). If the observed hazard ratio 
(R-CHOP vs VcR-CAP) for PFS in the 
third interim is equal to or less than 1.03 
(a value of >1 favoring VcR-CAP), then 
the study may be terminated due to 
futility. There will also be a review of the 
safety data at the third interim analysis.
To define criteria and 
appropriate boundaries for 
futility, in the event the 
conditional power falls below 
30% at third interim analysis. 
Assuming that the observed 
hazard ratio (HR) is ≤1.03 at 
the third interim, the 
conditional power with future 
HR of 1.4 would be <30%, 
suggesting low probability of 
success at the end of the study. 
A stopping boundary with an 
observed HR of 1.03 at the 
third interim would only 
increase Type II error rate by 
<1%, having negligible impact 
on the overall power of the 
study. The proposed futility 
stopping boundary could lead 
to early study termination, but 
still maintain the overall study 
power if the study is not 
stopped.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
9
Amendment INT-4 (23 September 2010)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The amendment was based on the feedback from IDMC on 
the second interim analysis for safety and to provide more clarity and guidance on some aspects of the 
study.
Applicable 
Section(s)
Text Changes
(new text in bold, deleted text in strikeout)
Description of change /
Rationale for Change
Throughout
Correction of minor typographical errors
Synopsis, Overview 
of Study Design
Randomization can only occur after
central confirmation of diagnosis of 
MCL; except for potential patients in 
China, where central confirmation of 
sample adequacy on lymph node tissue is 
required. if an adequate lymph node tissue 
block has been submitted for central 
confirmation of diagnosis of MCL.
Confirmation of MCL as
requirement prerandomization, 
with the exception of patients
in China, added. Restriction to 
lymph node tissue for diagnosis 
of MCL removed, with 
exception of potential patients 
in China.
Time and Events 
Schedule procedure
Lymph node tTissue sample for biomarker 
studyv
Restriction to lymph node 
tissue for diagnosis of MCL 
removed, with exception of 
potential patients in China.
Time and Events 
Schedule procedure
MCL lymph node biopsy tissue block or 
unstained slides (preferably of lymph 
node origin) for MCL confirmationn
Restriction to lymph node 
tissue for diagnosis of MCL 
removed, with exception of 
potential patients in China.
Time and Events 
Schedule procedures
Hepatitis B screeningdd
Addition per IDMC 
recommendation.
Time and Events 
Schedule footnote dd
HBsAg and anti-HBc testing to be 
performed
Introduction of specific 
mandatory hepatitis B 
screening at recommendation 
of IDMC.
Time and Events 
Schedule footnote j
…..bone marrow aspirate can be used for 
the pharmacogenomics analysis 
(see footnote py below).
Corrected to refer to the 
corresponding footnote (ie, 
pharmacogenomics).


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
10
Applicable 
Section(s)
Text Changes
(new text in bold, deleted text in strikeout)
Description of change /
Rationale for Change
Time and Events 
Schedule footnote n
Diagnosis of MCL (Stage II, III or IV) 
should be evidenced by lymph node
histology and either……such as by 
cytogenetics, fluorescent in situ 
hybridization (FISH) or polymerase chain 
reaction (PCR). The lymph node biopsy 
sample tissue block (preferably of lymph 
node origin) and supportive data…..should 
be sent to the central laboratory during the 
screening visit and the adequacy of this 
sample must be confirmed before 
randomization. In some cases, a A
confirmation of MCL diagnosis may be is
needed before the patient is randomized 
into the study with the exception of China, 
where confirmation of sample adequacy, 
based on lymph node tissue, is required. 
……..In the event that there is no lymph 
node tissue block available, 10 unstained 
slides of 3-4 micron thickness PLUS 10 
unstained slides of 10 micron thickness 
should be sent (these unstained slides are in 
addition to those required for 
pharmacogenomics testing).
Confirmation of MCL as 
requirement pre-randomization, 
with the exception of patients 
in China, added. Restriction to 
lymph node tissue for diagnosis 
of MCL removed, with 
exception of potential patients 
in China.
Time and Events 
Schedule footnote v
The primary lymph node diagnosis tissue 
(either block or slides) will also be used for 
pharmacogenomics testing per the patient’s 
consent.
Restriction to lymph node 
tissue for diagnosis of MCL 
remove, with exception of 
potential patients in China.
Section 4.2, 
Inclusion Criteria

Diagnosis of MCL (Stage II, III or IV) 
as evidenced by lymph node histology 
and either expression of cyclin D1….

Paraffin embedded lymph node
biopsy tissue block (preferably of 
lymph node origin) must be sent to 
the 
central 
laboratory 
for 
confirmation of MCL diagnosis, 
prior to randomization. In China, a 
paraffin embedded lymph node 
biopsy tissue block must be sent for 
central confirmation of sample 
adequacy prior to randomization. In 
some instances a central confirmation 
of diagnosis may be required prior to 
randomization
Central pathology confirmation 
of MCL as requirement pre-
randomization, with the 
exception of patients in China, 
added. Chinese patients require 
local pathology diagnosis of 
MCL and central confirmation 
of sample adequacy before 
randomization. Restriction to 
lymph node tissue for diagnosis 
of MCL removed, with 
exception of potential patients 
in China.
Section 4.2, 
Inclusion Criteria
Total bilirubin ≤21.5 x ULN
Changed to make consistent 
with other Velcade protocols 
and NCI-CTCAE v3.0 
(excluding moderate and severe 
hepatic impairment).


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
11
Applicable 
Section(s)
Text Changes
(new text in bold, deleted text in strikeout)
Description of change /
Rationale for Change
Section 5.2, 
Procedures
Patients can only be randomized if the
central laboratory has confirmed 
diagnosis of MCL or, in the case of 
patients in China, if the lymph node tissue 
sample……to confirm the diagnosis of 
MCL. The IVRS will therefore be blocked 
after the screening call until the central 
laboratory has provided the requisite 
confirmation. that the lymph node tissue 
block for analysis is adequate.
Confirmation of MCL as 
requirement pre-randomization, 
with the exception of patients 
in China, added. Restriction to 
lymph node tissue for diagnosis 
of MCL removed with the 
exception of potential patients 
in China.
Section 6.2, Dose 
Adjustments for 
Rituximab
Carriers of hepatitis B should be closely 
monitored for clinical and laboratory 
signs of active HBV infection for several 
months following Rituximab therapy.
Additional safety monitoring 
recommended for patients at 
risk of Hepatitis B 
re-activation.
Sections 8.3
8.3. Permitted Medications and Supportive 
Therapies Prophylaxis for Hepatitis B 
Re-activation
It is recommended that hepatitis B 
surface antigen positive patients receive 
lamivudine 100 mg/day (or equivalent 
prophylaxis) orally until 8 weeks after 
last chemotherapy.
Recommended prophylaxis of 
hepatitis B re-activation during 
chemotherapy.
Section 8.4
8.4. Excluded Medication Permitted 
Medications and Supportive Therapies
This section was moved below 
to keep prophylactic treatments 
of herpes zoster (8.2) and 
hepatitis B (8.3) together.
Section 8.5
8.5. Excluded Medications
This section was created to 
move what was previously 
Section 8.4 (Excluded 
Medications)


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
12
Applicable 
Section(s)
Text Changes
(new text in bold, deleted text in strikeout)
Description of change /
Rationale for Change
Sections 9.1.1, 
Overview; 
9.1.2, Pretreatment 
Phase; 
9.5, 
Pharmacogenomics 
Evaluations; 
9.5.1.1, Somatic 
Mutational Status of 
Tissue; 
9.5.1.3, Biomarkers; 
9.5.2, 
Pharmacogenomics
and Biomarker 
Samples; 
9.5.3, DNA Storage 
for Future Analyses 
(Part 2); 
10.3, Withdrawal 
From the Study; 
Attachment 5, 
Pharmacogenomics 
Sample Collection 
and Shipment 
Procedure
Lymph node
Deleted reference to lymph 
node tissue for diagnosis as 
restriction to lymph node for 
diagnosis of MCL is removed, 
with exception of potential 
patients in China.
Section 9.6, Safety 
Evaluation 
Clinical Laboratory Tests
Calcium, alkaline phosphatase, 
phosphate, glucose, uric acid

Hepatitis B Screening

Hepatitis B surface antigen

Hepatitis B core antibody
Added to address 
inconsistencies between the 
Time and Events Schedule and 
this section.
Introduction of specific 
mandatory hepatitis B 
screening at recommendation 
of IDMC.
Section 13.4, 
Preparation and 
Handling
Aseptic technique must be strictly 
observed throughout the reconstitution 
and handling of VELCADE since no 
preservative is present. Each vial of 
VELCADE for Injection should be 
reconstituted under a laminar flow biological 
cabinet (hood), within 8 hours…..
Added to resolve reconstitution 
procedure of VELCADE 
according to the existing 
VELCADE prescribing 
guidelines (ie, Summary of 
Product Characteristics), 
relevant to the participating 
countries.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
13
Amendment INT-3 (16 September 2009)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20EC of the European Parliament and the Council of the European Union. 
The overall reasons for the amendment: The IDMC recommendation for an additional interim
analysis on safety has been added. To ensure the potential for feedback to the investigator regarding 
the quality of the samples sent for central review and whether they will be adequate for analysis.
Provided clarity on what constitutes central MCL diagnosis. Changes to inclusion and exclusion 
criteria to include that a check of the quality of the lymph node sample be performed before the patient 
can be randomized and added in the potential to use steroids if they are waiting for the quality check of 
sample, and the patient has high burden disease. Clearer guidance is given on dose adjustments of 
cyclophosphamide and doxorubicin for hematologic toxicities. Implemented IDMC recommendations 
on herpes zoster prophylaxis. The sensitivity analysis on MCL diagnosed patients has been clarified. 
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Throughout
Correction of minor typographical errors or 
grammatical errors.
Synopsis, Overview 
of Study Design
Randomization can only occur if an 
adequate lymph node tissue block has 
been submitted for central confirmation 
of diagnosis of MCL.
To clarify that in order for a 
patient to be randomized, a 
lymph node tissue sample must 
be submitted to central review 
for confirmation of MCL 
diagnosis.
Synopsis, Overview 
of Study Design;
Section 3.1, 
Study Design;
Section 9.1.1, 
Overview
The total study duration from randomization 
of the first patient until the last PD PFS
event required…..enrollment and 
approximately 18 months for follow up). 
Clarification that events for the 
efficacy analysis of the primary 
endpoint are defined as PFS,
not PD.
Synopsis, Overview 
of Study Design; 
Section 3.1, 
Study Design
Two Three interim analyses are planned for 
this study. The first interim analysis will 
occur after the first….is compared with the 
investigator assessment of the diagnosis.
Following the first interim 
analysis, the IDMC 
recommended to assess 
cumulative toxicity by 
reviewing safety data after 
100 patients in each arm have 
completed or discontinued 
study treatment. This means the 
addition of a new interim 
analysis for the review of 
safety only. The study will now 
incorporate 3 interim analyses, 
instead of the originally 
planned 2- the first and second 
will be for safety only and the 
third, as was originally planned 
after 148 events, will be for 
safety and efficacy. 


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
14
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Synopsis, Overview 
of Study Design; 
Section 3.1 Study 
Design (Continued)
Central review is defined as a review by 
an independent pathologist and in the 
event that there is insufficient tumor 
material available for pathological 
confirmation of MCL, an independent 
lymphoma expert will review relevant 
local diagnostic and clinical information 
to verify the diagnosis of MCL. Samples 
determined as negative for MCL 
diagnosis by the independent pathologist 
cannot be evaluated by the independent 
lymphoma expert and will not be 
considered MCL confirmed.
Following the analysis of the 
MCL diagnosis by central 
pathology compared with the 
investigator assessment, there 
were a number of samples that 
were deemed indeterminate by 
central pathology due to 
insufficient sample availability
for analysis. These patients had 
met the inclusion entry criteria
for the diagnosis of MCL made 
by the investigator. In such 
cases, the diagnostic data used 
by the site will be presented to 
another independent lymphoma 
expert to verify the diagnosis.
The concordance rate of the diagnosis of 
MCL will also be reviewed at 50% 
accrual. This will may be used to 
recalculate the sample size so that only 
patients with MCL provide the required 
number of events required for the final 
analysis to ensure an adequate number of 
PFS events (approximately 280) in those 
subjects with a centrally confirmed MCL 
diagnosis at the time of the final analysis
(295 PFS events in total).
The IDMC agreed that a review 
of the concordance rate of the 
diagnosis of MCL should occur 
at 50% accrual. The adjustment 
of the sample size may be 
assessed after that review. The 
final analysis will occur after 
295 events in the ITT 
population, however at that 
time, a sensitivity analysis will 
be performed on the efficacy in 
the population of patients with 
confirmed MCL by central 
review. This statement has 
been added to clarify that the 
sensitivity PFS analysis in the 
subset of subjects with 
centrally confirmed MCL 
diagnosis is adequately 
powered: 280 events provides 
approximately 80% power to 
detect a hazard ratio of 1.4 with 
a 2-sided log-rank test 
(α=0.05).


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
15
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Synopsis, Overview 
of Study Design;
Section 3.1, Study
Design (Continued)
The A second interim analysis for safety 
will occur after 100 patients in each arm 
(200 patients in total) have either 
completed the study treatment or 
discontinued the study treatment, which 
allows sufficient exposure for review of 
cumulative toxicity. 
The third interim analysis is planned after at 
least 148 events have occurred in the 
intent-to-treat (ITT population).
If, at the third interim analysis, 
pre-specified boundaries for PFS are met 
then the study will be …over the comparator
arm (R-CHOP).
If pre-specified boundaries are not met at the
third interim stage analysis, the final 
analysis of the study will occur after 295 
events have been observed in the ITT 
population.
The study will now incorporate 
3 interim analyses, instead of
the originally planned 2- the 
first and second will be for 
safety only and the third, as 
was originally planned after 
148 events, will be for safety 
and efficacy.
The study will now incorporate 
3 interim analyses, instead of 
the originally planned 2- the 
first and second will be for 
safety only and the third, as 
was originally planned after 
148 events, will be for safety 
and efficacy. To clarify that the 
required number of event are 
from the ITT population.
Synopsis, Overview 
of Study Design
The IDMC will review the data for the two 3 
interim analyses and provide 
recommendations according to the charter.
The study will now incorporate 
3 interim analyses, instead of 
the originally planned 2- the 
first and second will be for 
safety only and the third, as 
was originally planned after 
148 events, will be for safety 
and efficacy.
Synopsis, Safety 
Evaluations
Blood samples for serum chemistry, and
hematology and urinalysis will be collected.
Urinalysis (other than for 
pregnancy testing) does not add 
any further value to the clinical 
and blood laboratory data on 
the safety analysis parameters 
in this study, therefore it is 
being removed to avoid further 
unnecessary investigations.
Synopsis, Statistical 
Methods; 
Section 11.1, 
Sample Size 
Determination
If 280 PFS events are observed in the 
subset of subjects with a centrally 
confirmed diagnosis of MCL, the study 
can achieve approximately 80% power to 
detect a hazard ratio of 1.4 in this subset 
of patients with a 2-sided log-rank test 
(α=0.05).
To clarify that the PFS 
sensitivity analyses in the 
subset of subjects with a 
confirmed MCL diagnosis is 
adequately powered. 


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
16
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Synopsis, Statistical 
Methods; 
Section 11.3, 
Efficacy Analyses
For all efficacy endpoints, the primary 
analysis is to be performed in the ITT 
population. A sensitivity analysis will be 
performed in the subset of subjects with a
centrally confirmed diagnosis of MCL. 
Approximately 280 events are expected in 
this subset of subjects at the time of the 
final analysis (295 PFS events in total), 
which can provide around 80% power to 
detect a hazard ratio of 1.4 using a 2-
sided log-rank test (α=0.05).
To clarify that, while primary 
efficacy analyses are to be 
performed in the ITT 
population, adequately 
powered sensitivity analyses 
are to be performed in those 
subjects with centrally 
confirmed MCL diagnosis.
Time and Events 
Schedule
Reordered letters in footnotes and added 
footnote u to the table
Previous version was missing 
2 letters and footnote u was not 
cited in the table.
Time and Events 
Schedule Procedure
Urinalysis
Urinalysis (other than for 
pregnancy testing) does not add 
any further value to the clinical 
and blood laboratory data on 
the safety analysis parameters 
in this study, therefore it is 
being removed to avoid further 
unnecessary investigations.
Lymph node Archived or fresh tissue 
sample or slides for biomarker studyv
Archive tissue and slides are 
not the recommended tissue 
material for this analysis.
Optional bone marrow sample for biomarker 
analysis (only need to consider if no tissue 
samples are available)v
To clarify when this option 
should be exercised.
MCL lymph node biopsy tissue block or 
unstained slides for MCL confirmationn
To clarify that no archive tissue 
will be available as patients 
recruited in this study are 
newly diagnosed so no banked 
tissue will be stored.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
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17
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Time and Events 
Schedule Footnote n
Biopsy samples and supportive materials for 
central …is not necessary before enrollment 
or treatment. Diagnosis of MCL (Stage II, 
III or IV) should be evidenced by lymph 
node histology and either expression of 
cyclin D1 (in association with CD20 and 
CD5) or evidence of t(11;14) 
translocation, such as by cytogenetics, 
fluorescent in situ hybridization (FISH) 
or polymerase chain reaction (PCR). The 
pathology slides lymph node biopsy 
sample and supportive data such as …..used 
for MCL diagnosis will be collected for 
independent pathology confirmation of 
diagnosis and then should be sent to the 
central laboratory during the screening 
visit and the adequacy of this sample 
must be confirmed before randomization. 
In some cases, a confirmation of MCL 
diagnosis may be needed before the 
patient is randomized into the study. 
After study completion, the samples will 
be returned to the study center. These slides 
and supportive material are to be submitted 
before Day 1 of Cycle 2. In the event that 
there is no lymph node tissue block 
available, 10 unstained slides of 
3-4 micron thickness PLUS 10 unstained 
slides of 10 micron thickness should be 
sent (these unstained slides are in 
addition to those required for 
pharmacogenomics testing).
To provide clarity on the 
requirements of the diagnosis 
for MCL to ensure the correct 
study population is enrolled 
and to provide clarity on the 
tumor material required for 
central confirmation of 
diagnosis.
To ensure the potential for 
feedback to the site regarding 
the quality of the samples sent 
for central review and whether 
they will be adequate for 
analysis. This has been 
implemented to ensure that no 
more patients are diagnosed as 
indeterminate due to 
insufficient material being sent 
to the central laboratory for 
confirmation of diagnosis.
Time and Events 
Schedule Footnote v
Patients must provide archival tumor 
material The primary lymph node tissue 
(either block or slides) for this study will 
also be used for pharmacogenomics
testing per the patient’s consent. If this 
sample is not available insufficient for 
pharmacogenomics testing, the patient has 
the option to consent to a fresh tumor lymph 
node sample collection.
To clarify when this option 
should be exercised.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
18
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Time and Events 
Schedule Footnote x
Samples The pregnancy test samples can 
be taken up to 24 hours prior to dosing day 
provided the results are available before the 
dose of study medication is given. For 
pregnancy tests, if the pregnancy test during 
screening is within 28 days of for screening 
pregnancy testing, a negative test up to 
28 days prior to Cycle 1 Day 1, it does not 
need to be repeated is acceptable.
Reworded for clarity.
Time and Events 
Schedule, 
Footnote cc; 
Section 9.1.4.1, 
Short-term 
Follow-up; 
Section 9.2.1.3 
Criteria for 
Response Categories
Time and Events 
Schedule, 
Footnote cc
When the patient is recorded to have an 
event of PD, a repeat CT scan to confirm 
PD must be undertaken at least 30 days 
after the scan that was used to determine 
PD. In the event a patient starts 
subsequent anti-lymphoma treatment, it 
is highly recommended that this repeat 
CT scan be performed before the patient 
starts treatment. The repeat CT scan 
must be done using i.v. and oral contrast 
and must be of the neck, chest, abdomen,
and pelvis. If the patient is intolerant of 
i.v. contrast agents, the scan may be 
performed with only oral contrast.
At the time of the initial documentation of
PD, a PD fax form together with 
documentation of PD (e.g., CT scan
report) must be sent to the sponsor’s 
medical representative within 24 hours.
To ensure that patients are not 
lost to follow-up, censored 
inappropriately, and to 
minimize the discrepancy 
between the investigator 
determination of PD and 
independent review 
determination of PD. 
Section 3.1, Study 
Design
This is a randomized, open-label, 
multicenter, prospective study to ….who 
have newly diagnosed MCL and who are 
ineligible or not considered for bone marrow 
transplantation.
An IDMC has been commissioned for this 
study.
This population is no longer 
permitted to enter the study. 
This was to be removed in 
INT-2 but due to a 
typographical error was not 
deleted in this part of the 
protocol. A note to file was 
issued to explain this.
Removed redundant text.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
19
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 4.2, 
Inclusion Criteria

Diagnosis of MCL (Stage II, III or IV) as 
evidenced by ….evidence of t(11;14),
translocation, such….
–
Paraffin embedded lymph node 
biopsy tissue block must be sent to 
the central laboratory for 
confirmation of adequacy prior to 
randomization. In some instances a 
central confirmation of diagnosis 
may be required prior to 
randomization.
Inadvertent omission in 
previous versions.
To ensure the potential for 
feedback to the site regarding 
the quality of the samples sent 
for central review and whether 
they will be adequate for 
analysis. This has been 
implemented to ensure that no 
more patients are diagnosed as 
indeterminate due to 
insufficient material being sent 
to the central laboratory for 
confirmation of diagnosis.
Section 4.3, 
Exclusion Criteria; 
Section 8.4, 
Excluded 
Medications
–
Short course (maximum of 
10 days; not exceeding 100 mg/day) 
prednisone or equivalent steroids 
are allowed to treat symptoms in 
subjects with advanced disease 
who enter the screening phase and 
are waiting to be randomized.
To allow investigators to 
manage symptoms while 
waiting for the results of the 
sample adequacy test.
Section 5.2, 
Procedures
Patients can only be randomized if the 
lymph node tissue sample sent to the 
central laboratory at screening has been 
evaluated as adequate for analysis to 
confirm the diagnosis of MCL. The IVRS 
will therefore be blocked after the 
screening call until the central laboratory 
has provided confirmation that the lymph 
node tissue block for analysis is adequate. 
To clarify that in order for a 
patient to be randomized, a 
lymph node tissue sample must 
be submitted to central review 
for confirmation of MCL 
diagnosis.
Section 6, Dosage 
and Administration
However, careful evaluation of the 
toxicity (particularly hematologic 
toxicities) should occur when considering 
causality to study medication to ensure 
that the correct dose adjustments take 
place. For example, when considering 
causality for neutropenia in Arm A it is 
important to consider that 
cyclophosphamide or doxorubicin (or 
both) may be causal agent(s).
To provide clearer guidance on 
causality and ensure that 
appropriate dose adjustments 
are made in cases of 
hematologic toxicity. 
Section 6.3, Dose 
Adjustments for 
Cyclophosphamide
In light of this, a patient can only start a 
cycle with cyclophosphamide if the ANC 
is 1.5 x 109 cells/L and platelets are 
100 x 109 cells/L.
Replaced Table 2 relating to dose 
modifications of cyclophosphamide and 
doxorubicin for hematologic toxicities.
To provide clearer guidance on 
the dose adjustment for 
hematologic toxicities causally 
related to cyclophosphamide 
and doxorubicin.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
20
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 6.4, Dose 
Adjustments for 
Doxorubicin
The maximum dose given for each patient in 
this study will be 300 mg/m2 (it may be 
higher, for example, if the patients receive 
8 cycles of treatment or have a large BSA. 
However, the total exposure should not 
exceed the lifetime cumulative dose limit).
Dose modifications for hematologic 
toxicities should be performed as 
indicated in Table 2.
The original maximum total 
exposure was based on average 
BSA and 6 cycles of exposure, 
but it is recognized that some 
patients with a high BSA or 
those that receive 8 cycles may 
have higher exposure. However 
in either case, the total 
maximum lifetime exposure 
must not be exceeded.
To provide clearer guidance on 
the dose adjustment for 
hematologic toxicities causally 
related to cyclophosphamide 
and doxorubicin.
Section 6.7, Cycle 
Delay

Platelet count 50100 x 109 cells/L 
(prior platelet transfusion is allowed)
Patients with thrombocytopenia due to 
bone marrow infiltration from MCL are 
permitted to have platelets of 
50 x 109 cells/L on the first day of each 
cycle.
The platelet count has been 
increased at start of cycle to 
allow the patient a sufficient 
baseline to tolerate potential 
toxicity from 
cyclophosphamide. This 
ensures that patients are more 
likely to be able to receive 
maximum drug exposure of all 
study medications for each 
cycle.

ANC 1.0 1.5 x 109 cells/L
The neutrophil count has been 
increased at start of cycle to 
allow the patient a sufficient 
baseline to tolerate potential 
toxicity from 
cyclophosphamide. This 
ensures that patients are more 
likely to be able to receive 
maximum drug exposure of all 
study medications for each 
cycle.
Section 8.2, 
Prophylactic 
Treatment for 
Herpes Zoster
Prophylaxis for herpes zoster reactivation 
is mandatory during the Treatment 
Phase. Acceptable antiviral therapy 
includes acyclovir (e.g., 400 mg given 
orally, 3 times a day), famcyclovir (e.g., 
125 mg given orally, twice a day), or
valacyclovir (e.g., 500 mg given orally, 
twice a day).
Recommendation by IDMC 
following the first interim 
analysis for safety. New section 
added and subsequent sections 
were renumbered.


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21
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 8.3, 
Permitted 
Medications and 
Supportive 
Therapies 
Colony stimulating growth factors are not
permitted in the first cycle, anytime during 
the study for the prevention of 
neutropenia and also thereafter they can be 
prescribed for the management of treatment-
emergent toxicities.
G-CSF can be given for the 
prevention or treatment of 
neutropenia or febrile 
neutropenia.
Section 9.1.1, 
Overview
For the pharmacogenomics analysis, 
archived paraffin embedded tumor lymph 
node tissue blocks… will be collected. If
banked paraffin embedded samples are not 
available, the patient has the option of 
consenting to a fresh lymph node tissue 
biopsy.
This fresh tumor lymph node biopsy is 
optional and not required to participate in 
this study. If sufficient sample is 
available….required for central histology 
review for this study may will be utilized in 
the absence of archived material. In the 
absence of archival tumor sufficient lymph 
node tissue blocks or fresh tumor lymph 
node tissue sample collection, the patient 
has the option to consent to a 5 mL bone 
marrow sample for the biomarker analyses.
Patients must provide paraffin…to a fresh
tumor lymph node tissue biopsy, (in the 
absence of archived material), whole blood, 
bone marrow and serum sampling.
To clarify that no archive tissue 
will be available as patients 
recruited in the study are newly 
diagnosed so no banked tissue 
would be stored. Reworded 
sentences for clarity.
Section 9.1.2, 
Pretreatment Phase
All patients must provide an adequate 
lymph node tissue block for central 
review prior to randomization.
Biopsy samples and supportive …..are 
required for the study.; however, 
confirmation is not necessary before 
enrollment or treatment.
Confirmation of MCL by 
central review is required prior 
to randomization into the study. 
In the event there is insufficient tumor 
material available for the independent 
pathologist confirmation of MCL, an 
independent lymphoma expert will review 
relevant local diagnostic and clinical 
information to verify the diagnosis of 
MCL. Samples determined as negative 
for MCL cannot be evaluated by the 
independent expert and will not be 
considered MCL confirmed. 
To clarify that central review is 
conducted either by an 
independent pathologist or by 
an independent lymphoma 
expert in those cases where 
insufficient tumor material is 
available to the independent 
pathologist.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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22
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 9.1.2, 
Pretreatment Phase 
(Continued)
Representative stained tissue block or 
unstained microscope slides from a prior
lymph node biopsy that demonstrate the 
diagnosis of MCL, and other supporting 
data… to the central pathologist. These 
materials must be sent to the central 
pathologist before Day 1 of Cycle 2 during 
screening and adequacy of these samples 
must be confirmed before the patient can 
be randomized.
To ensure the potential for 
feedback to the site regarding 
the quality of the samples sent 
for central review and whether 
they will be adequate for 
analysis. This has been 
implemented to ensure that no 
more patients are diagnosed as 
indeterminate due to 
insufficient material being sent 
to the central laboratory for 
confirmation of diagnosis.
Section 9.1.4.1, 
Short-term 
Follow-up; 
Section 9.2.1.3, 
Criteria for 
Response Categories
Death and events of progression 
constitute PFS, the primary endpoint for 
this study; it is therefore important that 
instances of PD, death or study 
discontinuation be reported to the 
sponsor as soon as possible. A PD fax 
form provided by the sponsor together 
with documentation of PD (e.g., CT scan 
report must be sent to the sponsor’s 
medical representation within 24 hours of 
the event. 
To ensure that patients are not 
lost to follow-up, censored 
inappropriately, and to 
minimize the discrepancy 
between the investigator 
determination of PD and 
independent review 
determination of PD. 
Section 9.5, 
Pharmacogenomics
Evaluations

Correlations of somatic… subunits from 
paraffin embedded lymph node tissue or 
fresh frozen lymph node tissue or bone 
marrow (additional genes associated 
with response to drug treatment may also 
be evaluated).
To clarify that no archive tissue 
will be available as patients 
recruited in the study are newly 
diagnosed so no banked tissue 
would be stored. Reworded 
sentences for clarity.

Evaluation of Ki-67, NF-kB and 
PSMA5,and other protein …in paraffin 
embedded lymph node tissue or fresh 
frozen lymph node tissue or bone 
marrow (e.g., p27, p53, cyclin D1, 
CTAG1B, CYCLIN A, B, E, P21, ICAM, 
VCAM,…..
A previously embedded paraffin tumor  
tissue sample, a whole …. 5 mL bone 
marrow sample), and three 5 mL serum 
samples (30 mL in total). Samples will be 
collected from patients who give separate 
written informed consent…as described.
Archived paraffin embedded tumor samples
will be collected from all …. Ki-67, NF-kB 
and PSMA5 analyses .


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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23
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 9.5, 
Pharmacogenomics
Evaluations 
(Continued)
If sufficient sample is available, a portion of 
the biopsy embedded paraffin lymph node
tissue required for central review may will 
be utilized for the analyses. for proteasome 
and Ki-67 analyses in the absence of 
archival  material. If there is no archived
tumor insufficient lymph node tissue 
sample available, patients can optionally 
consent to undergo a biopsy to obtain fresh 
tumor lymph node tissue sample or to 
provide a 5 mL sample of bone marrow. 
Whole blood (10 mL) and three 5 mL
serum samples will be collected…
Same as on previous page.
Section 9.5.1.1, 
Somatic Mutational 
Status of Tumor 
Lymph Node Tissue
Previously obtained paraffin-embedded,….
will be collected, if available. These tumor 
tissues may be from the time of the patient’s 
initial tumor diagnosis or … study 
medication administration. If an archived 
tumor sample is not available, the …sample 
or provide a 5 mL bone marrow sample. If 
sufficient sample is available, a portion of 
the embedded paraffin lymph node biopsy 
tissue sample required for central review of
the diagnosis of MCL may will be utilized.
in the absence of archival material. If there 
is insufficient lymph node tissue sample 
available, patients can optionally consent 
to undergo a biopsy to obtain a fresh 
lymph node tissue sample or to provide a 
5 mL sample of bone marrow. Purified 
DNA from these tumor tissues will be 
examined…..
Suspected drug target genes including 
…will may be prospectively analyzed in 
tumor lymph node tissue of all patients in 
order    within this clinical trial.
DNA extracted from archived tumor lymph
node tissue or bone marrow samples will be 
utilized for these analyses.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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24
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 9.5.1.3, 
Biomarkers
If sufficient sample is available, a portion 
of the embedded paraffin lymph node 
tissue sample required for central review 
will be utilized. If there is insufficient 
lymph node tissue sample available, 
patients can optionally consent to 
undergo a biopsy to obtain a fresh lymph 
node tissue or to provide a 5 mL sample 
of bone marrow. Paraffin-embedded, 
formalin-fixed tumor or fresh frozen tissue 
will also be These samples will be
subjected to immunohistochemical analysis 
to quantify the levels of Ki-67, p27, … 
prognostic proteins.
Same as on previous page.
Section 9.5.2, 
Pharmacogenomics
and Biomarker 
Samples
Primary tumor (archived) tissue is an 
archived …. patients, if available. If 
archived tumor tissue is …..tumor tissue 
sample or a 5 mL bone marrow sample. If 
sufficient sample is available, a portion of 
the embedded paraffin lymph node tissue 
sample required for the central review
will be utilized. If there is insufficient 
lymph node tissue sample available, 
patients can optionally consent to 
undergo a biopsy to obtain a fresh lymph 
node tissue sample or to provide a 5 mL 
sample of bone marrow.
Section 9.5.3, DNA 
Storage for Future 
Analyses (Part 2)
Patients will be asked to consent to 
…..archival paraffin embedded tumor  
lymph node tissue or fresh lymph node 
tissue frozen samples….
Section 9.6 Safety 
Evaluations
Blood samples for serum chemistry, and 
hematology and urinalysis
Removed urinalysis laboratory parameters
Urinalysis (other than for 
pregnancy testing) does not add 
any further value to the clinical 
and blood laboratory data on 
the safety analysis parameters 
in this study, therefore it is 
being removed to avoid further 
unnecessary investigations.
Section 10.3 
Withdrawal From 
the Study
The DNA extracted from the patient's blood, 
bone marrow or fresh or archived paraffin 
embedded lymph node tissue will be 
retained…..
To clarify that no archive tissue 
will be available as these 
patients are newly diagnosed so 
no banked tissue will be stored.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
25
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 11.5, 
Pharmacogenomics
Analyses
The pharmacogenomics exploratory 
statistical analysis will be performed 1) at 
the time of the second third interim 
analysis, if required; and 2) at the 
completion of the trial in order to inform 
subsequent lymphoma trials.
The IDMC recommended 
addition of 1 more interim 
analysis for safety.
Section 11.8, Interim 
Analyses
There will be two 3 interim analyses 
planned in the study.
The first interim analysis will …when 
central review is compared with the 
investigator assessment of the diagnosis. 
The concordance rate of the diagnosis of 
MCL when central review is compared 
with the investigator assessment of the 
diagnosis will also be reviewed at 50% 
accrual. This will may be used to 
recalculate the sample size to allow for
ensure an adequate number of PFS events 
for (approximately 280) in those subjects 
with a centrally confirmed MCL 
diagnosis at the time of the final analysis
(295 PFS events in total).
If the observed difference is less than 95%, 
the sample size will may be adjusted to 
provide adequate PFS events for 
(approximately 280) in those subjects 
with a centrally confirmed MCL 
diagnosis at the time of the final analysis 
(295 PFS events in total). There is no alpha 
adjustment for the 1st IA first 2 interim 
analyses since no efficacy analyses will be 
performed. 
Following the first interim 
analysis, the IDMC 
recommended to assess 
cumulative toxicity by 
reviewing safety data after 100 
patients in each arm have 
completed or discontinued
study treatment. This means the 
addition of a new interim 
analysis for the review of 
safety only. The study will now 
incorporate 3 interim analyses, 
instead of the originally 
planned 2- the first and second 
will be for safety only and the 
third, as was originally planned 
after 148 events, will be for 
safety and efficacy. The IDMC 
agreed that a review of the 
concordance rate of the 
diagnosis of MCL should occur 
at 50% accrual. The adjustment 
of sample size may be assessed 
after that review. To clarify that 
the PFS sensitivity analyses in 
those subjects with a centrally 
confirmed MCL diagnosis is 
adequately powered: 280 
events provides 80% power to 
detect a hazard ration of 1.4 
with a 2-sided log-rank test 
(α = 0.05). 


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
26
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 11.8, Interim 
Analyses 
(Continued)
The second interim analysis will review the 
safety data and be performed after 100 
patients per arm have either completed or 
discontinued study treatment. 
The third interim analysis has been 
planned for this study after at least 
148 events have occurred in the ITT 
population. If, at the third interim analysis, 
pre-specified boundaries for PFS are met 
then the study will be ….over the 
comparator arm (R-CHOP). There will also 
be a review of the safety data at 2nd the 
third interim analysis.
Assuming that 148 events are observed at 
the second third interim analysis, the alpha 
…for the final analysis is 0.049 (2-sided). 
If pre-specified boundaries are not met at the 
third interim stage, the final analysis of the 
study will occur after 295 events in patients 
have been observed in the ITT
population.
To clarify that the required 
number of events are to be 
from the ITT population.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
27
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Attachment 5, 
Pharmacogenomics
Sample Collection 
and Shipment 
Procedure
Paraffin Embedded Lymph Node Tissue, 
Stained and Unstained Slides,
(including bone marrow samples), Fresh
Frozen Lymph Node Tissue
Archived
Paraffin embedded lymph node or fresh 
frozen lymph node tissue samples will be 
labeled …… on the tubes. A form will 
accompany each archived lymph node …..
as part of study specific materials 
(see Section 14.0).

Confirm that patient has an archived a 
paraffin embedded lymph node tissue 
sample. Determine location of archival
and contact person. Determine if site is 
….. block or fresh frozen lymph node 
tissue sample.

Send the paraffin embedded tumor 
lymph node sample from the primary 
biopsy or tumor lymph node resection 
specimen using the kit provided. 

All tumor lymph node tissue blocks 
should be sent to the address specified 
by the central laboratory.

If the lymph node tissue block from the 
primary biopsy or tumor lymph node
tissue resection…
DO NOT package the tumor paraffin 
embedded lymph node tissue block in dry 
ice.
To clarify that no archive tissue 
will be available as these 
patients are newly diagnosed so 
no banked tissue will be stored.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
28
Amendment INT-2 (26 February 2009)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20EC of the European Parliament and the Council of the European Union.
The overall reasons for the amendment: Modification of inclusion criterion restricting enrollment to 
patients who are truly not eligible for transplantation and the criterion for platelet counts was modified 
to include patients with lower baseline platelet counts secondary to mantle cell lymphoma. Exclusion 
criterion regarding serious medical conditions was clarified. Criteria for efficacy response were 
modified to make measurements operationally feasible and to comply with modified IWRC 
recommendations. Some laboratory tests considered not to be mandatory were eliminated. Adverse 
event collection wording was clarified to ensure the capture of adverse events relevant to the study. A 
new section for treatment of tumor lysis syndrome was added to ensure that appropriate measures are 
taken to prevent tumor lysis syndrome.  
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Abbreviations 
Abbreviations were updated
Synopsis, Overview 
of Study Design
The Treatment Phase will extend from 
randomization until 6 cycles of treatment 
have been given (or 2 cycles beyond a 
response documented in Cycle 6).
Text added to be consistent with 
main body of the protocol.
Synopsis, Study 
Population
Patients must also be ineligible or not 
considered for bone marrow transplantation 
as determined by their treating physician.
To maintain a homogenous 
evaluable study population 
comprising patients who are 
truly not eligible for 
transplantation, the enrollment 
of those patients not considered 
for transplant will be 
terminated. All current patients 
falling into this category will be 
analyzed and evaluable per 
protocol.
Synopsis, Safety 
Evaluations
After 30 days after the last dose of study 
drug, only Grade3 and 4 adverse events 
will be reported until completion of the last 
study-related procedure.
Not needed in the synopsis and 
the wording has been revised in 
other sections.
Time and Events 
Schedule, ECOG 
performance status, 
vital signs, and BSA
Removed inappropriate cross out marks for 
ECOG and vital sign evaluations during 
Response Evaluation. Removed X for BSA 
evaluation during Short-term Follow-up. 
Correction of typographical 
errors, ECOG and vital sign 
evaluations should be included 
during Response Evaluation 
period. BSA is not needed 
during Short-term Follow-up 
period. 
Time and Events 
Schedule, Footnote h
CT scans must be performed as part of 
the screening process, however if a 
previous scan is available, this may be 
used as the screening scan providing that 
it was performed no more than 56 days 
prior to randomization and meets the 
criteria required for study entry scans.
To clarify that patients do not 
need to undergo a repeat scan 
for screening providing there is 
a scan that meets the entry 
criteria and is less than 56 days 
old.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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29
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Time and Events 
Schedule, 
Footnote m
Bone marrow aspirate and biopsy will be 
repeated… assessment that was positive, 
indeterminate, or insufficient, or not done.
Patients who do not have a bone 
marrow assessment at screening 
are not eligible for study entry 
Time and Events 
Schedule, Footnote n
Hematology includes hemoglobin, 
hematocrit,…
Hematocrit is not mandatory
Time and Events 
Schedule, Footnote o
Clinical chemistry at screening includes 
sodium, potassium, bicarbonate, chloride, 
…calcium, and magnesium (optional)
Removed tests from the list that 
are not mandatory
All these evaluations, with the exception of 
bicarbonate and ß-2 microglobulin,….
To clarify that bicarbonate only 
needs to be measured at 
screening.
ß-2 microglobulin needs only to be done at 
screening and at the time of documentation 
of PD
ß-2 microglobulin measurement 
is not needed at the time of PD, 
the rest of the sentence was 
redundant and therefore the 
entire sentence was deleted.
Time & Events 
Schedule, Footnote u
The total dose per day for each patient will 
be capped at 100 mg.
The dose of prednisone is not 
capped.
Time & Events 
Schedule, Footnote v
After 30 days after the last dose of study 
drug medication, only grade 3 and 4 
adverse events will be collected. 
Adverse events occurring after 30 days 
following the last dose of study drug 
should be reported if considered related 
to study drug. 
To clarify that only adverse 
events considered related to 
study drug will be collected 
after treatment is terminated
Time & Events 
Schedule, 
Footnote w
ß-2 microglobulin will only be collected at 
the time of documentation of PD.
-2 microglobulin is not needed 
at the time of PD.
Time & Events 
Schedule, 
Footnote ff
Hematology samples on Day 1, 4, 8, 11…
Samples must be taken on the 
first day of each cycle.
No site visits are required on Day 4 and 
Day 8 of each cycle for patients 
randomized to Arm B
To clarify that patients in 
Arm B do not need to attend for 
visits on Day 4 and Day 8 of 
each cycle.
Section 4.1, General 
Considerations
In addition, those patients for whom bone 
marrow transplantation is not available or 
who refuse a transplant as the treatment 
option for the frontline management of 
their MCL will be eligible to take part in 
this study.
Only those patients truly not 
eligible for transplantation will 
be allowed to enter study from 
this amendment onwards
Section 4.2, 
Inclusion Criteria
Diagnosis of MCL… as evidenced by 
lymph node histology….
To clarify that histology has to 
be confirmed on a lymph node 
biopsy and not other sites of 
disease


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
30
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Not eligible or not considered for bone 
marrow transplantation as assessed by the 
treating physician (e.g., age or the 
presence…. Those patients who are 
eligible, but not considered for 
transplantation (e.g., due to costs or study 
site not performing transplantation) are no 
longer eligible to be enrolled into the study.
Those patients who are eligible, 
but not considered for 
transplantation (e.g., due to 
costs or study site not 
performing transplantation) are 
no longer eligible to be enrolled 
into the study.
Platelets ≥100,000 cells/μL or 
≥75,000 cells/μL if thrombocytopenia is 
considered by the investigator to be 
secondary to MCL (e.g., due to bone 
marrow infilitration or sequestration 
from splenomegaly)
Platelet count of 
100,000 cells/L can be too 
high for this patient population 
given that some patients with 
bone marrow involvement or 
splenomegaly due to MCL may 
have low platelet counts, but 
could benefit from therapy.
Section 4.3, 
Exclusion Criteria
Serious medical (e.g., cardiac failure 
[New York Heart Association; NYHA 
Class III or IV, Attachment 12 or left 
ventricular ejection fraction; LVEF 
<50%], active peptic ulceration, 
uncontrolled diabetes mellitus)…
To exclude those patients at 
high risk from severe toxicities 
associated with some of the 
study medication.
Section 6.1, Dose 
Adjustments for 
VELCADE
The EMEA (European Medicines 
Agency) has contraindicated the use of 
VELCADE in subjects with acute diffuse 
infiltrative pulmonary disease and 
pericardial disease.
This risk information was 
mistakenly incorporated into 
this document during the last 
update. 
Section 8.1, Therapy 
for Tumor Lysis 
Syndrome
For subjects at risk for tumor lysis 
syndrome, allopurinol treatment should 
be considered and special attention 
should be given to adequate hydration.
New section added to ensure 
that appropriate measures are 
undertaken for the prevention of 
tumor lysis syndrome.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
31
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 9.1.2, 
Pretreatment Phase
All patients must undergo…….with oral 
and i.v.contrast…..(may be performed up 
to 28 days before randomization); this may 
be performed using only oral contrast. CT 
scans must be performed as part of the 
screening process, however if a previous 
scan is available, this may be used as the 
screening scan providing that it was 
performed no more than 56 days prior to 
randomization and meets the criteria 
required for study entry scans.
To clarify that scans need to be 
done with both forms of 
contrast unless the patient is 
intolerant of i.v. contrast. 
Clarification of the 
requirements for CT scans 
during the Pretreatment Phase.
9.1.4.1, Short-term 
Follow-up
Following the End-of-Treatment visit, all 
patients will have efficacy assessments 
every 6 weeks (± 4 days) for 18 weeks 
(±7 days) and thereafter every 8 weeks  
(± 7 days)…..
Correction
For safety assessments, after 30 days after 
last dose of study drug, only adverse 
events considered related to study drug
will be reported.
To clarify which adverse events 
need to be reported after 
termination of treatment
9.1.4.2, Long-term 
Follow-up for 
Survival Status 
(Every 12 Weeks)
Only survival data, adverse events 
considered related to study 
drug,……Follow-up Phase
To clarify which adverse events 
need to be reported in long-term 
follow-up.
Section 9.2, Efficacy
During the study……….CT scans with 
oral and i.v. contrast
To clarify that scans need to be 
done with both forms of 
contrast unless the patient is 
intolerant of i.v. contrast
For patients intolerant of i.v. contrast 
agents, the chest, and abdomen and pelvic 
CTs may be performed with oral contrast 
agents.
Removed redundant wording
Section 9.2.1.3, 
Criteria for Response 
Categories
All measurable lymph nodes and nodal 
masses (including splenic and extranodal 
nodes and masses) must have regressed….
Changes to the complete 
response criteria to make the 
measurements operationally
feasible as assessable lesions are 
not measured or quantified. 
Previous wording did not allow 
for necessary measurements to 
be logistically possible.
Non-measurable and assessable nodes 
(including splenic and extranodal nodes 
and masses) that were 1.1 to 1.5 …..(SPD)
as visually estimated


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
32
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 9.2.1.3, 
Criteria for Response 
Categories 
(continued) 
All extranodal sites of disease must have 
completely disappeared.
To comply with modified 
IWRC recommendations all 
extranodal sites of disease must 
have completely disappeared
Any residual lymph node mass >1.5 cm in 
longest transverse dimension or 
extranodal site of disease (irrespective of 
size) must have regressed by more than 
75%….
Changes to the unconfirmed 
complete response criteria make 
the measurements operationally 
feasible as assessable lesions are 
not measured or quantified. 
Previous wording did not allow 
for necessary measurements to 
be logistically possible.
At least a 50% decrease in the sum of the 
product of the product of the diameters…
Deleted repeated wording.
Non-measurable nodes and nodules must 
regress by 50% in their SPD or, for single 
non-measurable nodules lesions, in the 
greatest transverse diameter as visually 
estimated.
Clarification of partial response 
criteria
A) 50% increase from nadir in the SPD of 
any all measurable sites of disease >1.5 cm 
in the long axis and >1.0 cm in the short 
axis at the time that progressive or relapsed 
disease is identified and the absolute 
change in at least one 1 dimension is 0.5 
cm for at least 1 lesion; or B) 50% 
increase in the long axis of any measurable 
site of disease >1.5 cm in the long axis and 
>1.0 cm in the short axis at the time that 
progressive or relapsed disease is identified 
and the absolute change in the long axis is 
0.5 cm.
Clarification of progressive 
disease criteria


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
33
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 9.2.1.3, 
Criteria for Response 
Categories 
(continued)
2. A) 50% increase from nadir in the SPD 
of any all non-measurable sites of disease 
(excluding truly assessable disease) as 
visually estimated that measures >1cm in 
2 perpendicular dimensions at the time that 
progressive or relapsed disease is 
identified, and the absolute change….is 
0.5 cm for at least 1 non-measured 
lesion as estimated visually; or B) 50% 
increase in the long axis of any non-
measurable site of disease (excluding truly 
assessable disease) that measures >1cm in 
2 perpendicular dimensions at the time that 
progressive or relapsed disease is 
identified, and the absolute change in the 
long axis is 0.5 cm, as estimated 
visually.
3. 50% increase from nadir the SPD of 
any other previously identified site of 
disease any truly assessable site of 
disease as visually estimated.
4. Appearance of any new lymph 
node…..in short axis, any new 
unequivocal extranodal site of disease 
(irrespective of size), or unequivocal …
5. Appearance of a new organ 
enlargement or unequivocal increase of 
an organ enlargement that was present 
since baseline.
Section 9.2.1.4, 
Reappearing Nodes
Reappearing nodes (from a nadir of 
0 cm x 0 cm): Any node(s) that reappear 
(measured or not measured) >1.5 x 1.0 
cm or unequivocally reappearing 
extranodal lesions (irrespective of size 
and whether measured or not) should 
result in PD.
New section added to provide 
clarity on how to classify 
reappearing nodes.
Section 9.3, 
Patient-Reported 
Outcomes
PRO questionnaires must be filled out 
during the Screening visit (within 7 days 
prior to randomization)
PRO is part of the screening 
process, therefore the time 
window should not be 7 but 
28 days.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
34
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 9.6, Safety 
Evaluations
The evaluation period will be defined as 
starting from signing the ICF to at least 30 
days after the last dose of study drug. After 
30 days after the last dose of study drug, 
only grade 3 and 4 adverse events will be 
reported until completion of the last study-
related procedure.
All adverse events, with the exception of 
progression of MCL, will be reported 
from the time a signed and dated 
informed consent form is obtained until 
30 days following the last dose of study 
drug or until the start of subsequent 
systemic anti-lymphoma therapy, if 
earlier. Adverse events reported after 30 
days following the last dose of study 
drug should also be reported if 
considered related to study drug.
To ensure the capture of adverse 
events that are relevant to the 
study.
Hematocrit removed from hematology 
panel
Clarification and updated based 
on changes in Time and Events 
Schedule
In addition to the above laboratory 
parameters, chloride, bicarbonate, alkaline 
phosphatase, calcium, magnesium, 
phosphate, uric acid, glucose, and ß-2 
microglobulin will be measured at 
screening and at relevant time points 
during the study…
Please see Time and Events Schedule for 
exact time points of these and other 
assessments. Also included are ß-2 
microglobulin and bicarbonate, which 
are measured only at screening. 
Reworded to provide clarity.
Section 11.8, Interim 
Analysis
Assuming that 148 events are observed 
at the second interim analysis, the alpha 
allocated for the interim is 0.003 (2-sided) 
and for the final analysis is 0.049 (2-sided).
Clarification


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
35
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 12.2.1, All 
Adverse Events
After 30 days after the last dose of study 
drug, only grade 3 and 4 adverse events 
will be reported until completion of the last 
study-related procedure.
All adverse events, with the exception of 
progression of MCL, will be reported 
from the time a signed and dated 
informed consent form is obtained until 
30 days following the last dose of study 
drug or until the start of subsequent 
systemic anti-lymphoma therapy, if 
earlier. Resolution information after 
30 days following the last dose of study 
drug should also be provided. Adverse 
events occurring after 30 days should 
also be reported if considered related to 
study drug.
To ensure the capture of adverse 
events that are relevant to the 
study
Attachment 12
Attachment 12: New York Heart 
Association Classification of Cardiac 
Disease
Addition of new attachment in 
support of modified exclusion 
criterion (noted above). 
Throughout the 
protocol
Minor grammatical, spelling, or format 
changes were made
Minor errors were noted.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
36
Amendment INT-1 (1 October 2008)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20EC of the European Parliament and the Council of the European Union.
The original protocol, issued 13 Dec 2007, was named Protocol 26866138-LYM-3002 INT-1. This 
amendment corrects the name to Protocol 26866138-LYM-3002, and is Amendment INT-1.
Editorial changes and typographical errors were made and corrected throughout the document. New 
abbreviations were added to the abbreviations list. “Subject” was changed to “patient” for consistency. 
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Synopsis, Secondary 
Objectives
Section 2, 
Secondary 
Objectives
To determine the duration of response 
(DoR), time to next treatment (TNT), and 
treatment-free interval
To add other variables of 
clinical benefit
Synopsis, 
Exploratory 
Objectives
Section 2, 
Exploratory 
Objectives
To evaluate medical resource utilization 
(MRU) information which may be used 
in future economic evaluation models
MRU has been added as an 
exploratory objective to allow 
for formal analysis
Synopsis, Overview 
of Study Design
Section 3.1, Study 
Design
Patients who are withdrawn from the 
study.…willing to continue study follow-up 
procedures can should be followed up as 
per protocol for PD.
As per the ICF, patients who 
withdraw consent are not 
mandated to provide any further 
data, however they may agree to 
provide further information such 
as outcome of adverse events or 
survival status but this is 
completely at their discretion.
Synopsis, Overview 
of Study Design
Section 3.1, Study 
Design
Section 6, Dosage 
and Administration
Section 8.3, 
Subsequent 
Therapies
Section 9.1.1, Study 
Procedures 
Overview
Section 9.1.3, 
Treatment Phase
A clarification was made to these sections 
that patients with response first documented 
in Cycle 6 could receive 2 further cycles of 
therapy, for a total of 18 or 24 weeks of 
therapy
Ensure that all treatment arms 
are balanced and that all patients 
receive the same amount of 
study medication.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
37
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Synopsis, Overview 
of Study Design
Section 3.1, Study 
Design
This will be used to recalculate the sample 
size to allow for so that only patients with 
MCL provide the required an adequate
number of events for the final analysis
The study population is patients 
with MCL, however, MCL is a 
difficult diagnosis and can 
sometimes be misdiagnosed. It 
is critical for the final analysis 
that the total number of events 
includes only patients with a 
definitive diagnosis of MCL
Synopsis, Overview 
of Study Design
Section 3.1, Study 
Design
A central review of this data by the IDMC 
will occur. If the concordance rate 
adequately meets a pre-specified target, a 
decision will be made to discontinue central 
confirmatory review of the diagnosis of 
MCL. If the concordance rate does not meet 
the pre-specified criteria, central histology 
review will continue and the sample size 
may have to be adjusted
Central review of diagnosis of 
MCL for each patient will 
continue throughout the whole 
study for all patients
Synopsis, Overview 
of Study Design
An Independent Data Monitoring 
Committee (IDMC) will be formed and 
constituted according to regulatory 
agency guidelines. Detailed information 
regarding the composition of the IDMC 
and detailed IDMC procedures will be 
provided in the IDMC charter. The 
IDMC will review the data for the two 
interim analysis and provide 
recommendations according to the 
charter.
Defines upfront that an IDMC 
will be constituted and review 
of data at interim stage will be 
conducted by IDMC.
Synopsis, Study 
Population
Section 3.1, Study 
Design
Section 4.2, 
Inclusion Criteria
Patients must also be ineligible or not 
considered for bone marrow 
transplantation as determined by their 
treating physician and verified by the 
sponsor’s study physician
Patients in centers where bone 
marrow transplantation is not 
conducted or where patients 
refuse transplantation as 
recommended by their treating 
physician but would otherwise 
receive chemotherapy can be 
eligible for study entry.
Synopsis, Dosage 
and Administration
All patients will receive a minimum of 6 
cycles of therapy irrespective of the 
treatment arm to which they are 
randomized. In both treatment arms, if a 
patient shows a documented response at 
cycle 6 efficacy assessment that has not 
been documented previously, they can be 
considered for two further cycles (as per 
the investigator discretion) to consolidate 
that response. Thereafter, study 
medication dose and schedule reduction for 
toxicity will be allowed during the study
It is recommended for both R-
CHOP and VELCADE that 
responses should be 
consolidated with two further 
cycles of therapy.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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38
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Synopsis: Efficacy 
Evaluations
…progression-free survival (PFS), which is 
defined … the date of PD or relapse if CR 
or CRu…
To clarify definition of PFS
Synopsis: Efficacy 
Evaluations
Section 9.2.2.2, 
Secondary 
Endpoints
The death due to PD will be considered … 
after last disease assessment (or, at most, 1 
missing disease assessment visit)….
Provide clarity on which 
patients will be censored
Synopsis: Efficacy 
Evaluations
Patients who withdraw from study 
(withdrawal from study or lost to follow 
up) or receive subsequent anti-
lymphoma therapy without documented 
progression will be censored at the time 
of the last adequate disease assessment 
(before the start of such therapies). 
Patients who have not progressed and 
are still alive at the cutoff date for the 
final analysis will be censored at the last 
adequate disease assessment.
Provide clarity on how the final 
data analysis will handle 
censoring of patients.
Synopsis: Efficacy 
Evaluations
Section 9.2.2.2, 
Secondary 
Endpoints
ORR is defined as the proportion of patients 
who achieve CR, CRu, or PR relative to the 
per-protocol population. Disease response 
and progression will be evaluated according 
to the modified International Workshop to 
Standardize Response Criteria Group 
(IWRC) recommendations by radiographic 
imaging, and other appropriate 
investigations physical examination, and 
other procedures as necessary
Provide clarity that the central 
radiology review and 
assessments will be based on 
radiology alone and that the 
IWRC has been modified for the 
purposes of this study to allow 
for appropriate assessments for 
patients with MCL. The 
investigator may use other 
procedures to make a clinical 
diagnosis. For example, the 
diagnosis of CR would require a 
confirmation of a negative bone 
marrow examination if positive 
at baseline.
Synopsis: Efficacy 
Evaluations
Section 9.2.2.2, 
Secondary 
Endpoints
CR rate is defined as the proportion of 
patients who achieve CR and CRu relative 
to the per-protocol population. Disease 
response and progression will be evaluated 
according to the modified International 
Workshop to Standardize Response Criteria 
Group (IWRC) recommendations by 
radiographic imaging and other 
appropriate investigations. physical 
examination, and other procedures as 
necessary.
See above.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
39
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Synopsis, Efficacy 
Evaluations
Section 9.2.2.2, 
Secondary 
Endpoints
Additionally, the CT scans or other 
radiographic evaluations will be locally 
assessed by a radiologist during the conduct 
of the study for the purpose of treatment 
decision-making.
Assessments will be made 
locally but not necessarily by a 
radiologist.
Synopsis, Efficacy 
Evaluations
The death due to PD will be considered as 
an event if the date of death is within 6 
month after last disease assessment (or 
within one disease assessment period), 
otherwise, death will be censored at the 
date of last disease assessment
TTP does not include the event 
of death only progression
Synopsis, Safety 
Evaluations
The evaluation period will be defined as 
starting from first study related procedure
signing of informed consent to …..only 
grade 3 and 4  adverse events will be 
collected reported until completion
To clarify that all adverse events 
that are grade 3 and 4 will be 
collected
Synopsis, Safety 
Evaluations
In addition, 12-lead electrocardiograms 
(ECGs), echocardiograms/multiple 
uptake acquisition (MUGA) scans, vital 
signs…will be performed
Both Doxorubicin and 
VELCADE can give cardiac 
disorders and it is therefore 
considered important to 
document baseline left 
ventricular function or any 
cardiac abnormality.
Synopsis, Statistical 
Methods
For the secondary efficacy endpoints, the 
OS, 18-month survival, and TTP, and TNT
will be compared using stratified log-rank 
test. The 18-month survival rate will be 
compared using the standard error 
estimated from the Greenwood formula.
The Kaplan-Meier method will be used to 
estimate the distribution of PFS, OS 
(including the 18-month survival rate), 
TTP, and TNT for each treatment.
To provide clarity in analysis of 
data
Synopsis, Statistical 
Methods
The duration of response and treatment-free 
interval time to subsequent anti-lymphoma 
therapy will be summarized descriptively 
using the Kaplan-Meier method.
See above.
Synopsis, Statistical 
Methods
TNTThe time to subsequent anti-lymphoma 
therapy will be summarized descriptively
Changed name of this secondary 
endpoint to time to next 
treatment (TNT)
Time and Events 
Schedule
Numerous changes have been made to keep 
the Time and Events Schedule consistent 
with changes made to the body of the 
protocol.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
40
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 4.1, General 
Considerations
Section 4.2, 
Inclusion Criteria
Patients must also be ineligible for bone
…and verified with the sponsor study 
physician
Verification is no longer 
required as the data will be 
collected in eCRF.
Section 4.1, General 
Considerations
In addition, those patients for whom 
bone marrow transplantation is not 
available or who refuse a transplant as 
the treatment option for the frontline 
management of their MCL will be 
eligible to take part in this study. 
Clarification of study entry 
criteria.
Section 4.2, 
Inclusion Criteria
Male or female patients 18 years or older
(the patient must be at least the legal age 
limit to be able to give informed consent 
within the jurisdiction the study is taking 
place).
In some countries taking part in 
this study, the legal age limit to 
be able to give written consent 
is more than 18 years old.
Section 4.2, 
Inclusion Criteria
…such as by cytogenetics, fluorescent in 
situ hybridization (FISH) or polymerase 
chain reaction (PCR) Patients with a 
diagnosis of Stage 1 MCL will not be 
permitted to enter study
To clarify that Stage 1 is 
excluded.
Section 4.2, 
Inclusion Criteria
Female patients must be post menopausal 
…. They must also be prepared to 
continue birth control measures for at 
least 6 months after terminating 
treatment.
Vincristine recommendation in 
the SmPC.
Section 4.3, 
Exclusion Criteria
Active systemic infection requiring 
treatment and patients with known 
diagnosis of HIV or active hepatitis B 
(carriers of Hepatitis B are permitted to 
enter study)
Exclude high risk patients from 
study entry
Section 5.2, 
Procedures
The IPI will be assessed according to the 
following risk factors: age, stage of 
disease, performance status, LDH level 
and number of extranodal sites 
(attachment 10). For stratification, the 
scores will then be categorized (low [0-1 
factor], low-intermediate [2 factors], 
high- intermediate [3 factors] and high 
[4-5 factors]).
The stage of disease at diagnosis will also 
be used for stratification and be assessed 
using the American Joint Committee on 
Cancer NHL staging system 
(Attachment 11).
Provide detailed  information 
and guidance on how to 
calculate the IPI and assess the 
stage of disease for this study.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
41
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 6, Dosage 
and Administration
Study medication will be administered 
within 72 hours of randomization.
Provide a time window and 
limit for the period between 
randomizing and delivering the 
first dose of study medication to 
the patient.
Section 6, Dosage 
and Administration
Study medication dose and schedule 
reduction…. The time interval between 
sequential VELCADE doses must be at 
least 72 hours.
Provide a sufficient time 
interval between the VELCADE 
doses.
Section 6, Dosage 
and Administration
Last 4 paragraphs of Section 6 were added 
in this amendment.
Provide clarity that if a patient 
discontinues one or two drugs 
for  toxicity reasons, the patient 
is still to complete 6 cycles of 
therapy assigned to that arm to 
ensure that the patient is not 
withdrawn from study; and to 
provide an explanation that in 
the event of a toxicity, more 
than one drug may be found to 
be causally related and therefore 
more than one drug may need to 
have a dose adjusted or skipped
Section 6.1, Dose 
Adjustments for 
VELCADE
Dose adjustments for VELCADE must 
follow the SmPC. 
Section 6.1, Dose 
Adjustments for 
VELCADE
The EMEA (European Medicines 
Agency) has contraindicated the use of 
VELCADE in subjects with acute diffuse 
infiltrative pulmonary disease and 
pericardial disease.
Updated risk.
Section 6.1, Dose 
Adjustments for 
VELCADE
… VELCADE is to be held for up to 2 
weeks until the patient has an ANC 750 
cells/L and a platelet count 3025,000 
cells/L
Dose re-escalations of VELCADE are not 
permitted after dose modifications for 
the above toxicities.
On any day of VELCADE 
administration during a cycle (other than 
day 1 of each cycle) the hematology 
results must be:

Platelet count 25,000cells/L

ANC 750cell/L
If the above parameters are not met, the 
VELCADE dose can be held up to 2 
days. Doses of study drug that need to be 
To ensure consistency in 
recommendations
Provide clear guidance on the 
management of toxicities due to 
VELCADE and dose 
modification and to be 
consistent with the 
recommendation in the 
VELCADE SmPC.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
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Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
held within a cycle will be skipped, the 
dose will not be made up later in the 
cycle.
For VELCADE, cycle delays or study 
drug discontinuation are not required for 
lymphopenia of any grade.
Section 6.1.1, 
Velcade Dose 
Modifications for 
Neuropathic Pain or 
Peripheral Sensory 
Neuropathy
Dose or schedule re-escalations are not 
permitted for VELCADE after 
modification for neuropathic pain or 
sensory peripheral neuropathy.
See above.
Section 6.2, Dose 
Adjustments for 
Rituximab
In patients who develop viral hepatitis, 
rituximab should be discontinued and 
appropriate treatment including antiviral 
therapy initiated. Hepatitis B virus 
reactivation with fulminant hepatitis, 
hepatic failure and death has been 
reported in some patients treated with 
rituximab. It is recommended to closely 
monitor carriers of hepatitis B. In 
patients who develop worsening of their 
status, rituximab should be discontinued 
and appropriate treatment initiated. 
Patients with active hepatitis should not 
receive rituximab
Allow the inclusion of patients 
who are known to be carriers of 
Hepatitis B provided they are 
closely monitored. Patients with 
active hepatitis B are not to be 
included.
Section 6.3, Dose 
Adjustments for 
Cyclophosphamide
The most common adverse events 
experienced with cyclophosphamide are 
hematological toxicities. 
Myelosuppression with leucopenia, 
anemia, and thrombocytopenia can 
occur. The lowest leukocyte and 
thrombocyte levels occur in the first to 
second week after treatment is started. 
Recovery usually occurs within 3-4 weeks 
after treatment is started. Patients who 
develop hematological toxicities thought to 
be causally related to cyclophosphamide
must have their dose adjusted on Day 1 of 
each cycle according to the following 
table:…
Following treatment with 
cyclophosphamide, hemorrhagic cystitis 
and hematuria can occur. These may 
necessitate interruption of dosing.
Provide more guidance on the 
side effect profile of 
cyclophosphamide.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
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Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 6.4, Dose 
Adjustments for 
Doxorubicin
Dose adjustments for Doxorubicin must 
follow the provided SmPC.
Dose limiting toxicities of doxorubicin 
are myelosuppression and cardiotoxicity. 
Myelosuppresion includes leucopenia, 
anemia and thrombocytopenia reaching 
nadir at 10-14 days after treatment. 
Cardiotoxicity as an arrhythmia may 
occur directly after administration and 
ECG changes may last up to 2 weeks 
after administration. Cardiotoxicity may, 
however, occur several weeks or months 
after administration
Provide more guidance on the 
side effect profile of 
doxorubicin.
Section 6.5, Dose 
Adjustments for 
Vincristine
Dose adjustments for vincristine must 
follow the provided SmPC.
Neurologic toxicity is the most common 
adverse event experienced with 
vincristine and it is related to dose and 
age. In case of serious neurotoxicity, 
vincristine should not be administered, 
especially if there are signs of paraesthesia 
or paresis
Provide more guidance on when 
the dose of vincristine should be 
held in the event of a neurotoxic 
event.
Section 6.6, Dose 
Adjustments for 
Prednisone
Entire Section 6.6 is new addition to the 
protocol.
Allows for dose adjustment of 
high dose prednisone within the 
study if a patient develops an 
adverse event and is not tolerant 
of 100mg/m2. But the patient 
still needs to receive a minimum 
amount of prednisone during the 
study.
Section 6.7, Cycle 
Delay
The following parameters must be met 
on the first day of each cycle (other than 
cycle 1):
·Platelet count 50 x 109 cells/L (prior 
platelet transfusion is allowed)
·Hemoglobin 8g/dL (4.96mmol/L) 
(prior RBC transfusion or recombinant 
human erythropetin use is allowed)
·ANC 1.0 x 109 cells/L
·Nonhematologic toxicity must have 
recovered to Grade 1 or baseline. 
If the above parameters are not met, the 
start of the next cycle will be held on a 
weekly basis for a maximum of 3 weeks 
for recovery to the specified levels
Provide clarity on what the 
minimum requirements are at 
the beginning of each cycle 
prior to study drug 
administration.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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FINAL – 3 February 2014
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Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 7, 
Compliance
Patients will be given diary cards to 
complete for the prednisone dosing at 
home on Days 2-5. The patients must 
bring these to the site on every visit so 
that the diary cards can be checked by 
study site personnel for compliance.
To highlight that compliance 
and drug accountability will be 
ensured for the prednisone 
dosing that the patient will be 
self medicating on Days 2-5.
Section 8.1, 
Permitted 
Medications and 
Supportive 
Therapies
All supportive therapies (such as any 
antinausea medication, MESNA for the 
prevention of hemorrhagic cystitis or 
antiviral prophylaxis for herpes) …
To provide clarity that any 
supportive care required for the 
patient can be given with the 
exceptions listed. 
Section 9.1.1, Study 
Procedures 
Overview
If sufficient sample is available, a portion 
of the biopsy required for central histology 
review for this study may be utilized…
Clarify which tissue sample is 
being referenced
Section 9.1.1, Study 
Procedures 
Overview
In the absence of archival tumor tissue 
blocks or fresh tumor sample collection, 
the patient has the option to consent to a 
5 mL bone marrow sample for the 
biomarker analyses.
To clarify that the 5 mL bone 
marrow sample for biomarker 
analysis is optional and not 
mandatory.
Section 9.1.2, 
Pretreatment Phase
All patients must sign informed consent … 
in Sections 4.2 and 4.3 before 
randomization before the first dose of 
investigational product can be administered
To clarify when informed 
consent must be signed.
All patients must undergo … (may be 
performed up to 28 days before 
randomization); this may be performed with
using oral contrast….
To clarify that oral contrast 
should be used instead of IV if 
the patient is intolerant of IV 
contrast.
Evaluation of other sites …. before first 
dose of study medication randomization.
To clarify when sites of disease 
need to be evaluated
These materials must be sent to the central 
pathologist after the patient receives the 
first dose of study medication on Day 1 
Cycle 1  before Day 1 of Cycle 2.
To clarify when the material 
required for central review must 
be sent to the central laboratory.
Section 9.1.3, 
Treatment Phase
Treatment must start within 72 hours of 
randomization
Provide a time window and 
limit within which the patient 
has to receive study medication.
All patients who, on Day 1 Cycle 1 of  the 
treatment phase, continue to meet the 
eligibility requirements as assessed during 
screening will be randomized in the study 
and start treatment within 72 hours of 
randomization with the assigned study 
medication.
Provide clarity on when the 
patient must meet eligibility 
criteria.
Section 9.1.3, 
Treatment Phase
This visit will be performed 30 days (with 
a maximum window of +7 days) after the 
last dose…
Provide a maximum time limit 
for when the end of treatment 
visit can occur.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
45
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 9.1.4, 
Follow-up
For both short-term and long-term follow-
up, time windows were added to visits
Provide maximum time limits 
within which the visits should 
occur
Section 9.1.4, 
Follow-up
For both short-term and long-term follow-
up, clarified that grade 3 and 4 adverse 
events will be reported.
After treatment only grade 3 and 
4 adverse events need to be 
collected.
Section 9.1.4.1, 
Short-term 
Follow-up
Following the End-of-Treatment visit, all 
patients will have efficacy assessments 
every 6 weeks (± 4 days) for 18 weeks 
(± 7 days)
To provide a time window for 
when patients should be 
contacted.
Section 9.1.4.2, 
Long-term 
Follow-up for 
Survival Status 
(Every 12 Weeks)
Patients will be contacted every 12 weeks 
(± 7 days) until death, via telephone or 
office visit to assess survival status.
Only survival data, grade 3 and 4 adverse 
events and information on subsequent anti-
lymphoma therapies will be collected in the 
long-term follow-up phase.
To provide a time window for 
when patients should be 
contacted.
To clarify that information on 
subsequent anti-lymphoma 
therapy will also be collected.
Section 9.2, Efficacy
During the study, disease response will be 
assessed using CT scans with IV contrast of 
the neck, chest, abdomen and pelvis (at 
minimum, oral contrast should  be used if 
IV contrast is contraindicated
Emphasize that all CT scans 
should be done with IV contrast 
in the first instance and oral to 
be used in the event that IV is 
contraindicated.
Section 9.2, Efficacy
…review of hematology and clinical 
chemistry results may also occur at the 
site level, but for the purpose of the 
central review, only radiographic 
evaluations will be assessed.
Clarification
Section 9.2.1.2, 
Definitions of 
Measurable and 
Assessable Disease
Measurable sites of disease are defined as 
lymph nodes or lymph node masses, 
splenic nodules, hepatic nodules, and other  
or extranodal sites of lymphoma.
Many patients will have 
extranodal sites of lymphoma 
and for MCL it is important to 
allow that these sites of disease 
be evaluable for response.
Section 9.2.1.2, 
Definitions of 
Measurable and 
Assessable Disease
Measurement must be determined by 
radiological imaging or physical 
examination
Measurable lesions can only 
accurately be measured by 
radiological imaging.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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Section(s)
Text Changes
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Description of Change /
Rationale for Change
Section 9.2.1.2, 
Definitions of 
Measurable and 
Assessable Disease
Up to 10 measurable sites of disease
Dominant lymph node masses include up to 
6 nodal masses that are clearly 
measurable… will be followed for each 
patient. Measurable sites of disease The 
dominant nodal masses should be chosen 
such that they are representative of the 
patient’s disease (this includes splenic and 
extranodal disease). If there are lymph 
nodes or lymph node masses… should 
always be included in the dominant masses. 
In addition, selection of measurable 
lesions the dominant masses should be 
from as disparate regions of the body as 
possible. Extranodal sites of disease cannot 
be chosen as dominant lymph node masses
For MCL and assessments in 
frontline setting, the distinction 
between dominant and non 
dominant lesions are irrelevant 
as all sizeable lesions that fit the 
definition of measurable 
(maximum 10) should be 
potentially considered for study 
evaluation
Section 9.2.1.2, 
Definitions of 
Measurable and 
Assessable Disease
All other measurable sites of disease that 
are not included as dominant lymph node 
masses are considered nondominant 
measurable disease.
·Up to 10 measurable sites of disease (the 
total number of dominant lymph node 
masses and nondominant sites of disease) 
will be followed for each patient. All other 
sites of disease will be considered 
assessable, even if they are >1 cm in 2 
perpendicular dimensions.
For MCL, there is extensive 
extranodal involvement and the 
wording has been adapted to 
allow for the selection of 
extranodal sites of disease as 
measurable disease to be 
monitored, this will be more 
representative of  the disease.
Section 9.2.1.3, 
Criteria for 
Response Categories
All measurable lymph nodes and nodal 
masses (including splenic and extranodal 
nodes and masses) must have regressed… 
>1.5 cm before therapy). New bullet next:
Non-measurable and assessable nodes
and any Previously involved nodes
(including splenic and extranodal nodes 
and masses) that were 1.1 to 1.5 cm …
Clarify that splenic, hepatic and 
extranodal sites of disease can 
be used as measurable lesions 
and that all measurable sites of 
disease must fulfil these criteria. 
The is changed to > as a 
typographical correction. 
Provide clarity on how much all 
other nodes than those selected 
as measurable nodes should 
regress by in order for the 
criteria of CR to be met. This is 
a frontline study so there will be 
no previously measured lesions 
available


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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Section(s)
Text Changes
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Description of Change /
Rationale for Change
Section 9.2.1.3, 
Criteria for 
Response Categories
At least a 50% decrease in sum of the 
product of the diameters (SPD) of up to six 
of the largest dominant nodes or nodal 
masse the measurable sites of disease
Criteria for PR have been 
changed to align with the 
changes in CR.
At least 50% or greater decrease in the SPD 
of nondominant measurable sites of disease
No increase should be observed in the size 
of other nodes, liver, or spleen any site of 
disease that meet the criteria for relapsed 
or progressive disease
Non-measurable Splenic and hepatic
nodules must regress by 50% in their SPD 
or, for single nodules, in the greatest 
transverse diameter
With the exception of splenic and hepatic 
nodules, involvement of other organs is 
usually assessable and no measurable 
disease should be present
No new sites of disease should be observed 
that meet the criteria for relapsed or
progressive disease
Progressive Disease (after PR/SD) or 
Relapsed Disease (after CR/Cru)
Changes are made to 
incorporate extranodal disease 
as measurable disease, so the 
PD criteria have been changed 
to reflect this.
Progressive or relapsed disease requires 
any one of the following:
In #1, dominant node or nodal mass
replaced with measurable site of disease
In #2, any measured extranodal site of 
disease replaced with any non-measurable 
site
#3, 50% increase from nadir in the SPD of 
any other previously identified site of 
disease non-measured site of disease that 
was followed from baseline, as visually 
determined


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
#4. Appearance of any new lymph node site 
of disease that measures >1.5 cm in long 
axis and >1.0 cm in short axis, or any 
measurable extranodal site of disease that 
measures >1 cm in 2 perpendicular 
dimensions unequivocal evidence of a new 
site of assessable disease (for example 
effusions, acites, masses with indistinct 
borders, new involvement of the bone 
marrow).
#5. Deleted.
Disease that is only assessable (e.g., pleural 
effusions, bone lesions) will be recorded as 
no change, increased, decreased, or new, 
present or absent only, unless, while an 
abnormality…
To be consistent with CRF data 
collection
Section 9.2.2.2, 
Secondary 
Endpoints
CR rate is defined as the proportion of 
patients who achieve CR and CRu relative 
to the per-protocol population. Disease 
response and progression will be evaluated 
according to the International Workshop to 
Standardize Response Criteria Group 
(IWRC) recommendations by radiographic 
imaging, physical examination, and other 
procedures as necessary
Correction of typographical 
error, this sentence is repeated 
from above.
Section 9.2.2.2, 
Secondary 
Endpoints
TTP will be analysed in the ITT 
population and is defined as….
Clarify to which study 
population the analysis will 
apply.
Section 9.2.2.2, 
Secondary 
Endpoints
OS will be analysed in the ITT 
population
Clarify to which study 
population the analysis will 
apply.
Section 9.2.2.2, 
Secondary 
Endpoints
TNT subsequent anti-lymphoma therapy
will be assessed… to the start of anti-
lymphoma therapy subsequent to study 
treatment alternative therapy. Patients who 
do not receive alternate therapy… analysis 
at the date of the last visit. death or at the 
last known date alive
Define time to next treatment
Section 9.2.2.2, 
Secondary 
Endpoints
Treatment-free interval will be assessed, 
for those patients who have terminated 
study treatment, from the end of the 
study treatment to the start of anti-
lymphoma therapy subsequent to the 
study treatment. Patients who do not 
receive alternate therapy will be 
censored in the analysis at the date of the 
last visit.
Define treatment-free interval


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Section(s)
Text Changes
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Description of Change /
Rationale for Change
Section 9.3, Patient 
Reported Outcomes
Time windows for eligible assessment will 
be +/- 2 weeks of the scheduled assessment.
Section 9.4, Medical 
Resource Utilization
MRU data associated with …. will be 
collected for all patients during the 
study…. This will be collected at the 
beginning of each cycle; the data entered 
will relate to the previous cycle
Section 9.5, 
Pharmacogenomics
Evaluations
A previously embedded paraffin tumor 
sample, a whole blood sample (10 mL), (in 
the absence of paraffin tumor, a fresh 
tumor sample or 5 mL bone marrow 
sample), and three 5 mL serum samples…
See below.
Section 9.5, 
Pharmacogenomics
Evaluations
…a portion of the biopsy required for this 
study for the central review of diagnosis 
of MCL may be utilized for proteasome
and Ki-67 analyses in the absence of 
archival material. If there is no archived 
tumor sample available, patients can 
optionally consent to undergo a biopsy to 
obtain fresh tumor sample or to provide 
a 5 mL sample of bone marrow. Whole 
blood, bone marrow and serum samples
For the biomarker part of the 
study changes are made to 
clarify that the only mandatory 
requirement is the provision of 
the archived tumour sample. 
The consent to provide a 10ml 
whole blood sample plus the 
three 5 mL serum samples is 
optional.
Section 9.5.1.1, 
Somatic Mutational 
Status of Tumor 
Tissue
…the patient has the option to consent to 
collection of a fresh tumor tissue sample or 
provide a 5 mL bone marrow sample. If 
sufficient sample is available, a portion of 
the biopsy required for this study for the 
central review of the diagnosis of MCL
may be utilized in the absence of archival 
material. A bone marrow sample will also 
be collected from all patients at baseline.
See above.
Section 9.5.1.1, 
Somatic Mutational 
Status of Tumor 
Tissue
DNA extracted from archived tumor tissue 
and/or bone marrow samples will be 
utilized for these analyses
See above.
Section 9.5.1.3, 
Biomarkers
Paraffin embedded, formalin-fixed tumor or 
fresh frozen tissue will also be subjected to 
immunohistochemical analysis to quantify 
the levels of Ki-67, p27, p65 subunit of
NF-Kb
Clarification
Section 9.5.2, 
Pharmacogenomics
and Biomarker 
Samples
If archived tumor tissue is not available for 
mutation testing, the patient can still be 
entered into the study and has the option of 
providing a fresh tumor tissue sample. A or 
a 5 mL bone marrow sample. and A whole 
blood sample will be collected…
See explanation under Section 
9.5


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
50
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 9.6, Safety 
Evaluations
After 30 days after the last dose…only 
grade 3 and 4 adverse events will be 
reported…
To clarify that all adverse events 
that are grade 3 and 4 will be
collected
Section 9.6, Safety 
Evaluations
ß -2 microglobulin will be measured at 
screening and at relevant time points 
during the study, eg efficacy assessment 
timepoints and whenever PD is 
documented.
ß -2 microglobulin is potentially 
a prognostic indicator, 
collection of these samples 
allows for future subanalyses
Section 9.6, Safety 
Evaluations
During short-term follow-up, only LDH 
will be measured is required
Grammatical correction 
Section 9.6, Safety 
Evaluations
Urinalysis (if not all parameters are 
captured by the laboratory performing 
the tests, the investigator should report 
whichever ones are available)
Not all of these tests are 
routinely done by all the 
laboratories, however it is 
important to capture as much 
information as is analysed.
Section 9.6, Safety 
Evaluations
Electrocardiogram 
(ECG)/Echocardiography or Multiple 
Uptake Gated (MUGA) scans
Both Doxorubicin and 
VELCADE can give cardiac 
disorders and it is therefore 
considered important to 
document baseline left 
ventricular function or any 
cardiac abnormality.
Section 9.6, Safety 
Evaluations
Echocardiography or MUGA scans will 
be performed as mandatory at screening 
but thereafter optionally according to 
clinical need. The purpose is to document 
baseline ventricular and septal 
parameters as well as baseline 
ventricular function. Any follow-up test 
method should be the same as the 
screening method.
To ensure consistency in 
follow-up measurements and 
assessments of cardiac status.
Section 10.3, 
Withdrawal From 
the Study
The DNA extracted from the patient's 
blood, bone marrow or fresh or archived 
paraffin embedded tissue will be retained 
and used in accordance
Clarification
Section 11.1, 
Sample Size 
Determination
The median PFS… is 18 months36
Reference added.
Section 11.3, 
Efficacy Analyses
The overall response rate and overall 
complete response rate will be obtained… 
using the Cochran-Mantel-Haenszel 
(CMH) chi-square test
Clarification as to which 
chi-square test will be used
Section 11.3, 
Efficacy Analyses
The duration of response and treatment-
free interval time to subsequent anti-
lymphoma therapy will be summarized.
Change of secondary endpoint 
to treatment-free interval


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
51
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 11.8, Interim 
Analyses
If the observed concordance rate is 95% 
… and central histological review of the 
diagnosis of MCL will be discontinued. If 
the observed difference is less than 95% … 
and central confirmation of the diagnosis of 
MCL will continue.
Central review of histological 
diagnosis will continue 
irrespective of concordance rate.
Section 11.8, Interim 
Analyses
The first interim analysis will also review 
the safety data collected to date. Safety 
data will be reviewed after at least one 
cycle for the first 100 treated patients, 
irrespective of whether they complete 
treatment within that first cycle. 
To clarify that the first IA will 
also review the safety data in 
the intent-to-treat population.
….of the experimental arm (VcR-CAP) will 
be declared over the comparator arm 
(R-CHOP). There will also be a review of 
the safety data at 2nd interim analysis.
Clarify that the 2nd IA will also 
have a review of the safety data.
Section 11.9, 
Independent Data 
Monitoring 
Committee
…to evaluate safety data and results of the 
prospectively defined interim analyses of 
efficacy and central histological review.
Clarify that the IDMC will 
review both interim analyses 
data.
Section 12.2.1, 
Procedures
PD or relapse will not be reported as an 
adverse event, however, unexpected 
clinical signs or symptoms must be 
reported, even if they are eventually 
attributable to PD or relapse.
Provide clarity on what should 
be reported.
Section 12.2.3, 
Pregnancy
Any patient who becomes pregnant during 
the study must be promptly withdrawn from 
treatment within the study
Clarify that if the patient 
becomes pregnant they should 
not receive any more treatment 
but should in fact be followed 
up for outcome.
Section 13.1, 
Physical description 
of study drugs
Vincristine is supplied as a lyophilized 
powder or as United States Pharmacopeia 
(USP), sterile, preservative–free, single 
use only, solution available for 
intravenous use in 2 mL vial.
Clarification on Vincristine 
information
Section 13.2, 
Packaging
Packaging information was updated for all 
study medication.
Providing clarity
Section 13.2, 
Packaging
Prednisone 5 mg and 20 mg tablets….
Correcting typographical error
Section 13.4, 
Preparation and 
Handling
Prednisone should be stored at Store at 
Controlled Room Temperature 15º to room 
temperature 
To ensure compliance as 
prednisone will be self 
medicated by the patient at 
home


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
PROTOCOL AMENDMENTS (CONTINUED)
FINAL – 3 February 2014
52
Applicable 
Section(s)
Text Changes
(new text in bold; deleted text in strikeout)
Description of Change /
Rationale for Change
Section 13.4, 
Preparation and 
Handling
Cyclophosphamide is a cytostatictoxic  
agent. As with all cytostatictoxic agents, 
caution is required when preparing and 
handling cyclophosphamide. Cytostatictoxic 
agents….
Doxorubicin is a cytostatictoxic agent. As 
with all cytostatictoxic agents, caution is 
required when preparing and handling 
doxorubicin. Cytostatictoxic agents….
Vincristine is a cytostatictoxic agent. As 
with all cytostatictoxic agents, caution is 
required when preparing and handling 
Vincristine. Cytostatictoxic agents….
Clarify the classification of 
agents.
Section 13.5, Drug 
Accountability
Patients will be given diary cards to 
complete for the prednisone dosing at home 
on days 2-5. The patients must bring these 
to the site on every visit so that the diary 
cards can be checked by study site 
personnel for compliance.
To highlight that compliance 
and drug accountability will be 
ensured for the prednisone 
dosing that the patient will be 
self medicating on days 2-5
Section 15.2.3, 
Informed Consent
date a separate pharmacogenomics
informed consent form indicating 
agreement to participate in 
pharmacogenomics and biomarker 
research.
Clarification
Attachment 5
Change in shipping address
Samples will be received and 
handled through J&JPRD, 
Department of 
Pharmacogenomics. Samples 
will be distributed from the 
repository at JJPRD to the 
vendor identified to perform the 
protocol specified analyses.
Attachment 7
Deleted last page
The questionnaire has been 
updated and no longer includes 
the last page.
Attachment 10 and 
Attachment 11
Added to the protocol.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
53
A Randomised, Open-Label, Multicentre Phase 3 Study of the Combination of 
Rituximab, Cyclophosphamide, Doxorubicin, VELCADE, and Prednisone 
(VcR-CAP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and 
Prednisone (R-CHOP) in Patients With Newly Diagnosed Mantle Cell Lymphoma 
who are not Eligible for a Bone Marrow Transplant
SYNOPSIS
OBJECTIVES
Primary Objectives
To determine which regimen rituximab, cyclophosphamide, doxorubicin, VELCADE, and prednisone 
(VcR-CAP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) 
provides greater benefit in patients with newly diagnosed mantle cell lymphoma (MCL), as assessed 
by significant prolongation of progression-free survival (PFS).
Secondary Objectives
The secondary objectives are:

To determine overall survival (OS)

To determine time to progression (TTP)

To determine the 18-month survival rate

To determine overall response (CR+CRu+PR) and CR  (CR + CRu) rates

To determine the duration of response, time to next treatment (TNT), and treatment-free interval

To evaluate the safety of VcR-CAP compared to R-CHOP
Exploratory Objectives

To evaluate patient-reported outcomes (PROs) utilizing the European Organisation for Research 
and Treatment of Cancer-quality of life questionnaire (EORTC-QLQ-C30), EQ-5D, and Brief 
Fatigue Inventory (BFI) instruments

To evaluate medical resource utilization (MRU) information which may be used in future economic 
evaluation models

To identify patient populations that are more or less likely to respond to VcR-CAP or R-CHOP 
through the evaluation of biomarker analyses
OVERVIEW OF STUDY DESIGN
This is a randomized, open-label, multicenter, prospective study to compare the efficacy and safety of 
the combination of VcR-CAP to that of R-CHOP in patients who have newly diagnosed MCL of
Stage II, III, or IV and who are ineligible to undergo bone marrow transplantation.
At least 486 patients will be randomized into one of 2 arms (Treatment Arm A or Treatment Arm B) in 
a 1:1 ratio taking into account the following stratification factors: International Prognostic Index (IPI) 
and stage of disease at diagnosis.
Treatment Arm A: (VcR-CAP) rituximab 375 mg/m2 intravenous (i.v.) on Day 1, cyclophosphamide 
750 mg/m2 i.v. on Day 1, doxorubicin 50 mg/m2 i.v. on Day 1, VELCADE 1.3 mg/m2 i.v. on Days 1, 
4, 8 and 11, prednisone 100 mg/m2 per os (p.o.) on Day 1 to Day 5 of a 21 day (3 week) cycle for 
6 cycles (or 8 cycles if a response is first documented at Cycle 6 assessment).
Treatment Arm B: (R-CHOP) rituximab 375 mg/m2 i.v. on Day 1, cyclophosphamide 750 mg/m2 i.v. 
on Day 1, doxorubicin 50 mg/m2 i.v. on Day 1, vincristine 1.4 mg/m2 (maximum total of 2 mg) i.v. on 
Day 1, prednisone 100 mg/m2 p.o. on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles (or 
8 cycles if a response is first documented at Cycle 6 assessment).


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
SYNOPSIS (CONTINUED)
FINAL – 3 February 2014
54
Patient participation will include a Screening Phase, a Treatment Phase, a Short-term Follow-up Phase, 
and a Long-term Follow-up Phase. The Screening Phase will be up to 28 days (56 days for bone 
marrow evaluation) prior to randomization. Randomization can only occur after central confirmation 
of diagnosis of MCL except for potential patients in China, where central confirmation of sample 
adequacy on lymph node tissue is required. The Treatment Phase will extend from randomization until 
6 cycles of treatment have been given (or 2 cycles beyond a response documented in Cycle 6). The 
Short-term Follow-up Phase will extend from the End-of-Treatment Phase to PD (progressive disease) 
(or relapse if the patient achieves a CR or CRu), initiation of alternate antineoplastic therapy, decision 
by the patient to completely withdraw from the study or refusal to take part in any further study related 
procedures or follow-up, or death. The Long-term Follow-up Phase will be used to assess survival and 
will document when the patient has died. Patients who are withdrawn from the study due to adverse 
events, or reasons other than above and are willing to continue study follow-up procedures can be 
followed up as per protocol for PD. Upon notification by the sponsor that clinical cutoff for the 
primary analysis (295 PFS events) has been reached, radiographic assessment of disease progression 
will stop, and all subjects in short-term follow-up will enter the Long-term Follow-up Phase.
Patients will be randomized and assigned to either Treatment Arm A or B. They will receive 6 cycles 
of therapy; if a documented response is noted at Cycle 6 assessment that has not been previously
observed, the patients can receive a further 2 cycles to consolidate the response. Patients may receive 
less therapy or deviate from the planned treatment dose and schedule due to adverse events, as 
specified by the dose and schedule modifications and cycle delays defined in the protocol. 
The total study duration from randomization of the first patient until the last PFS event required for the 
final analysis is expected to be approximately 42 months (approximately 24 months for enrollment and 
approximately 18 months for follow up). 
Three interim analyses are planned for this study. The first interim analysis will occur after the first 
100 patients have been randomized into the study and will assess safety and the concordance rate of 
the diagnosis of MCL when central review is compared with the investigator assessment of the 
diagnosis. Central review is defined as a review by an independent pathologist and in the event that 
there is insufficient tumor material available for pathological confirmation of MCL, an independent 
lymphoma expert will review relevant local diagnostic and clinical information to verify the diagnosis 
of MCL. Samples determined as negative for MCL diagnosis by the independent pathologist cannot be 
evaluated by the independent lymphoma expert and will not be considered MCL confirmed. The 
concordance rate of the diagnosis of MCL will also be reviewed at 50% accrual. This may be used to 
recalculate the sample size to ensure an adequate number of PFS events (approximately 280) in those 
subjects with a centrally confirmed MCL diagnosis at the time of the final analysis (295 PFS events in 
total). A second interim analysis for safety will occur after 100 patients in each arm (200 patients in 
total) have either completed the study treatment or discontinued the study treatment, which allows 
sufficient exposure for review of cumulative toxicity. The third interim analysis is planned after at least 
148 events have occurred in the intent-to-treat (ITT) population. 
If, at the third interim analysis, pre-specified boundaries for PFS are met then the study will be 
terminated and superiority of the experimental arm (VcR-CAP) will be declared over the comparator 
arm (R-CHOP). If pre-specified boundaries are not met at the third interim analysis, the final analysis 
of the study will occur after 295 events have been observed in the ITT population.
An Independent Data Monitoring Committee (IDMC) will be formed and constituted according to 
regulatory agency guidelines. Detailed information regarding the composition of the IDMC and 
detailed IDMC procedures will be provided in the IDMC charter. The IDMC will review the data for 
the 3 interim analyses and provide recommendations according to the charter.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
SYNOPSIS (CONTINUED)
FINAL – 3 February 2014
55
STUDY POPULATION
Male and female patients who have a confirmed molecular diagnosis of MCL (Stage II, III or IV) and 
have had no other prior treatments for their disease will be eligible to take part in the study. Patients 
must also be ineligible for bone marrow transplantation as determined by their treating physician.
DOSAGE AND ADMINISTRATION
Patients randomized to Treatment Arm A will receive rituximab 375 mg/m2 i.v. on Day 1, 
cyclophosphamide 750 mg/m2 i.v. on Day 1, doxorubicin 50 mg/m2 i.v. on Day 1, VELCADE 
1.3 mg/m2 (i.v.) on Days 1, 4, 8 and 11, prednisone 100 mg/m2 p.o. on Day 1 to Day 5 of a 21 day 
(3 week) cycle for 6 cycles (VcR-CAP). VELCADE will be administered as a 3 to 5 second 
intravenous bolus before the other medications are administered. Thereafter, rituximab will be 
administered followed by the other study medications as per the directions provided in the respective 
product labels.
Patients randomized to Treatment Arm B will receive rituximab 375 mg/m2 i.v. on Day 1, 
cyclophosphamide 750 mg/m2 i.v. on Day 1, doxorubicin 50 mg/m2 i.v. on Day 1, vincristine 
1.4 mg/m2 (maximum total of 2 mg) i.v. on Day 1, prednisone 100 mg/m2 p.o. on Day 1 to Day 5 of a 
21 day (3 week) cycle for 6 cycles (R-CHOP). All study medications will be administered according to 
the directions provided in the respective product labels.
All patients will receive a minimum of 6 cycles of therapy irrespective of the treatment arm to which 
they are randomized. In both treatment arms, if a patient shows a documented response at Cycle 6 
efficacy assessment that has not been documented previously, they can be considered for 2 further 
cycles (as per the investigator discretion) to consolidate that response.
EFFICACY EVALUATIONS/CRITERIA
The primary endpoint is progression-free survival (PFS), which is defined as the interval between the 
date of randomization and the date of PD or relapse if CR or CRu or death, whichever is first reported, 
in the intent-to-treat (ITT) population. Death due to PD will be considered as an event if the date of 
death is within 6 months after last disease assessment (or, at most, 1 missing disease assessment visit), 
otherwise, death will be censored at the date of last disease assessment. Patients who withdraw from 
study (withdrawal from study or lost to follow-up) or receive subsequent anti-lymphoma therapy 
without documented progression will be censored at the time of the last adequate disease assessment 
(before the start of such therapies). Patients, who have not progressed and are still alive at the cutoff 
date for the final analysis, will be censored at the last adequate disease assessment.
Secondary endpoints are:

ORR is defined as the proportion of patients who achieve CR, CRu, or PR. Disease response and 
progression will be evaluated according to the modified International Workshop to Standardize 
Response Criteria for Non-Hodgkin’s Lymphoma (IWRC) recommendations by radiographic 
imaging and other appropriate investigations.
The computed tomography (CT) scans or other radiographic evaluations will be centrally assessed 
by independent radiology review to confirm disease response for the purpose of the efficacy 
analyses. Additionally, the CT scans or other radiographic evaluations will be locally assessed 
during the conduct of the study for the purpose of treatment decision-making. 
CR rate is defined as the proportion of patients who achieve CR and CRu. Disease response and 
progression will be evaluated according to the modified IWRC recommendations by radiographic 
imaging and other appropriate investigations.

Duration of response (CR, CRu, or PR) will be calculated from the date of initial documentation of 
a response to the date of first documented evidence of PD (or relapse for patients who experience 
CR or CRu on this study).


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
SYNOPSIS (CONTINUED)
FINAL – 3 February 2014
56

TTP is defined as the duration from the date of randomization until the date of first documented 
evidence of PD (or relapse for patients who experience CR or CRu on this study).

OS is measured from the date of randomization to the date of the patient’s death. If the patient is 
alive or the vital status is unknown, the date of death will be censored at the date that the patient is 
last known to be alive. Long-term follow-up will continue until June 2017. 

18-month survival is defined as estimated survival rate at 18 months (Kaplan-Meier estimate).

TNT is measured from the date of randomization to the start date of any anti-lymphoma treatment 
subsequent to the study treatment. Those patients without subsequent treatment will be censored at 
the date of the last visit. 

Treatment-free interval is measured from the end of the study treatment to the start date of any 
anti-lymphoma treatment subsequent to the study treatment. Those patients without subsequent 
treatment will be censored at the date of the last visit.
PHARMACOGENOMICS EVALUATIONS
Pharmacogenomics evaluations in this study will help to identify patient populations that are more or 
less likely to respond to VcR-CAP or R-CHOP through the evaluation of a defined set of biomarkers. 
Analysis of selected somatic and germline mutations are mandatory where health authorities have 
approved of this testing, and will require a separate patient informed consent.
SAFETY EVALUATIONS
All patients who receive treatment will be considered evaluable for toxicity. The evaluation period will 
be defined as starting from signing of informed consent to at least 30 days after the last dose of study 
drug. Blood samples for serum chemistry and hematology will be collected. In addition, 12-lead 
electrocardiograms (ECGs), echocardiograms/multiple uptake gated acquisition (MUGA) scans, vital 
signs, and physical examinations will be performed. Instances of second primary malignancy will be 
documented for the duration of a subject’s participation in the study, regardless of onset date and 
relationship to study drug.
STATISTICAL METHODS
The sample size calculation for the study population is based on the following assumptions. The
median PFS of R-CHOP is 18 months. Assuming that VcR-CAP improves this median PFS by 40%, 
i.e., from 18 months to 25 months, a total number of 295 (PD or death) events provides 80% power 
(alpha = 0.05, 2-sided) to detect such improvement. Assuming a 24 month accrual and 18 month 
follow-up, a total of 486 patients is needed for the study (243 per arm).
If 280 PFS events are observed in the subset of subjects with a centrally confirmed diagnosis of MCL, 
the study can achieve approximately 80% power to detect a hazard ratio of 1.4 in this subset of patients 
with a 2-sided log-rank test (α=0.05).
Demographic and baseline characteristics will be summarized according to treatment group. 
Stratified log-rank test will be used to compare PFS between the 2 treatment arms in the primary 
efficacy analysis.
For the secondary efficacy endpoints, the OS, TTP, and TNT will be compared using stratified 
log-rank test. The 18-month survival rate will be compared using the standard error estimated from the 
Greenwood formula. The Kaplan-Meier method will be used to estimate the distribution of PFS, OS 
(including the 18-month survival rate), TTP, and TNT for each treatment.
ORR and CR rate will be obtained and comparison of the rates will be performed between 2 treatment 
arms using the Cochran-Mantel-Haenszel (CMH) chi-square test. The 95% confidence interval for the 
difference of response rate between 2 treatment arms will be given.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
SYNOPSIS (CONTINUED)
FINAL – 3 February 2014
57
The duration of response and treatment-free interval will be summarized descriptively using the 
Kaplan-Meier method. There will be no formal comparison of these endpoints between treatment 
groups because they are not statistically comparable.
TNT will be summarized descriptively. There will be no formal comparison of these endpoints 
between treatment groups because they are not statistically comparable.
For all efficacy endpoints, the primary analysis is to be performed in the ITT population. A sensitivity 
analysis will be performed in the subset of subjects with a centrally confirmed diagnosis of MCL. 
Approximately 280 events are expected in this subset of subjects at the time of the final analysis 
(295 PFS events in total), which can provide around 80% power to detect a hazard ratio of 1.4 using a 
2-sided log-rank test (α=0.05).
Detailed tabulations of safety data (adverse events, vital signs, physical examinations and clinical 
laboratory tests) will be provided for all patients who receive study drug.  The number and percent of 
patients with treatment-emergent adverse events will be summarized. Summary of other safety 
parameters by treatment group will be provided where appropriate.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
58
TIME AND EVENTS SCHEDULE
Procedure
Screening
Cycles 1- 6 (and 7-8, if applicable)
Response 
Evaluationd
Days 11-21 of 
Cycles 2, 4, 6 
(and 8, if 
applicable)
Early Withdrawal/ 
End-of-Treatment 
Phasee
Short-term 
Follow-upf until 
PD/initiation 
alternate 
therapy/withdrawal
Long-term 
Follow-upg 
until death
Day1
Day4
Day 8
Day 11
Informed consent
X
Inclusion/ Exclusion
X
Demographics/Medical history
X
Complete physical examination
X
X
X
Limited physical examinationaa
Xa
X
X
X
X
ECOG performance status
X
Xa
X
X
X
Vital signs
Xa
X
X
X
X
X
X
Weight/Height
Xa
X
X
BSA
Xa
ECG
X
Xa
X
Echocardiogram/MUGA scany
X
Neck and chest CT with oral and i.v. 
contrasth
X
X
X
X
Abdomen and pelvis CT with oral and i.v. 
contrasth
X
X
X
Xcc
Evaluation of other sites of diseasei
X
X
X
Xcc
Bone marrow aspirate and biopsy
Xj
Xk
Xk
Xk
Hematologyl
X
Xx
Xbb
Xbb
Xbb
X
X
Clinical Chemistrym
X
Xx
X
X
Xt
Serum/Urine -HCG pregnancy test
(for females)
X
Xa, x
X
Hepatitis B Screeningdd
X
PRO (EORTC-QLQ-C30, EQ5D, BFI)o
X
X
X
Medical resource utilizationz
X
X
X
NOTE: Footnotes are provided at the end of the table
(Continued)


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
TIME AND EVENTS SCHEDULE (CONTINUED)
FINAL – 3 February 2014
59
Procedure
Screening
Cycles 1- 6 (and 7-8, if applicable)
Response 
Evaluationd
Days 11-21 of 
Cycles 2, 4, 6 
(and 8, if 
applicable)
Early Withdrawal/ 
End-of-Treatment 
Phasee
Short-term 
Follow-upf until 
PD/initiation 
alternate 
therapy/withdrawal
Long-term 
Follow-upg 
until death
Day1
Day4
Day 8
Day 11
FACT/GOG neurotoxicity questionnaireu
X
X
X
Tissue sample for biomarker studyv
X
Optional bone marrow sample for 
biomarker analysis (only need to consider 
if no tissue samples are available)v
X
Whole blood sample for 
pharmacogenomics and future testing (10 
mL)p
X
Serum sample collection 
(5 mL blood)q
X
MCL biopsy tissue block or unstained 
slides (preferably of lymph node origin) 
for MCL confirmationn
X
Concomitant medications/procedures
X
X
X
X
X
X
X
Xw
Xw
Adverse events
X
X
X
X
X
X
X
Xs
Xs
Survival
X
Rituximab dosing
X
Prednisone dosing
Xr
Doxorubicin dosing
X
Vincristine dosingb
X
Cyclophosphamide dosing
X
VELCADE dosingc
X
X
X
X
NOTE: Footnotes are provided at the end of the table
                                                                                                                                                                                        (Continued)


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
TIME AND EVENTS SCHEDULE (CONTINUED)
FINAL – 3 February 2014
60
ALC = absolute lymphocyte count, ALT = alanine transaminase, ANC = absolute neutrophil count, AST = aspartate transaminase, -HCG = beta-human chorionic gonadotropin, 
BFI = Brief Fatigue Inventory, BSA = body surface area, BUN = blood urea nitrogen, CR = complete response, CT = computed tomography, EORTC-QLQ-C30 = European 
Organisation for Research and Treatment of Cancer-quality of life questionnaire, FACT = Functional Assessment of Cancer Therapy; FISH = fluorescent in situ hybridization, 
GOG = Gynecologic Oncology Group, i.v. = intravenous, LDH = lactate dehydrogenase, MCL = mantle cell lymphoma, PCR = polymerase chain reaction, PD = progressive disease, 
PR = partial response, PRO = patient-reported outcomes,  WBC = white blood cell
a To be performed prior to first dose in Cycle 1 Day 1, height at screening only 
b Vincristine dosing for patients randomized to Treatment Arm B only
c
VELCADE dosing for patients randomized to Treatment Arm A only
d Disease response assessments must be completed between Day 11 (after VELCADE administration for patients randomized to Arm A) and Day 21 inclusive. These disease response 
assessment results must be available before the first dose in the next cycle
e This visit is required for all patients. It should take place 30 days after the last dose of study medication with a window of +7 days. Early withdrawal is defined as stopping treatment 
before 6 complete cycles are given. If the patient requires alternate antineoplastic therapy in the interim period following the last dose of study medication and the End of Treatment visit 
then this visit should be completed earlier, i.e., just prior to initiation of alternate antineoplastic therapy
f
Short-term Follow-up visits to assess disease progression will be required if treatment is discontinued prior to PD. Short-term Follow-up visits will be completed every 6 weeks for 
18 weeks with a window of 4 days and then every 8 weeks thereafter until PD with a window of 7 days. The interval between Short-term Follow-up visits should be maintained at 
6 or 8 weeks as required; if a visit occurs earlier or later than the scheduled visit date then the next visit date should be rescheduled to maintain the required interval from the previous 
visit. Upon notification by the sponsor that clinical cutoff for the primary analysis (295 PFS events) has been reached, radiographic assessment of disease progression will stop, and all 
subjects in short-term follow-up will enter the Long-term Follow-up Phase.
g Long-term Follow-up (physician visit or telephone contact) to assess survival will be required for all patients following PD or start of alternate antineoplastic therapy until death. 
Long-term Follow-up will be completed every 12 weeks with a window of 7 days. The interval between Long-term Follow-up visits should be maintained at 12 weeks; if a visit occurs 
earlier or later than the scheduled visit date then the next visit date should be rescheduled to maintain the required interval from the previous visit. Long-term follow-up will continue 
until June 2017.
h May be performed with only oral contrast, if patient is intolerant of i.v. contrast agents. CT scans must be performed as part of the screening process, however if a previous scan is 
available, this may be used as the screening scan providing that it was performed no more than 56 days prior to randomization and meets the criteria required for study entry scans.
i
Evaluation of other sites of disease may be performed by radiological imaging, physical examination, or other procedures as necessary, and should be performed throughout the study 
using the same method of assessment per patient. The physical examination scheduled on Day 1 of the immediately following cycle may be used. The hematology and clinical chemistry 
results from the nearest visit to the disease response assessments may be used for the disease response assessments during the rest periods of Cycles 2, 4 and 6. For patients consenting 
to the pharmacogenomics part of the study, one 5 mL sample of bone marrow will also be collected if the patient provides consent. This sample will be collected in addition to the 
clinically defined aspirate but will be collected at the same time.
j
May be performed up to 56 days before first dose of study medication, 5 mLs of the bone marrow aspirate can be used for the pharmacogenomics analysis (see footnote p below).
k Bone marrow aspirate and biopsy will be repeated once during the study for confirmation of CR within 30 days of initial documentation of CR in patients with a screening bone marrow 
assessment that was positive, indeterminate, or insufficient.
l
Hematology includes hemoglobin, platelets, complete WBC, ANC, and ALC. 
m Clinical chemistry at screening includes sodium, potassium, bicarbonate, BUN/urea, creatinine, calcium, AST, ALT, total bilirubin, alkaline phosphatase, albumin, LDH, phosphate, 
uric acid, glucose, and ß-2 microglobulin. All these evaluations, with the exception of bicarbonate and ß-2 microglobulin, have to be repeated also at efficacy assessment time points and 
at the end-of-treatment or early withdrawal. On Day 1 of each cycle beginning with Cycle 2, clinical chemistry includes sodium, potassium, BUN/urea, creatinine, AST, ALT, total 
bilirubin, albumin, and LDH.
(continued)


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n Diagnosis of MCL (Stage II, III or IV) should be evidenced by  histology and either expression of cyclin D1 (in association with CD20 and CD5) or evidence of t(11;14) translocation, 
such as by cytogenetics, fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR). The  biopsy sample tissue block (preferably of lymph node origin) and supportive 
data such as flow cytometry, cytogenetics, FISH, and PCR used for MCL diagnosis should be sent to the central laboratory during the screening visit. A confirmation of MCL diagnosis 
is needed before the patient is randomized into the study with the exception of China, where confirmation of sample adequacy, based on lymph node tissue, is required. After study 
completion, the samples will be returned to the study center. In the event that there is no tissue block available, 10 unstained slides of 3-4 micron thickness PLUS 10 unstained slides 
of 10 micron thickness should be sent (these unstained slides are in addition to those required for pharmacogenomics testing).
o To be completed before any other scheduled assessments are performed or treatment given.
p Patient participation in the pharmacogenomics component of the study is optional. A 10 mL blood sample will be collected only from patients who give informed consent for the 
pharmacogenomics component of this study. A pharmacogenomics blood sample drawn at a different visit does not constitute a protocol violation and will not require a protocol waiver.
q Cycles 1, 2 and 3 only. Cycle 1 sampling should be done before drug administration.
r
Prednisone on Day 1 through Day 5 of each cycle. 
s Adverse events occurring after 30 days following the last dose of study drug should be reported if considered related to study drug; however, all cases of second primary malignancy 
will be reported for the full duration of a subject’s participation in the study, regardless of onset date and relationship to study drug.
t
Only LDH will be collected during short-term follow-up. 
u
FACT/GOG will not be captured in the eCRF or clinical database but will be used as source document. 
v The primary diagnosis tissue (either block or slides) will also be used for pharmacogenomics testing per the patient’s consent. If this sample is insufficient for pharmacogenomics 
testing, the patient has the option to consent to a fresh lymph node sample. If neither of these samplings are possible, the patients have the option to consent to giving a 5 mL bone 
marrow sample for biomarker analysis instead. If this is the case then it is possible to use 5 mL of the bone marrow sample drawn at screening (required for assessing the MCL 
involvement in the bone marrow), if sufficient sample is available.
w During the Short-term and Long-term Follow-up Phases, this will only include documentation of subsequent therapy and procedures for the treatment of MCL. No need to collect other 
concomitant medications 30 days after last dose
x The pregnancy test samples can be taken up to 24 hours prior to dosing; for screening pregnancy testing, a negative test up to 28 days prior to Cycle 1 Day 1 is acceptable.
y Echocardiography or MUGA scan is mandatory at baseline, thereafter it can be repeated optionally at any time during the study if clinically relevant either at an assessment visit or at 
unscheduled visit
z Medical resource utilization collected throughout study.
aa Limited physical examination includes cardiac, pulmonary and abdominal examination with examination and documentation of any clinically relevant abnormalities.
bb Hematology samples on Days 1, 4, 8, and 11 of each cycle are required only for patients in Arm A prior to VELCADE dosing. For patients randomized to Arm B hematology samples 
will be taken on Day 1 and 11 of each cycle. No site visits are required on Day 4 and Day 8 of each cycle for patients randomized to Arm B. Samples can be taken up to 24 hours prior 
to dosing day, provided the results are available before the dose of study medication is given. For pregnancy tests, if the pregnancy test during screening is within 28 days of Cycle 1 
Day 1, it does not need to be repeated.
cc When the patient is recorded to have an event of PD, a repeat CT scan to confirm PD must be undertaken at least 30 days after the scan that was used to determine PD. In the event a 
patient starts subsequent anti-lymphoma treatment, it is highly recommended that this repeat CT scan be performed before the patient starts treatment. The repeat CT scan must be done 
using i.v. and oral contrast, and must be of the neck, chest, abdomen, and pelvis. If the patient is intolerant of i.v. contrast agents, the scan may be performed with only oral contrast. At 
the time of the initial documentation of PD, a PD fax form together with documentation of PD (e.g., CT scan report) must be sent to the sponsor’s medical representative within 
24 hours.
dd HBsAg and anti-HBc testing to be performed.


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DOSE AND ADMINISTRATION TABLE
Patients will be randomized to either Treatment Arm A or Treatment Arm B
Rituximab
Cyclophosphamide Doxorubicin
Prednisone
Vincristine 
VELCADE
Treatment Arm A 
(VcR-CAP)
Day 1
Day 1
Day 1
Days 1- 5
Days 1, 4, 8, 11
Treatment Arm B 
(R-CHOP)
Day 1
Day 1
Day 1
Days 1- 5
Day 1
Rituximab - 375 mg/m2, i.v.
Cyclophosphamide - 750 mg/m2, i.v.
Doxorubicin - 50 mg/m2, i.v.
Vincristine - 1.4 mg/m2, i.v. (max. total 2 mg)
Prednisone – 100 mg/m2, p.o.
VELCADE - 1.3 mg/m2, i.v.
For Treatment Arm A, VELCADE must be administered first, followed by rituximab. Thereafter, other study medications will be 
administered according to the directions provided in the respective product labels.
Each cycle is 21 days.
Maximum number of 6 cycles per arm or 2 cycles beyond a documented response.


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ABBREVIATIONS
ADL
activities of daily living
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
BFI
Brief Fatigue Inventory
BSA
body surface area
CHOP
cyclophosphamide-doxorubicin-prednisone-vincristine
CMH
Cochran-Mantel-Haenszel 
CRF
case report form
CR
complete response
CRu
complete response, unconfirmed
CT
computed tomography
CVAD
cyclophosphamide, vincristine, doxorubicin, and dexamethasone
CVP
cyclophosphamide, vincristine, and prednisone (only included once in document)
DCF
data correction form
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eDC
electronic data capture
EORTC-QLQ
European Organisation for Research and Treatment of Cancer-Quality of Life 
Questionnaire
FACT
Functional Assessment of Cancer Treatment
FDA
United States Food and Drug Administration
FISH
fluorescence immunohistochemisty
GCP
Good Clinical Practice
GOG
Gynecologic Oncology Group
J&JPRD
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IPI
International Prognostic Index
IRB
Institutional Review Board
IRC
Institutional Review Committee
IVRS
Interactive voice response system
IWRC
International Workshop to Standardize Response Criteria for Non-Hodgkin’s 
Lymphoma
LDH
lactate dehydrogenase
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRU
medical resource utilization
MUGA
multiple uptake gated acquisition
NCI-CTCAE
National Cancer Institute Common Toxicity Criteria for Adverse Events
NHL
non-Hodgkin’s lymphoma
ORR
overall response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PR
partial response
PRO
patient-reported outcomes
QALY
quality-adjusted life years
QOL
quality of life
R-CHOP
rituximab-cyclophosphamide-doxorubicin-prednisone-vincristine 
SmPC
Summary of Product Characteristics


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SPD
sum of the product of the diameters
TNT
time to next treatment
TTP
time to progression
ULN
upper limit of normal
VcR-CAP
VELCADE-Rituximab-Cyclophosphamide-Doxorubicin-Prednisone
WBC
white blood cell count


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1.
INTRODUCTION
VELCADE(Bortezomib for Injection) is being codeveloped by Millennium 
Pharmaceuticals, Inc. (Millennium) and Janssen Research & Development.
The term sponsor used throughout this document refers to the entities listed 
in the Contact Information page(s), which will be provided as a separate 
document.
1.1.
Background
Mantle cell lymphoma (MCL) is an incurable subtype of non-Hodgkin’s 
lymphoma (NHL) that was recognized as a unique clinicopathologic entity in 
the 1990’s. It is relatively uncommon representing, 6% of all NHL cases in 
the Western world. At the molecular level, MCL is uniquely characterized by 
over expression of the cell cycle regulator protein cyclin D1. This is due to 
the chromosomal translocation t(11;14)(q13;q32), which puts the cyclin D1 
gene, B-cell leukemia/lymphoma 1 (bcl-1), under the control of the 
immunoglobulin heavy chain enhancer with subsequent overexpression of 
cyclin D1.3-5 In association with overexpression of cyclin D1, other markers 
such as CD20 and CD5 are also evident in MCL. A variety of other 
molecular abnormalities commonly found in MCL are also important 
prognostic indicators. These include reduced expression of p27, a 
cyclin-dependent kinase (CDK) inhibitor, and inactivating p53 mutations, 
both of which are associated with poor survival in MCL.6 The intracellular 
levels of both p27 and p53 primarily are regulated by proteasomal 
degradation, and VELCADE is known to increase the levels of both of these 
proteins. Therefore, modulation of these key cell cycle regulators may be an 
important part of the mechanism of action of VELCADE in MCL.
It is often said to incorporate the worst aspects of both the aggressive and 
indolent lymphomas. The disease progresses quickly, like the aggressive 
lymphomas, but it is incurable, like the indolent lymphomas.7-9 The result is 
a median survival of about 3 years from diagnosis, the shortest median 
survival of all NHL subtypes. This is in marked contrast to the median 
survival of about 7 years in follicular lymphoma, and the 40% to 50% cure 
rate in diffuse large B-cell lymphoma.10-11


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At initial diagnosis, most patients with MCL, predominantly males over 
60 years of age, present with advanced stage disease (Stage III or IV), with 
extranodal involvement frequently occurring in the gastrointestinal tract, 
bone marrow, liver, lungs, and soft tissues.7,12
Once the disease has progressed, the prognosis is dismal, and following 
relapse, the median survival is approximately 18 months and, like all 
lymphomas, the expected survival is progressively shorter with each 
subsequent relapse.13-15 In a recent study of the treatment of patients with 
relapsed or refractory MCL, VELCADE, as a single agent, has been shown 
to provide substantial clinical benefit in the form of durable responses and 
prolonged time to alternative therapy in the relapsed setting. Additionally, 
patients who were refractory to their previous line of therapy were shown to 
respond to single agent VELCADE, some achieving a complete response 
(CR). 
In the frontline setting, even despite intensive therapies such as rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) 
showing substantial response rates (CR rates of up to 48%), these favorable 
clinical responses were not associated with prolonged progression free 
survival (median 16.6 months).36 The aim, therefore, of introducing 
VELCADE into the frontline treatment option for MCL is not only to 
improve response rates but also to prolong PFS, translating into a prolonged 
survival for these patients.
Hence, MCL represents a serious and life-threatening malignancy for which 
there is an unmet medical need for newly diagnosed patients.
Current initial therapy for the treatment of MCL is similar to that for other 
aggressive lymphomas and includes cyclophosphamide, doxorubicin, 
vincristine, and prednisone (CHOP) or hyperfractionated cyclophosphamide, 
vincristine, doxorubicin, and dexamethasone alternating with methotrexate 
and cytarabine (Hyper-CVAD), often in combination with rituximab 
(R-CHOP or R-Hyper CVAD); however, many chemotherapeutic regimens 
have been evaluated. Younger patients with good performance status are 
frequently considered for more intensive induction therapy with 
combinations such as R-Hyper CVAD and consolidation therapy with 
autologous stem cell transplant (ASCT) also is considered; however, this 
degree of intensive therapy is not an option for most patients with MCL 


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because of their age and comorbidities.16,17 In addition, there is still no 
consensus that more intensive therapy is beneficial in the treatment of MCL. 
Randomized studies have not demonstrated a benefit with the addition of an 
anthracycline to CVP (cyclophosphamide, vincristine, and prednisone) or 
fludarabine in terms of response rate or survival, and stem cell transplant 
(SCT) does not appear to be curative in relapse or at first remission.18,19,20
Response rates in the frontline setting in excess of 90% have been achieved 
in small-uncontrolled studies of intensive chemotherapeutic regimens with or 
without ASCT. In 1 randomized study, rituximab was shown to improve 
overall 
and 
complete 
response 
rates 
when 
added 
to 
CHOP 
(cyclophosphamide, doxorubicin, vincristine, and prednisone) in previously 
untreated patients, although this did not result in increased progression-free 
survival (PFS).21-24 Anthracycline based therapies in combination with 
rituximab are now recognized by all international experts as the treatment of-
choice in the first-line therapy of MCL, although durable responses are still 
inadequate. 
1.1.1.
VELCADE
VELCADE has proven clinical efficacy in MCL. Potential mechanisms of 
action may include inhibition of MCL tumor growth by cell cycle arrest and 
induction of cell death, both of which involve inhibition of nuclear factor kB 
(NFkB) activation. Cell cycle arrest occurred in G1 with rapid induction of 
apoptosis. In addition, G1 cell cycle arrest was associated with inhibition of 
cyclin D1 expression. Other mechanisms of action of VELCADE also may 
be active in MCL. Reduced expression of p27, and loss of normal p53 
function are both associated with a poor prognosis in MCL. The intracellular 
levels of p27 and p53 are both modulated by proteasomal degradation. 
Therefore, it is possible that inhibition of the proteasome by VELCADE 
results in increased intracellular levels of p27 and p53, and that this 
contributes to VELCADE’s activity in MCL.
At least 5 MCL studies have demonstrated the efficacy of single agent 
VELCADE in relapsed/ refractory MCL. A total of 283 patients with MCL 
were evaluated for safety and efficacy. Data from these studies confirmed 
the intrinsic activity of single agent VELCADE in patients with MCL.


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One study, the largest study in this setting, recruited 155 patients and 
demonstrated that single agent VELCADE (1.3 mg/m2 administered on 
Days 1, 4, 8, and 11) provides a clinical benefit in the form of durable 
response rates with a substantial time to next treatment. In addition, updated 
data for survival now show that the median overall survival (OS) is 
23.5 months from the time of documented relapse, and 35.4 months in those 
patients achieving a response. VELCADE is now approved for the treatment 
of relapsed MCL in 23 countries globally, including the US.
1.2.
Overall Rationale for the Study
The next logical step, therefore, was to assess whether this benefit can be 
translated in the frontline setting and provide the durable response rates with 
significant improvement in PFS and survival that the R-CHOP combination 
is currently lacking.
Two studies have been initiated to assess the safety of combining 
VELCADE with R-CHOP; one is a Phase 2 study to evaluate the 
combination of R-CHOP plus VELCADE in patients with newly diagnosed 
B lymphomas. Patients were randomized between 2 schedules of 
VELCADE: Arm A (Days 1, 4, 8, 11), Arm B (Days 1, 8). For the first 
24 patients (step 1), VELCADE was administered at 1 mg/m² in Arm A and 
1.3 mg/m² in Arm B. For the next 24 patients (step 2), it was increased to 
1.3 mg/m² and 1.6 mg/m² respectively. The safety profile to date has 
demonstrated that Grade 3-4 thrombocytopenia occurred in 14% of cycles 
(35% Arm A, 0% Arm B, 14% step 2). Of the 48 patients evaluable for 
response, 40 achieved CR/CRu (18/20 in Arm A, 22/28 in Arm B). Five 
patients achieved partial response (PR) (1 Arm A, 4 Arm B). After 1-year 
median follow up, OS was 100% and event-free survival of 80%. Although 
the hematologic toxicities in both arms were acceptable, higher neurological 
toxicities were observed at higher doses (1.3 mg/m2 Days 1, 4, 8, 11, and 
1.6 mg/m2 on Days 1 and 8). Nine patients developed Grade 2 neuropathy 
mostly in Arm B and 9 patients developed Grade 3-4 neuropathy in both 
arms. This study recommended that the combination of VELCADE and 
vincristine should not be administered concomitantly.2
Another study of R-CHOP plus VELCADE combination has been initiated 
in patients with newly diagnosed diffuse large B cell lymphoma (DLBCL).1
40 patients have been recruited into this study which shows that treatment 


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was generally well tolerated, however, peripheral neuropathy occurred in 
22 patients (55%), with 45% Grade 1, 5% Grade 2, and 5% Grade 3.
VELCADE is approved for the treatment of relapsed MCL, and is currently 
being assessed in the frontline setting in combination with R-CHOP. In line 
with the above recommendation, the aim of this study is to substitute 
vincristine with VELCADE in the R-CHOP combination and to compare the 
efficacy of the two combinations. No data exists to isolate the contribution of 
the efficacy of vincristine in R-CHOP regimen in the treatment of MCL 
(studies in lymphoma with single agent vincristine are over 30 years old, 
MCL has been recognized as a unique disease entity only in the last 
10 years), however, given the durable responses seen in the Phase 2 study, it 
is expected that VELCADE will provide added benefit in the frontline 
setting to patients with newly diagnosed MCL who are ineligible for bone 
marrow transplant.
An Independent Data Monitoring Committee (IDMC) will be constituted for 
this study.
2.
OBJECTIVES
Primary Objective
To determine which regimen of chemotherapy rituximab, cyclophosphamide, 
doxorubicin, VELCADE, and prednisone (VcR-CAP) or rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) 
provides greater benefit in newly diagnosed MCL patients with Stage II, III, 
or IV disease, as assessed by significant prolongation of PFS.
Secondary Objectives
The secondary objectives are:
To determine OS
To determine time to progression (TTP)
To determine the 18-month survival rate
To determine overall response (CR+CRu+PR) and CR rates (CR+CRu)
To determine the duration of response, time to next treatment (TNT), and 
treatment-free interval
To evaluate the safety of VcR-CAP compared to R-CHOP


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Exploratory Objectives
To evaluate patient-reported outcomes (PROs) utilizing the European 
Organisation for Research and Treatment of Cancer quality of life 
questionnaire (EORTC-QLQ-C30), EQ-5D, and Brief Fatigue Inventory 
(BFI) instruments
To evaluate medical resource utilization (MRU) information which may 
be used in future economic evaluation models
To identify patient populations that are more or less likely to respond to 
VcR-CAP or R-CHOP through the evaluation of biomarker analyses
3.
OVERVIEW OF STUDY DESIGN
3.1.
Study Design
This is a randomized, open-label, multicenter, prospective study to compare 
the efficacy and safety of the combination of VcR-CAP to that of R-CHOP 
in patients who have newly diagnosed MCL and who are ineligible for bone 
marrow transplantation.
At least 486 patients will be randomized into 1 of 2 arms (Treatment Arm A 
or Treatment Arm B) in a 1:1 ratio taking into account the following 
stratification factors: International Prognostic Index (IPI) and stage of 
disease at diagnosis.
Treatment Arm A: (VcR-CAP) rituximab 375 mg/m2 intravenous i.v. on 
Day 1, cyclophosphamide 750 mg/m2 i.v. on Day 1, doxorubicin 50 mg/m2
i.v. on Day 1, VELCADE 1.3 mg/m2 i.v. on Days 1, 4, 8, and 11, prednisone 
100 mg/m2 per os (p.o.) on Day 1 to Day 5 of a 21 day (3 week) cycle for 
6 cycles (or 8 cycles if a response is first documented at Cycle 6 assessment).
Treatment Arm B: (R-CHOP) rituximab 375 mg/m2 i.v. on Day 1, 
cyclophosphamide 750 mg/m2 i.v. on Day 1, doxorubicin 50 mg/m2 i.v. on 
Day 1, vincristine 1.4 mg/m2 (maximum total of 2 mg) i.v. on Day 1, 
prednisone 100 mg/m2 p.o. on Day 1 to Day 5 of a 21 day (3 week) cycle for 
6 cycles (or 8 cycles if a response is first documented at Cycle 6 assessment).


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Patient participation will include a Screening Phase, a Treatment Phase, a 
Short-term Follow-up Phase, and a Long-term Follow-up Phase. The 
Screening Phase will be up to 28 days (56 days for bone marrow evaluation) 
prior to randomization. The Treatment Phase will extend from randomization 
until 6 cycles of treatment have been given (or 2 cycles beyond a response 
documented in Cycle 6). The Short-term Follow-up Phase will extend from 
the End-of-Treatment Phase to progressive disease (PD; or relapse if patient 
achieves a CR or CRu), initiation of alternate antineoplastic therapy, 
decision by the patient to completely withdraw from the study and refuse any 
further study related procedure, or death. Patients who are withdrawn from 
the study treatment due to adverse events, or reasons other than above and 
are willing to continue study follow-up procedures can be followed per 
protocol for PD or death.
The Long-term Follow-up Phase will be used to assess survival and will 
document when the patient has died. Upon notification by the sponsor that 
clinical cutoff for the primary analysis (295 PFS events) has been reached, 
radiographic assessment of disease progression will stop, and all subjects in 
short-term follow-up will enter the Long-term Follow-up Phase.
Patients will be randomized and assigned to either Treatment Arm A or B. 
They will receive a maximum of 6 cycles of therapy or 2 cycles beyond a 
documented response if the response is first documented at Cycle 6 
assessment and not previously (up to 24 weeks). Patients may receive less 
therapy or deviate from the planned treatment dose and schedule due to 
adverse events, as specified by the dose and schedule modifications defined 
in the protocol. 
The total study duration from randomization of the first patient until the last 
PFS event required for the final analysis is expected to be approximately 
42 months (approximately 24 months for enrollment and approximately 
18 months for follow up). 
Three interim analyses are planned for this study. The first interim analysis 
will occur after the first 100 patients have been randomized into the study 
and will assess safety and the concordance rate of the diagnosis of MCL 
when central review is compared with the investigator assessment of the 
diagnosis. Central review is defined as a review by an independent 
pathologist and in the event that there is insufficient tumor material available 


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for pathological confirmation of MCL, an independent lymphoma expert will 
review relevant local diagnostic and clinical information to verify the 
diagnosis of MCL. Samples determined as negative for MCL diagnosis by 
the independent pathologist cannot be evaluated by the independent 
lymphoma expert and will not be considered MCL confirmed. The 
concordance rate of the diagnosis of MCL will also be reviewed at 50% 
accrual. This may be used to recalculate the sample size to ensure an 
adequate number of PFS events (approximately 280) in those subjects with a 
centrally confirmed MCL diagnosis at the time of the final analysis (295 PFS 
events in total). A review of this data will occur by the IDMC (See 
Section 11.8).
A second interim analysis for safety will occur after 100 patients in each arm 
(200 patients in total) have either completed the study treatment or 
discontinued the study treatment, which allows sufficient exposure for 
review of cumulative toxicity.
The third interim analysis is planned after at least 148 events have occurred 
in the ITT population. If, at the third interim analysis, pre-specified 
superiority boundaries for PFS are met then the study will be terminated and 
superiority of the experimental arm (VcR-CAP) will be declared over the 
comparator arm (R-CHOP). If the pre-specified futility boundaries for PFS 
are met, then the study may be terminated due to futility. If pre-specified 
boundaries are not met at the third interim analysis, the final analysis of the 
study will occur after 295 events have been observed in the ITT population.
The sample size calculation for the study population is based on the 
following assumptions. The median PFS of R-CHOP is 18 months. 
Assuming that VcR-CAP improves this median PFS by 40%, i.e., from 
18 months to 25 months, a total number of 295 events provides 80% power
(α=0.05, 2-sided) to detect such improvement. Assuming a 24 month accrual 
and 18 month follow-up, a total of 486 patients are needed for the study 
(243 per arm).
A flowchart of study procedures is provided in Figure 1.


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Figure 1:  Study Flowchart
Screening
Eligibility:
•
Male or female
•
18 years or older
•
Non transplant eligible
Treatment D
R-CHOP
Response assessment every 6 weeks for 18 weeks; 
thereafter, every 8 weeks until PD/initiation of 
alternate therapy/withdrawal from study/death
Survival follow-up every 12 weeks until death
Treatment A
VcR-CAP
Randomization
Stratify:
•
IPI
•
Stage of disease
Duration:
Up to 28 days
(Days -28 to 0)
Up to 8 cycles
(3 weeks per cycle)
Screening
Eligibility:
•
Male or female
•
18 years or older
•
New diagnosis of MCL
Eligibility:
•
Male or female
•
18 years or older
•
Treatment B
R-CHOP
Response assessment every 6 weeks for 18 weeks; 
thereafter, every 8 weeks until PD/initiation of 
alternate therapy/withdrawal from study/death
Survival follow-up every 12 weeks until death
-
Randomization
Stratify:
•
IPI
•
Stage of disease
Duration:
Up to 28 days
(Days -28 to 0)
Up to 8 cycles
(3 weeks per cycle)
3.2.
Study Design Rationale
This study is designed to compare and establish superiority of the efficacy 
and safety of VcR-CAP to that of R-CHOP. The study is justified because 
there is a high unmet need for the treatment of patients who develop MCL 
and regimens that improve the clinical outcome and prognosis of patients 
with this disease are required. To date, no known treatments are curative, and 
median survival from first diagnosis is 3 years. A major goal for new 
treatments is to meaningfully improve PFS. The proposed study is designed 
to demonstrate a 40% improvement of PFS from 1 of the commonly used 
regimens in the treatment of frontline MCL, R-CHOP. The use of 
VELCADE in combination with vinca-alkaloids (in this case, vincristine) 
poses a risk of increased neurotoxicity and therefore the next logical step 
would be to substitute vincristine with VELCADE in this combination. 
Single agent VELCADE provides durable response rates and substantial 
clinical benefit, and it is hypothesized that this same regimen would also be 
as active in the frontline setting. The dose and regimen used in this study are 
therefore the same as that in the Phase 2 study of single agent VELCADE in 


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relapsed/ refractory MCL, i.e., 1.3 mg/m2 on Days 1, 4, 8 and 11 of a 21 day 
cycle.
Rationale for Biomarker Evaluations
Molecular markers identified through pharmacogenomics and biomarker 
evaluations can facilitate more efficient drug development through their 
ability to identify patient subpopulations more or less likely to respond to 
drug treatment or experience a treatment-related adverse event. In this study, 
exploratory analyses focus on specific hypotheses to identify subpopulations 
of MCL patients that are sensitive or resistant to VcR-CAP or R-CHOP. 
Prior studies of prognostic molecular markers for MCL25,26 and of specific 
response markers for rituximab27,28 or VELCADE29,30 allow the nomination 
of 
a 
specific 
series 
of 
candidate 
proteins 
and 
target 
gene 
polymorphisms/mutations. Additional candidate selections were based on 
identification of target-signaling pathway-related genes, genes previously 
shown to have differential responses to VELCADE treatment and prognostic 
markers of MCL. Experimental results will be correlated with clinical 
endpoints in order to determine if these specific candidate markers identify 
study populations that are more or less sensitive to study treatments.
Patient-Reported Outcomes
Patient-reported outcomes are included in clinical trials because some 
treatment effects are known only to the patient. There are no observable or 
physical measures for these concepts. These most often refer to a patient’s 
symptoms or ability to function. In addition, patients provide a unique 
perspective on treatment effectiveness. When used to measure study 
endpoints, PRO instruments can augment what is known about the products 
based on the clinician perspective or physiologic measures. This is important 
because improvements in clinical measures of a condition may not 
necessarily correspond to improvements in how the patient functions or 
feels. PRO, when properly scaled, can be used in calculating quality-adjusted 
life years (QALY) for economic evaluation models to meet health authority 
requirements for reimbursement purposes. Formal assessment of the 
patient’s perspective may provide valuable information that can be lost when 
that perspective is filtered through a clinician’s evaluation of the patient’s 
response to clinical interview questions. A self-administered structured 


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interview technique minimizes measurement error, ensures consistency 
without influence from a third party’s interpretation. 
4.
STUDY POPULATION
4.1.
General Considerations
Male and female patients who have a confirmed molecular diagnosis of 
MCL Stage II, III, or IV and have had no other prior treatments for their 
disease will be eligible to take part in the study. Patients must also be 
ineligible for bone marrow transplantation as determined by their treating 
physician.
4.2.
Inclusion Criteria
Patients must satisfy all of the following criteria before entering the study: 
Male or female patients 18 years or older (the patient must be at least the 
legal age limit to be able to give informed consent within the jurisdiction 
the study is taking place)
Diagnosis of MCL (Stage II, III or IV) as evidenced by histology and 
either expression of cyclin D1 (in association with CD20 and CD5) or 
evidence of t(11;14) translocation such as by cytogenetics, fluorescent in 
situ hybridization (FISH) or polymerase chain reaction (PCR). Patients 
with a diagnosis of Stage I MCL will not be permitted to enter study.
– Paraffin embedded biopsy tissue block (preferably of lymph node 
origin) must be sent to the central laboratory for confirmation of 
MCL diagnosis prior to randomization. In China, a paraffin 
embedded lymph node biopsy tissue block must be sent for central 
confirmation of sample adequacy, prior to randomization.
At least 1 measurable site of disease 
No prior therapies for MCL
Not eligible for bone marrow transplantation as assessed by the treating 
physician (e.g., age or the presence of co-morbid conditions that may 
have a negative impact on the tolerability to transplantation). 
Eastern Cooperative Oncology Group (ECOG) status 2 (Attachment 1)
Absolute neutrophil count (ANC) 1500 cells/L
Platelets 100,000 cells/L or 75,000 cells/L if thrombocytopenia is 
considered by the investigator to be secondary to MCL (e.g., due to bone 
marrow infiltration or sequestration from splenomegaly).
Alanine transaminase 3 x upper limit of normal (ULN)
Aspartate transaminase 3 x ULN


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Total bilirubin 1.5 x ULN
Calculated creatinine clearance 20 mL/min. (Attachment 2)
Female patients must be post menopausal for at least 1 year (must not 
have had a natural menses for at least 12 months), surgically sterile, or 
practicing an effective method of birth control (e.g., prescription oral 
contraceptives, 
contraceptive 
injections, 
intrauterine 
device, 
double-barrier method, contraceptive patch, male partner sterilization) 
and have a negative serum HCG or urine pregnancy test at screening. 
They must also be prepared to continue birth control measures for at least 
6 months after terminating treatment.
Male patients must agree to use an acceptable method of contraception 
(for themselves or female partners as listed above) for the duration of the 
study.
All patients (or their legally acceptable representatives) must have signed 
an informed consent document indicating that they understand the 
purpose of and procedures required for the study and are willing to 
participate in the study. 
In order to participate in the pharmacogenomics component of this study, 
patients (or their legally acceptable representative) must have signed the 
informed consent form for pharmacogenomics
research indicating 
willingness to participate in the pharmacogenomics component of the 
study. Acquisition of tumor sample collections is required for all patients 
(where available); all other sample collections are optional.
4.3.
Exclusion Criteria
Potential patients who meet any of the following criteria will be excluded 
from participating in the study:
Prior treatment with VELCADE
Prior antineoplastic (including unconjugated therapeutic antibodies), 
experimental or radiation therapy, radioimmunoconjugates or toxin 
immunoconjugates for the treatment of MCL. In the event that a patient 
has received doxorubicin for the treatment of any condition, other than 
MCL, the maximum dose and exposure received prior to entry into this 
study should not exceed 150 mg/m2.
– Short course (maximum of 10 days; not exceeding 100 mg/day) 
prednisone or equivalent steroids are allowed to treat symptoms in 
subjects with advanced disease who enter the screening phase and 
are waiting to be randomized.  
Major surgery (at the discretion of the treating physician and in 
consultation with the sponsor’s medical monitor) within 2 weeks before 
randomization


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Peripheral neuropathy or neuropathic pain of Grade 2 or worse (as per the 
investigators assessment)
Diagnosed or treated for a malignancy other than MCL within 1 year of 
randomization, or who were previously diagnosed with a malignancy 
other than MCL and have any radiographic or biochemical marker 
evidence of malignancy. Patients with completely resected basal cell 
carcinoma, squamous cell carcinoma of the skin, or in situ malignancy are 
not excluded. 
Active systemic infection requiring treatment and patients with known 
diagnosis of HIV or active hepatitis B (carriers of hepatitis B are 
permitted to enter study)
History of allergic reaction attributable to compounds containing boron, 
mannitol, or hydroxybenzoates
Known 
anaphylaxis 
or 
immunoglobulin 
E 
(IgE)-mediated 
hypersensitivity to murine proteins or to any component of rituximab 
including polysorbate 80 and sodium citrate dihydrate
Female or male patients of child-bearing potential who will not use 
adequate contraception during the course of the study.
Serious medical (e.g., cardiac failure [New York Heart Association; 
NYHA Class III or IV, Attachment 12 or left ventricular ejection fraction 
[LVEF] <50%], active peptic ulceration, or uncontrolled diabetes 
mellitus), or psychiatric illness likely to interfere with participation in this 
clinical study
Concurrent treatment with another investigational agent.
5.
RANDOMIZATION AND BLINDING
5.1.
Overview
Randomization will be used to minimize the risk of bias in the assignment of 
patients to treatment, to increase the likelihood that known and unknown 
patient attributes (e.g., demographics and baseline characteristics) are evenly 
balanced across treatment groups, and to enhance the validity of statistical 
comparisons across treatment groups.
The sponsor and the sites will be blinded to all data reviewed by the IDMC.
5.2.
Procedures
Patients will be assigned in a 1:1 ratio to 1 of the 2 treatment groups based 
on a computer-generated randomization schedule prepared by the sponsor 
before the study. The sponsor and the investigational sites will be blinded to 
all data reviewed by the IDMC.


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Permuted blocks central randomization will be implemented in conducting 
this study. The randomization will be stratified by two stratification factors: 
International Prognostic Index (IPI) and stage of disease at diagnosis. The 
stratified randomization minimizes the imbalance in the distribution of 
treatment numbers within the levels of each individual stratification factors.
The IPI will be assessed according to the following risk factors: age, stage of 
disease, performance status, lactate dehydrogenase (LDH) level and number 
of extranodal sites (Attachment 10). For stratification, the scores will then be 
categorized (low [0-1 factor], low-intermediate [2 factors], high-intermediate 
[3 factors] and high [4-5 factors]).
The stage of disease at diagnosis will also be used for stratification and be 
assessed using the American Joint Committee on Cancer NHL staging 
system39 (Attachment 11).
The patient number and treatment code will be assigned after phoning into 
the Interactive Voice Response System (IVRS). The caller must use their 
own user ID and PIN, and then give the requested patient details (e.g., 
patient’s date of birth). Based on this information, the IVRS will assign a 
unique patient number and treatment code, which will dictate the treatment 
assignment for that patient.
Patients can only be randomized if the central laboratory has confirmed 
diagnosis of MCL or, in the case of patients in China, if the lymph node 
tissue sample sent to the central laboratory at screening has been evaluated 
as adequate for analysis to confirm the diagnosis of MCL. The IVRS will 
therefore be blocked after the screening call until the central laboratory has 
provided the requisite confirmation. 
6.
DOSAGE AND ADMINISTRATION
Study medication will be administered within 72 hours of randomization.
Active VELCADE be reconstituted as per the prescribing information.
Patients randomized to Treatment Arm A (VcR-CAP) will receive rituximab 
375 mg/m2 i.v. on Day 1, cyclophosphamide 750 mg/m2 i.v. on Day 1, 
doxorubicin 50 mg/m2 i.v. on Day 1, VELCADE 1.3 mg/m2 i.v. on Days 1, 
4, 8, and 11, prednisone 100 mg/m2 p.o. on Day 1 to Day 5 of a 21 day 


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(3 week) cycle for 6 cycles (or 8 cycles if a response is first documented at 
Cycle 6 assessment).
Patients randomized to Treatment Arm B (R-CHOP) will receive rituximab 
375 mg/m2 i.v. on Day 1, cyclophosphamide 750 mg/m2 i.v. on Day 1, 
doxorubicin 50 mg/m2 i.v. on Day 1, vincristine 1.4 mg/m2 (maximum total 
of 2 mg) i.v. on Day 1, prednisone 100 mg/m2 p.o. on Day 1 to Day 5 of a 
21 day (3 week) cycle for 6 cycles (or 8 cycles if a response is first 
documented at Cycle 6 assessment).
VELCADE will be administered as a 3 to 5 second intravenous bolus before 
the other medications are administered. Rituximab will then be administered. 
Thereafter, all other study medications will be administered according to the 
directions provided in the respective Summary of Product Characteristics 
(SmPC). Study medication dose and schedule reduction for toxicity will be 
allowed during the study, using the criteria defined in Section 6.1. The time 
interval between sequential VELCADE doses must be at least 72 hours.
A dose and administration schedule is provided following the Time and 
Events Schedule. The amount (in mg) of all study medications to be 
administered will be determined by body surface area (BSA), an example of 
a standard nomogram can be found in Attachment 3. Body surface area will 
be calculated on Day 1 of each cycle. The total calculated dose of 
VELCADE may be rounded to the nearest decimal point (e.g., a calculated 
dose of 2.47 mg can be rounded to 2.5 mg). If a patient experiences a 
>5% change in weight from the weight used in the previous BSA 
calculation, then the BSA and dose should be recalculated. Full doses of all 
study medications should be given based on the patient’s actual BSA 
measured on Day 1 of every cycle, only the doses of vincristine should be 
capped.
If a patient discontinues any of the study medications assigned to them for 
any reason, including toxicity, the patient must not be withdrawn from study 
but continue on the other therapies in the allocated arm until the completion 
of 6 cycles (or 8 cycles if there is a response documented at Cycle 6 not 
previously documented). 
Dose adjustments and modifications may be necessary for the causal agent as 
assessed by the investigator. However, as this study incorporates the use of a 


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number of chemotherapeutic agents given in combination, it may be difficult 
to isolate the causal agent and dose adjustments for more than one agent may 
be required at any given time. 
Treatment-emergent adverse events of R-CHOP combination therapy 
predominantly comprise hematoxicities (such as neutropenia, leukopenia, 
thrombocytopenia and anemia). Nonhematoxicologic disorders such as 
asthenia, sensory disturbance, mucositis, alopecia, sepsis, dyspnea, back 
pain, hyperglycemia, hypersensitivity and cardiac disorders have all also 
been reported when treatment with R-CHOP has been administered. It is not 
always easy to assess the role of any one agent in these events and therefore 
it is at the investigator’s discretion to decide if only one agent is causal and 
take action as described below or that the adverse event is as a result of more 
than one agent which should result in action being taken on the part of more 
than one agent.
It is expected that the combination of VcR-CAP in treatment Arm A, would 
result in a similar profile with a higher rate of hematologic toxicities 
compared to nonhematologic toxicities. However, careful evaluation of the 
toxicity (particularly hematologic toxicities) should occur when considering 
causality to study medication to ensure that the correct dose adjustments take 
place. For example, when considering causality for neutropenia in Arm A, it 
is important to consider that cyclophosphamide or doxorubicin (or both) may 
be causal agent(s). 
6.1.
Dose Adjustments for VELCADE
Dose adjustments for VELCADE must follow the SmPC.
Before each dose of study drug, the patient will be evaluated for possible 
toxicities that may have occurred after the previous dose(s). Toxicities will 
be assessed according to the National Cancer Institute Common Toxicity 
Criteria for Adverse Events (NCI CTCAE), Version 3.0. Previously 
established or new toxicities observed at any time, with the exception of 
VELCADE-related neuropathic pain or peripheral sensory neuropathy, are to 
be managed as follows:


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If the patient experiences Grade 3 neutropenia with fever, Grade 4 
neutropenia lasting more than 7 days, a platelet count <10,000 cells/L, 
or any Grade 3 nonhematologic toxicity considered by the investigator 
to be related to VELCADE, then study drug is to be held.
– For nonhematologic toxicities, VELCADE is to be held for up to 
2 weeks until the toxicity returns to Grade 2 or better.
– For hematologic toxicities, VELCADE is to be held for up to 2 weeks 
until the patient has an ANC 750 cells/L and a platelet count 
25,000 cells/L.
If, after VELCADE has been held, the toxicity does not resolve, as 
defined above, then study drug must be discontinued.
If the toxicity resolves, as defined above, and VELCADE is to be 
restarted, the dose must be reduced by approximately 25%, as follows:
– If the patient was receiving 1.3 mg/m2, reduce the dose to 1.0 mg/m2.
– If the patient was receiving 1.0 mg/m2 following a previous dose 
reduction, reduce the dose to 0.7 mg/m2.
– If the patient was receiving 0.7 mg/m2 following previous dose 
reduction, discontinue VELCADE. Dose reductions below 0.7 mg/m2
are not permitted.
Dose re-escalations of VELCADE are not permitted after dose modifications 
for the above toxicities.
On any day of VELCADE administration during a cycle (other than Day 1 of 
each cycle) the hematology results must be:
Platelet count 25,000 cells/L
ANC 750 cells/L
If the above parameters are not met, the VELCADE dose can be held up to 
2 days. Doses of study drug that need to be held within a cycle will be 
skipped; the dose will not be made up later in the cycle.
For VELCADE, cycle delays or study drug discontinuation are not required 
for lymphopenia of any grade.
6.1.1.
VELCADE Dose Modifications for Neuropathic Pain 
or Peripheral Sensory Neuropathy
Patients who experience VELCADE-related neuropathic pain or peripheral 
sensory neuropathy are to be managed as presented in Table 1. Dose or 
schedule re-escalations are not permitted for VELCADE after modification 
for neuropathic pain or sensory peripheral neuropathy. 


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Table 1:  Management of Patients With VELCADE-Related Neuropathic Pain or 
Peripheral Sensory Neuropathy
Peripheral Sensory Neuropathy
(NCI CTCAE Grade [Version 3.0])
0
1
2
3
4
Normal
Asymptomatic; 
Loss of deep 
tendon reflexes 
or paresthesia 
(including 
tingling) but not 
interfering with 
function
Sensory 
alteration or 
paresthesia 
(including 
tingling) 
interfering with 
function, but not 
interfering with 
ADL
Sensory 
alteration or 
paresthesia 
interfering 
with ADL
Disabling
Neuropathic Pain
  (NCI CTCAE Grade [Version 3.0])
0
None
No action
No action
Reduction by 
1 dose level
Hold; 
reduction by 
2 dose levels; 
schedule 
required
Discontinue 
VELCADE
1
Mild pain not 
interfering with 
function
No action
No action
Reduction by 
1 dose level
Hold; 
reduction by 
2 dose levels;
schedule 
required
Discontinue 
VELCADE
2
Moderate pain: 
pain or 
analgesics 
interfering with 
function, but not 
interfering with 
ADL
Reduction by 
1 dose level
Reduction by 
2 dose levels
Hold;
reduction by 
2 dose levels
Hold; 
reduction by 
2 dose levels; 
schedule 
required
Discontinue 
VELCADE
3
Severe pain: 
pain or 
analgesics 
severely 
interfering with 
ADL
Hold; 
reduction by 
2 dose levels;
schedule 
required
Hold; 
reduction by 
2 dose levels; 
schedule 
required
Hold; 
reduction by 
2 dose levels; 
schedule 
required
Discontinue 
VELCADE
Discontinue 
VELCADE
4
Disabling
Discontinue 
VELCADE
Discontinue 
VELCADE
Discontinue 
VELCADE
Discontinue 
VELCADE
Discontinue 
VELCADE
ADL = activities of daily living
Hold = Interrupt VELCADE until the toxicity returns to Grade 1 or better.
Schedule Required = Schedule change from VELCADE twice weekly (Days 1, 4, 8, 11,) to once weekly 
(Days 1, 8) required. 
For patients who have already been treated with 1.3 mg/m2 of VELCADE, “reduction by 1 dose level” means 
reduction to 1 mg/m2 of VELCADE, and “reduction by 2 dose levels” means reduction to 0.7 mg/m2 of 
VELCADE (+ schedule if indicated by the table). For patients who have been treated with 1 mg/m2 of 
VELCADE, “reduction by 1 dose level” means reduction to 0.7 mg/m2 of VELCADE; in case of “reduction by 
2 dose levels” a reduction to 0.7 mg/m2 of VELCADE always combined with a schedule should be applied. 
For patients previously treated with 0.7 mg/m2 of VELCADE, in case of “reduction by 1 dose level” and 
“reduction by 2 dose levels” a schedule should be applied.
According to the table above, for example, if a patient had peripheral sensory 
neuropathy with objective sensory loss or paresthesia that interfered with 
function but not activities of daily living (ADL) (Grade 2) and mild 


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neuropathic pain not interfering with function (Grade 1), then the 
VELCADE dose is to be reduced by 1 dose level. 
Neuropathic symptoms are more prominent than abnormalities on the 
clinical examination. The neurotoxicity-directed questionnaire Functional 
Assessment 
of 
Cancer 
Therapy/Gynecologic 
Oncology 
Group 
(FACT/GOG-Ntx) (see Attachment 4) is provided as a safety checklist to 
help determine the presence and intensity of neuropathic pain or peripheral 
neuropathy using the patients’ reports. The FACT/GOG-Ntx questionnaire 
should be completed by all patients at the Screening visit, before dosing on 
Day 1 of each cycle, and at the End-of-Treatment Visit and be reviewed by 
the study staff to assist with the evaluation of the onset and intensity of 
peripheral neuropathy and other neurotoxicities that may possibly require 
intervention or dose modification. 
6.2.
Dose Adjustments for Rituximab
Dose adjustments for rituximab must follow the provided SmPC.
Patients who develop severe infusion reactions should have rituximab 
infusion discontinued and supportive care measures as medically indicated 
(e.g., i.v. fluids, vasopressors, oxygen, bronchodilators, diphenhydramine, 
and acetaminophen). In most cases, the infusion can be resumed at a 50% 
reduction in rate (e.g., from 100 mg/hr to 50 mg/hr) when symptoms have 
completely resolved.
Patients requiring close monitoring during first and all subsequent infusions 
include those with pre-existing cardiac and pulmonary conditions and those 
with prior clinically significant cardiopulmonary adverse events.
Hepatitis B virus reactivation with fulminant hepatitis, hepatic failure and 
death has been reported in some patients treated with rituximab. It is 
recommended to closely monitor carriers of hepatitis B. In patients who 
develop worsening of their status, rituximab should be discontinued and 
appropriate treatment initiated. Patients with active hepatitis B should not 
receive rituximab. Carriers of hepatitis B should be closely monitored for 
clinical and laboratory signs of active HBV infection for several months 
following rituximab therapy.


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6.3.
Dose Adjustments for Cyclophosphamide
Dose adjustments for cyclophosphamide must follow the provided SmPC.
The most common adverse events experienced with cyclophosphamide are 
hematologic toxicities. Myelosuppression with leukopenia, anemia, and 
thrombocytopenia can occur. The lowest leukocyte and thrombocyte levels 
occur in the first to second week after treatment is started. Recovery usually 
occurs within 3-4 weeks after treatment is started. In light of this, a patient 
can only start a cycle with cyclophosphamide if the ANC is 
≥1.5 x 109 cells/L and platelets are ≥100 x 109 cells/L. Patients who develop 
hematologic toxicities thought to be causally related to cyclophosphamide 
must have their dose adjusted on Day 1 of each cycle according to the table 
below: 
Table 2. Dose Modifications of Cyclophosphamide and Doxorubicin for Hematologic 
Toxicities
ANC (µL) and neutropenia
Platelet count (µL)
Dose given
≥1,500/µL
>100,000/µL
100% of the designated dose
>500/µL and no febrile 
neutropenia
>50,000/µL
100% of the designated dose after 
recovery of ANC to 1,500/µL and 
platelets to 100,000/µL
<500/µL and/or febrile 
neutropenia 
(ANC <500/µL + fever 
≥38.5C)
N/A
Initiate G-CSF for all subsequent 
cycles
<500/µL and/or febrile 
neutropenia (ANC 
<500/µL + fever ≥38.5C 
despite growth factors
<50,000
25% dose reduction for subsequent 
cycles
Recurrence of <500/µL 
and/or febrile neutropenia 
(ANC <500/µL + fever 
≥38.5C despite growth 
factors
Recurrence of <50,000/µL
Additional 25% dose reduction for 
subsequent cycles
Third episode of <500/µL 
and/or febrile neutropenia 
(ANC <500/µL + fever 
≥38.5C despite growth 
factors and 2 dose 
reductions
Third episode of 
<50,000/µL
Discontinue 
ANC = absolute neutrophil count; G-CSF = granulocyte colony stimulating factor, 
N/A = not applicable. 
Note: Dose reductions due to low platelet counts are not required in patients with 
thrombocytopenia due to bone marrow infiltration from MCL. 


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Following treatment with cyclophosphamide, hemorrhagic cystitis and 
hematuria can occur. These may necessitate interruption of dosing.
6.4.
Dose Adjustments for Doxorubicin
Dose adjustments for Doxorubicin must follow the provided SmPC.
The recommended lifetime cumulative dose limit of doxorubicin is 
450-550 mg/m2. The maximum dose given for each patient in this study will 
be 300 mg/m2 (it may be higher, for example, if the patients receive 8 cycles 
of treatment or have a large BSA. However, the total exposure should not 
exceed the lifetime cumulative dose limit). 
Dose limiting toxicities of doxorubicin therapy are myelosuppression and 
cardiotoxicity. 
Myelosuppression 
includes 
leukopenia, 
anemia 
and 
thrombocytopenia 
reaching 
nadir 
at 
10-14 
days 
after 
treatment. 
Cardiotoxicity as an arrhythmia may occur directly after administration and 
electrocardiogram (ECG) changes may last up to 2 weeks after 
administration. Cardiotoxicity may, however, occur several weeks or months 
after administration.
Doxorubicin is metabolized by the liver and excreted in bile. Impairment of 
liver function results in slower excretion of the drug and consequently 
increased retention and accumulation in the plasma and tissues, resulting in 
enhanced clinical toxicity. 
Doxorubicin dosage must be reduced if hepatic function is impaired 
according to the following table:
Serum Bilirubin Levels
Recommended Dose
1.2 – 3.0 mg/dl (20.5 – 51.0 µmol/l)
50% normal dose
Over 3.0 mg/dl (>51.0 µmol/l)
25% normal dose
Dose modifications for hematologic toxicities should be performed as 
indicated in Table 2.
6.5.
Dose Adjustment for Vincristine
Dose adjustments for vincristine must follow the provided SmPC.
If the liver function is abnormal on the first day of treatment, the vincristine 
dose is 100% with a bilirubin concentration of less than 25 µmol/l, 50% with 


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a bilirubin concentration of 25-50 µmol/l and 25% with a bilirubin 
concentration of more than 50 µmol/l. (see also dose adjustments for 
doxorubicin above in the event of liver abnormality).
Neurologic toxicity is the most common adverse event experienced with 
vincristine and it is related to dose and age. In case of serious neurotoxicity,
vincristine should not be administered, especially if there are signs of 
paraesthesia or paresis. Upon a decrease of the symptoms after stopping 
administration of vincristine, treatment may be resumed at 50% of the dose.
6.6.
Dose Adjustments for Prednisone
Dose adjustments for prednisone must follow the provided SmPC.
A dose above 80 mg/day of prednisone constitutes treatment with high dose 
steroid.
By definition, high dose prednisone will be used in this study at 100 mg/m2. 
Patients administered high dose prednisone should be monitored carefully as 
there is a relatively higher risk of developing or exacerbating some 
conditions e.g., bacterial infections, viral infections, systemic mycoses, 
hypertension, diabetes mellitus, gastrointestinal conditions such as peptic 
ulcers and diverticulitis.
In the event that the patient develops an adverse event related to prednisone 
and are not able to tolerate 100 mg/m2 of prednisone as required per 
protocol, the dose should be adjusted to a level specific to that patient, but 
should be no less than 80 mg per day (so that the patient still receives a high 
dose of prednisone).
In exceptional circumstances, a patient may not tolerate sudden steroid 
withdrawal at the end of 5 days of prednisone therapy. In such an instance, a 
tapering regimen of prednisone (reducing by 20 mg per day) can prescribed 
to the patient after sponsor approval.
6.7.
Cycle Delay
After the rest period of each cycle (Day 11 to Day 21), the start of a NEW 
cycle can be delayed on a weekly basis (for a maximum of 3 weeks) until 
recovery of toxicity to a level allowing continuation of therapy. Delay of a 
new cycle for more than 3 weeks can only occur if there is clear clinical 
benefit observed and after approval by the sponsor. Otherwise, if there is a 


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delay in the start of a new cycle of more than 3 weeks due to insufficient 
recovery from toxicity, patients will discontinue study drug and have 
procedures performed as outlined in the End-of-Treatment Visit outlined in 
Section 9.1.3.
The following parameters must be met on the first day of each cycle (other 
than Cycle 1):
Platelet count ≥100 x 109 cells/L (prior platelet transfusion is allowed)
Hemoglobin ≥8 g/dL (≥4.96 mmol/L; prior RBC transfusion or 
recombinant human erythropoietin use is allowed)
ANC ≥1.5 x 109 cells/L
Nonhematologic toxicity must have recovered to Grade 1 or baseline. 
Patients with thrombocytopenia due to bone marrow infiltration from MCL 
are permitted to have platelets of ≥50 x 109 cells/L on the first day of each 
cycle.
If the above parameters are not met, the start of the next cycle will be held on 
a weekly basis for a maximum of 3 weeks for recovery to the specified 
levels.
7.
COMPLIANCE
The dose of VcR-CAP or R-CHOP to be administered will be calculated 
using BSA (Attachment 3). The dose of each study drug to be administered 
will be documented in the source documents and case report form (CRF). 
Health care professionals will administer all study drugs.
Study personnel will maintain a log of all study drug administered. Drug 
supplies for each patient will be inventoried and accounted for.
Patients will be given diary cards to complete for the prednisone dosing at 
home on Days 2-5. The patients must bring these to the site on every visit so 
that the diary cards can be checked by study site personnel for compliance.
8.
CONCOMITANT THERAPY
All therapies (prescriptions or over-the-counter medications, including 
vitamins and herbal supplements; non-pharmacologic therapies such as 
electrical stimulation, acupuncture, special diets, exercise regimens) different 


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from the study drug must be recorded in the concomitant therapy section of 
the CRF and in the source documents.
The sponsor must be notified in advance (or as soon as possible thereafter) of 
any instances in which prohibited therapies are administered.
8.1.
Therapy for Tumor Lysis Syndrome
For subjects at risk for tumor lysis syndrome, allopurinol treatment should be 
considered and special attention should be given to adequate hydration.
8.2.
Prophylactic Treatment for Herpes Zoster
Prophylaxis for herpes zoster reactivation is mandatory during the Treatment 
Phase. Acceptable antiviral therapy includes acyclovir (e.g., 400 mg given 
orally, 3 times a day), famcyclovir (e.g., 125 mg given orally, twice a day), 
or valacyclovir (e.g., 500 mg given orally, twice a day).
8.3.
Prophylaxis for Hepatitis B Re-activation
It is recommended that hepatitis B surface antigen positive patients receive 
lamivudine 100 mg/day (or equivalent prophylaxis) orally until 8 weeks after 
last chemotherapy.
8.4.
Permitted Medications and Supportive Therapies
All concomitant medications for medical conditions other than MCL are 
permitted, as clinically indicated. 
All supportive therapies (such as any antinausea medication, MESNA for the 
prevention of hemorrhagic cystitis or antiviral prophylaxis for herpes) other 
than anticancer treatment needed for the management of patients enrolled in 
this study are permitted. Colony stimulating growth factors are permitted 
anytime during the study for the prevention of neutropenia and also for the 
management of treatment-emergent toxicities.
The following are supportive therapies that may be used if needed during 
this study: 
Loperamide is recommended for the treatment of diarrhea, starting at the 
time of the first watery stool. The loperamide dose regimen should be 
according to standard practice.
Platelet and red blood cell transfusions are permitted, as necessary.


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Premedication 
for 
rituximab 
infusion 
(e.g., 
acetaminophen, 
diphenhydramine, and steroids) should be considered before each infusion of 
rituximab. Premedication may attenuate infusion reactions.
8.5.
Excluded Medications
The following medications and supportive therapies and procedures are 
prohibited at all times during the study: 
Any 
antineoplastic 
agent 
other 
than 
VELCADE, 
rituximab, 
cyclophosphamide, doxorubicin, vincristine or prednisone with the 
exception of medications that may have antineoplastic activity but are 
taken for other reasons, e.g., megestrol (Megace®), Cox-2 inhibitors, and 
bisphosphonates.
– Short course (maximum of 10 days; not exceeding 100 mg/day) 
prednisone or equivalent steroids are allowed to treat symptoms in 
subjects with advanced disease who enter the screening phase and 
are waiting to be randomized.  
Any experimental agent other than that defined in the protocol
Radiation therapy
8.6.
Subsequent Therapies
Administration of any other antineoplastic therapy after completion of 
6 cycles (or 2 cycles beyond a documented response of study drug 
administration (including maintenance or consolidation therapy) is not 
allowed until PD (or relapse if the patient achieves a CR or CRu) is 
established according to the criteria as described in the disease response 
criteria in Section 9.2.
Administration of any other antineoplastic therapy, to patients who 
discontinue study drug before completion of 6 cycles (or 8 cycles if a 
response is first documented in Cycle 6) of study drug administration for 
reasons other than PD, is strongly discouraged until PD is established.
After PD is established, subsequent therapy is left to the investigator’s 
discretion. Subsequent therapy for MCL (including start and end date and 
best response) should be documented in the appropriate section of the CRF.


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9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
Patient participation will include a pretreatment (Screening Phase), a 
Treatment Phase, a Short-term and a Long-term Follow-up Phase. The 
Screening Phase can be up to 28 days prior to randomization. Bone marrow 
results obtained up to 56 days prior to randomization will be allowed. 
The Treatment Phase will extend from randomization until completion of 
6 cycles of treatment (or 8 cycles if a response is first documented in 
Cycle 6) or a decision to discontinue protocol treatment (distinguished from 
withdrawing consent to participate in the study), or decision by the patient to 
withdraw consent from the study.
The Short-term Follow-up Phase will extend from the End-of-Treatment 
Phase to PD, initiation of alternate antineoplastic therapy, decision by the 
patient to completely withdraw from the study or refusal to participate in any 
further study related procedures or follow-up, or death. Long-term Follow-up 
Phase will be used to assess survival and will document when the patient has 
died. Upon notification by the sponsor that clinical cutoff for the primary 
analysis (295 PFS events) has been reached, radiographic assessment of 
disease progression will stop, and all subjects in short-term follow-up will 
enter the Long-term Follow-up Phase. Long-term follow-up will continue 
until June 2017.
The total study duration from randomization of the first patient until the last 
PFS event required for the final analysis is expected to be approximately 
42 months (approximately 24 months enrollment and approximately 
18 months follow up). Patients on study (in the screening or treatment phase) 
at this time will continue to complete the planned protocol.
For the pharmacogenomics analysis, paraffin embedded tissue blocks 
obtained from biopsy or surgical resection specimens obtained at the time of 
diagnosis or subsequently, but before treatment on this study, will be 
collected. If paraffin embedded samples are not available, the patient has the 
option of consenting to a fresh tissue biopsy. This fresh biopsy is optional 
and not required to participate in this study. If sufficient sample is available, 
a portion of the biopsy required for central histology review for this study 


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will be utilized. In the absence of sufficient tissue blocks or fresh tissue 
sample collection, the patient has the option to consent to a 5 mL bone 
marrow sample for the biomarker analyses.
In countries where health authorities have approved pharmacogenomics and 
biomarker testing, patients must sign a separate informed consent form 
indicating their willingness to participate in the pharmacogenomics and 
biomarker analyses described in Section 9.5. Patients must provide paraffin 
embedded tissue (if available) and have the option of consenting to a fresh 
tissue biopsy, whole blood, bone marrow and serum sampling. 
The Time and Events Schedule summarizes the frequency and timing of 
efficacy, safety, and other measurements.
The total volume of blood drawn for pharmacogenomics analysis will be 
10 mL for whole blood collection, 15 mL for serum and 5 mL for bone 
marrow for biomarker analysis.
9.1.2.
Pretreatment Phase
Screening procedures must be performed within 28 days prior to 
randomization.
All patients must sign informed consent prior to conduct of any study 
procedures, and satisfy all the inclusion criteria and none of the exclusion 
criteria listed in Sections 4.2 and 4.3 before randomization.
All patients must provide an adequate tissue block for central review prior to 
randomization.
Separate informed consent for the pharmacogenomics research component 
will be obtained during the Screening Phase. 
All patients must undergo a neck, chest, abdominal and pelvic computed 
tomography (CT) scan with oral and i.v. contrast; this may be performed 
using only oral contrast if patient is intolerant of i.v. contrast agents. CT 
scans must be performed as part of the screening process, however if a 
previous scan is available, this may be used as the screening scan providing 
that it was performed no more than 56 days prior to randomization and meets 
the criteria required for study entry scans.


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Evaluation of other sites of disease, as relevant, by radiological imaging, 
physical examination, or other procedures as necessary may be performed up 
to 28 days before randomization. Subsequent assessments performed 
throughout the study must use the same method of assessment per patient.
The CT scans or other radiological evaluations will be centrally assessed by 
independent radiology review to confirm disease response for the purpose of 
the final efficacy analyses. All details regarding shipping of radiology 
images will be provided in the study manual.
All patients must undergo a bone marrow aspirate and biopsy (may be 
performed up to 56 days before first dose of study medication).
Refer to the Time and Events Schedule for a complete list of procedures to 
be performed during the screening phase.
Biopsy samples and supportive materials for central confirmation of MCL 
diagnosis are required for the study. A central pathologist independent of the 
sponsor will confirm the diagnosis of MCL. In the event there is insufficient 
tumor material available for the independent pathologist confirmation of 
MCL, an independent lymphoma expert will review relevant local diagnostic 
and clinical information to verify the diagnosis of MCL. Samples determined 
as negative for MCL by the independent pathologist cannot be evaluated by 
the independent lymphoma expert and will not be considered MCL 
confirmed.
Representative tissue block or unstained microscope slides from a biopsy 
and other supporting data, such as flow cytometry data (not simply summary 
interpretations of the data), FISH, cytogenetics, and PCR will be sent to the 
central pathologist. These materials must be sent to the central pathologist
during screening and adequacy of these samples must be confirmed before 
the patient can be randomized. 
9.1.3.
Treatment Phase
Treatment must start within 72 hours of randomization.
The Treatment Phase will start on Day 1 of Cycle 1 and finish on Day 21 of 
Cycle 6 (or Cycle 8 if a response is first documented in Cycle 6) or until 
early discontinuation of the allocated study medication (End-of-Treatment 
Visit).


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All patients who meet the eligibility requirements as assessed during 
screening will be randomized in the study and start treatment within 72 hours 
of randomization with the assigned study medication.
Patients will not receive additional study medication per protocol beyond 
Day 11, Cycle 6 unless there is a documented response at Cycle 6, in which 
case 2 additional cycles of therapy can be given.
Patients will be evaluated throughout the Treatment Phase for possible 
toxicities and delays in dosing. Dose modifications will be made as required 
according to the dose-modification rules outlined in Section 6. Patients who 
discontinue 
investigational 
treatment 
due 
to 
toxicity 
will 
have 
End-of-Treatment procedures completed and enter the Short-term Follow-up 
Phase.
Throughout the Treatment Phase, the investigator will assess the patient’s 
response to therapy using efficacy measurements and disease response 
criteria described in Sections 9.2.
Refer to the Time and Events Schedule for a complete list of procedures to 
be performed.
End-of-Treatment Visit:
All patients must complete an End-of-Treatment visit.
This visit will be performed 30 days (with a maximum window of +7 days) 
after the last dose of investigational product is administered (approximately 
20 days after the end of Cycle 6) and will include End-of-Treatment 
procedures.
Refer to the Time and Events Schedule for a complete list of procedures to 
be performed.
9.1.4.
Follow-up
9.1.4.1.
Short-term Follow-up
Following the End-of-Treatment Visit, all patients will have efficacy 
assessments every 6 weeks (±4 days) for 18 weeks and thereafter every 
8 weeks (±7 days) until PD/withdrawal from study/initiation of alternate 
therapy/death. When the patient is recorded to have an event of PD, a repeat 
CT scan to confirm PD must be undertaken at least 30 days after the scan 


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that was used to determine PD. In the event a patient starts subsequent 
anti-lymphoma treatment, it is strongly recommended that this repeat CT 
scan be performed before the patient starts treatment. The repeat CT scan 
must be done using i.v. and oral contrast and must be of the neck, chest, 
abdomen and pelvis. If the patient is intolerant of i.v. contrast agents, the 
scan may be performed with only oral contrast.
Death and events of progression constitute PFS, the primary endpoint for this 
study; it is therefore important that instances of PD, death or study 
discontinuation be reported to the sponsor as soon as possible. A PD fax 
form provided by the sponsor together with documentation of PD (e.g., CT 
scan report) must be sent to the sponsor’s medical representation within 
24 hours of the event.
The interval between Short-term Follow-up visits should be maintained at 
6 or 8 weeks as required; if a visit occurs earlier or later than the scheduled 
visit date then the next visit date should be modified to maintain the required 
interval from the previous visit. Patients who experience progressive disease 
or start alternate antineoplastic therapy will enter Long-term Follow-up until 
time of death. Upon notification by the sponsor that clinical cutoff for the 
primary analysis (295 PFS events) has been reached, radiographic 
assessment of disease progression will stop, and all subjects in short-term 
follow-up will enter the Long-term Follow-up Phase.
For safety assessments, after 30 days after the last dose of study drug, only 
adverse events considered related to study drug will be reported. Refer to the 
Time and Events Schedule for a complete list of procedures to be performed.
9.1.4.2.
Long-term Follow-up for Survival Status 
(Every 12 Weeks)
Patients will be contacted every 12 weeks (±7 days) until death, via 
telephone or office visit to assess survival status. The interval between 
Long-term Follow-up visits should be maintained at 12 weeks; if a visit 
occurs earlier or later than the scheduled visit date then the next visit date 
should be rescheduled to maintain the required interval from the previous 
visit.
If a patient decides to discontinue study treatment prior to disease 
progression, the end-of-treatment assessments should be performed, after 


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which they will enter short-term follow-up until PD or start of alternate 
antineoplastic therapy, and then long-term follow-up every 12 weeks until 
death. Long-term follow-up will continue until June 2017. 
Only survival data, adverse events considered related to study drug, 
instances of second primary malignancy (regardless of relationship to study 
treatment), and information on subsequent anti-lymphoma therapies will be
collected in the Long-term Follow-up Phase.
9.2.
Efficacy
Efficacy will be assessed by central review of radiology.
During the study, disease response will be assessed using CT scans with oral 
and i.v. contrast of the neck, chest, abdomen and pelvis (at a minimum oral 
contrast should be used if i.v. contrast is contraindicated). Evaluation of 
other sites of disease by radiological imaging, physical examination, or other 
procedures as necessary (to be performed throughout the study using the 
same method of assessment per patient), and review of hematology and 
clinical chemistry results may also occur at the site level, but for the purpose 
of the central review, only radiographic evaluations will be assessed. 
9.2.1.
Evaluations
9.2.1.1.
Radiographic Image Assessment
An Independent Radiographic Organization will perform the collection, 
qualification, and independent assessment of the radiographic images 
obtained during this study based on a pre-specified Independent Review 
Committee (IRC) charter. Image Acquisition Guidelines and Investigator 
Site Operations Manual will be provided to all clinical sites as separate 
documents to facilitate the consistent and quality acquisition of imaging data 
across all clinical sites. All clinical sites and imaging centers will be 
qualified by the Independent Radiographic Organization according to their 
ability to obtain quality images before they can enroll patients in the study.
9.2.1.2.
Definitions of Measurable and Assessable Disease
Eligible patients must have at least 1 measurable site of disease.
Measurable sites of disease are defined as lymph nodes or lymph node 
masses or extranodal sites of lymphoma. Each measurable site of disease 
must be greater than 1.5 cm in the long axis and greater than 1.0 cm in the 


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short axis and clearly measurable in two perpendicular dimensions. All other 
sites of disease are considered assessable, but not measurable. Measurement 
must be determined by radiological imaging. 
Up to 10 measurable sites of disease that are clearly measurable in 
2 perpendicular dimensions and >1.5 cm in the long axis and >1.0 cm in 
the short axis will be followed for each patient. Measurable sites of 
disease should be chosen such that they are representative of the patient’s 
disease (this includes splenic and extranodal disease). If there are lymph 
nodes or lymph node masses in the mediastinum or retroperitoneum larger 
than 1.5 cm in 2 perpendicular dimensions, at least 1 lymph node mass 
from each region should always be included. In addition, selection of 
measurable lesions should be from as disparate regions of the body as 
possible.
All other sites of disease will be considered assessable.
Assessable disease includes objective evidence of disease that is identified 
by radiological imaging, physical examination, or other procedures as 
necessary but is not measurable as defined above. Examples of assessable 
disease include bone lesions, mucosal lesions in the gastrointestinal tract, 
effusions, pleural, peritoneal or bowel wall thickening, disease limited to 
bone marrow, and groups of lymph nodes that are not measurable but are 
thought to represent lymphoma. In addition, if more than 10 sites of disease 
are measurable, these other sites of measurable disease may be included as 
assessable disease.
9.2.1.3.
Criteria for Response Categories
The response criteria being used to assess efficacy are based on the 
International Workshop to Standardize Response Criteria for Non-Hodgkin’s 
Lymphoma (IWRC)24 as modified for this protocol. The criteria that must be 
met for each disease response category, CR, CRu, PR, SD, disease relapse 
and progression, are provided below.
Complete Response (CR) requires ALL of the following:
Complete disappearance of all detectable clinical and radiological 
evidence of disease and disease-related symptoms and normalization of 
biochemical abnormalities definitely assignable to lymphoma (e.g., LDH) 
if present before therapy.
All measurable lymph nodes and nodal masses must have regressed on 
CT to normal size (1.5 cm in their greatest transverse diameter for nodes 
>1.5 cm before therapy). 


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Non-measurable and assessable nodes that were 1.1 to 1.5 cm in their 
greatest transverse diameter before treatment must have decreased to 
1 cm in their greatest transverse diameter after treatment, or by more 
than 75% in the sum of the products of the greatest diameters (SPD), as 
visually estimated.
The spleen or liver, if considered enlarged due to involvement with 
lymphoma before therapy on the basis of a physical examination or CT 
scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies. Similarly, other organs 
considered to be enlarged before therapy due to involvement by 
lymphoma such as kidneys, must have decreased in size.
If the bone marrow was involved by lymphoma, indeterminate or not 
adequately assessed during screening, an adequate aspirate and biopsy of 
the same site must be clear of lymphoma.
All extranodal sites of disease must have completely disappeared.
Unconfirmed Complete Response (CRu) requires:
That the first and fourth criteria for CR be satisfied, however:
Any residual lymph node mass >1.5 cm in longest transverse dimension 
or extranodal site of disease (irrespective of size) must have regressed by 
more than 75% of the product of the longest perpendicular dimensions 
compared to the pretreatment baseline.
The bone marrow aspirate may be indeterminate (contain increased 
number or size of lymphoid aggregates without cytologic or architectural 
atypia).
If there are residual masses in a patient who would otherwise be considered 
to have achieved a CR or CRu, the patient should be classified as a partial 
responder.
Partial Response (PR) requires ALL of the following:
At least a 50% decrease in sum of the product of the diameters (SPD) of 
the measurable sites of disease. 
No increase should be observed in any site of disease that meet the 
criteria for relapsed or progressive disease. 
Non-measurable nodes and nodules must regress by 50% in their SPD 
or, for single non-measurable lesions, in the greatest transverse diameter, 
as visually estimated.


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Bone marrow assessment is irrelevant for determination of a PR if the 
sample was positive before treatment. However, patients who achieve a 
CR by the above criteria, but who have persistent morphologic bone 
marrow involvement will be considered partial responders. When the 
bone marrow was involved before therapy and a clinical CR was 
achieved, but with no bone marrow assessment after treatment, patients 
should be considered partial responders.
No new sites of disease should be observed that meet the criteria for 
relapsed or progressive disease.
Stable disease (SD) is defined as the following:
A patient is considered to have SD when he or she fails to attain the
criteria needed for a CR or PR, but does not fulfill those for progressive 
disease (see below).
Progressive Disease (after PR/SD) or Relapsed Disease (after CR/CRu)
Progressive or relapsed disease requires any one of the following:
1. A) 50% increase from nadir in the SPD of all measurable sites of disease 
at the time that progressive or relapsed disease is identified and the absolute 
change in at least 1 dimension is 0.5 cm for at least 1 lesion; or B) 50% 
increase in the long axis of any measurable site of disease at the time that 
progressive or relapsed disease is identified and the absolute change in the 
long axis is 0.5 cm.
2. A) 50% increase from nadir in the SPD of all non-measurable sites of 
disease (excluding truly assessable disease), as visually estimated, and the 
absolute change in at least 1 dimension is 0.5 cm for at least 
1 non-measured lesion as estimated visually; or B) 50% increase in the long 
axis of any non-measurable site of disease (excluding truly assessable 
disease), and the absolute change in the long axis is 0.5 cm, as estimated 
visually.
3. 50% increase from nadir in any truly assessable site of disease, as 
visually estimated. 
4. Appearance of any new lymph node site of disease that measures >1.5 cm 
in long axis and >1.0 cm in short axis, any new unequivocal extranodal site 
of disease (irrespective of size), or unequivocal evidence of a new site of 
assessable disease (for example effusions, ascites, masses with indistinct 
borders, new involvement of the bone marrow).


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5. Appearance of a new organ enlargement or unequivocal increase of an 
organ enlargement that was present since baseline.
Measurable extranodal disease should be assessed in a manner similar to that 
for nodal disease. For these recommendations, the spleen is considered nodal 
disease. Disease that is only assessable (e.g., pleural effusions, bone lesions) 
will be recorded as no change, increased, decreased, or new, unless, while an 
abnormality is still noted by imaging studies or physical examination, it is 
found to be histologically negative.
When the patient is recorded to have an event of PD, a repeat CT scan to 
confirm PD must be undertaken at least 30 days after the scan that was used 
to determine PD. In the event a patient starts subsequent anti-lymphoma 
treatment, it is strongly recommended that this repeat CT scan be performed 
before the patient starts treatment. The repeat CT scan must be done using 
i.v. and oral contrast and must be of the neck, chest, abdomen and pelvis. If 
the patient is intolerant of i.v. contrast agents, the scan may be performed 
with only oral contrast.
Death and events of progression constitute PFS, the primary endpoint for this 
study; it is therefore important that instances of PD, death or study 
discontinuation be reported to the sponsor as soon as possible. A PD fax 
form provided by the sponsor together with documentation of PD (e.g., CT 
scan report) must be sent to the sponsor’s medical representation within 
24 hours of the event.
9.2.1.4.
Reappearing Nodes
Reappearing nodes (from a nadir of 0 cm x 0 cm): Any node(s) that reappear 
(measured or not measured) >1.5 x 1.0 cm or unequivocally reappearing 
extranodal lesions (irrespective of size and whether measured or not) should 
result in PD.
9.2.2.
Efficacy Criteria
9.2.2.1.
Primary Endpoint
The primary endpoint is PFS, which is defined as the interval between the 
date of randomization and the date of PD or death, whichever is first 
reported, in the intent-to–treat (ITT) population. The death due to PD will be 
considered as an event if the date of death is within 6 month after last disease 


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assessment (or within one disease assessment period), otherwise, death will 
be censored at the date of last disease assessment.
9.2.2.2.
Secondary Endpoints
ORR is defined as the proportion of patients who achieve CR, CRu, or PR. 
Disease response and progression will be evaluated according to the IWRC 
recommendations 
by 
radiographic 
imaging 
and 
other 
appropriate 
investigations.
The CT scans or other radiographic evaluations will be centrally assessed by 
independent radiology review to confirm disease response for the purpose of 
the efficacy analyses. Additionally, the CT scans or other radiographic 
evaluations will be locally assessed during the conduct of the study for the 
purpose of treatment decision-making. 
CR rate is defined as the proportion of patients who achieve CR and CRu.
Duration of response (CR, CRu, or PR) will be calculated from the date of 
initial documentation of a response to the date of first documented evidence 
of PD (or relapse for patients who experience CR or CRu on this study).
TTP will be analysed in the ITT population and is defined as the duration 
from the date of randomization until the date of first documented evidence of 
PD (or relapse for patients who experience CR or CRu on this study). The 
death due to PD will be considered as an event if the date of death is within 
6 months after last disease assessment (or, at most, 1 missing disease 
assessment visit), otherwise, death will be censored at the date of last disease 
assessment.
OS is measured from the date of randomization to the date of the patient’s 
death. If the patient is alive or the vital status is unknown, the date of death 
will be censored at the date that the patient is last known to be alive. OS will 
be analyzed in the ITT population.
TNT will be assessed, for all patients, from the initiation of study treatment 
to the start of anti-lymphoma therapy subsequent to study treatment. Patients 
who do not receive alternate therapy will be censored in the analysis at the 
date of the last visit. 


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Treatment-free interval will be assessed, for those patients who have 
terminated study treatment, from the end of the study treatment to the start of 
anti-lymphoma therapy subsequent to the study treatment. Patients who do 
not receive alternate therapy will be censored in the analysis at the date of 
the last visit.
Eighteen-month survival is defined as survival rate at 18 months (Kaplan-
Meier estimate).
9.3.
Patient-Reported Outcomes
Three PRO instruments, the EQ-5D (Attachment 7), the EORTC QLQ-C30 
Version 3.0 (Attachment 8), and the BFI (Attachment 9) will be used. The 
EORTC questionnaire to assess the quality of life of cancer patients 
QLQ-C30 Version 3.0 is composed of multi-item and single scales. These 
include five functional scales (physical, role, emotional, social, and 
cognitive), three symptoms (fatigue, nausea and vomiting and pain) and a 
global health status/QoL scale and six single items (dyspnea, insomnia, 
appetite loss, constipation, diarrhea and financial difficulties). All scales and 
single items meet the standards for reliability. The reliability and validity of 
the questionnaire is highly consistent across different language and cultural 
groups. The time recall period is the past week. The average time to 
complete the EORTC QLQ-C30 questionnaire is approximately 10 to 
15 minutes.
Because oncology therapies may positively or negatively affect a patient’s 
quality of life, a common methodologic approach is used to quantify this 
effect by “quality-adjusting” survival in comparative treatment groups. The 
result, quality-adjusted life-years (QALYs), is a measure of both the length 
and quality of life and is used as a measure of benefit in cost-utility analysis. 
General PRO instruments such as the EORTC QLQ-C30 are not designed to 
measure patient preferences (or utilities) in a way that is suitable for 
calculating QALYs. Therefore, a separate validated instrument, in this case 
the EuroQOL EQ-5D, will be used to quantify utilities to calculate QALYs 
for a cost-utility analysis31,32,33,34,35. The EQ-5D is a standardized instrument 
for use as a measure of health outcome. Applicable to a wide range of health 
conditions and treatments, it provides a simple descriptive profile and a 
single index value for health status. It is cognitively simple, taking only a 
few minutes to complete.


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The BFI was developed for patients with fatigue due to cancer and cancer 
treatment. It was validated among patients with mostly hematologic 
malignancies including acute and chronic leukemias and lymphoma.38 It 
assesses severity of fatigue and the impact of fatigue on daily functioning 
including general activity, mood, walking, work, relationships, and 
enjoyment in the past 24 hours. This time interval can be changed to the past 
week if more appropriate. It is a single-page, 9-item questionnaire that can 
be completed within 5 minutes. 
Patients are eligible for the PRO assessment in this study if they fulfill the 
eligibility criteria and, more importantly, complete the baseline PRO 
questionnaire before randomization. Patients will be informed in the consent 
form that they will have their PRO assessment regularly while involved in 
this trial. PRO will be an exploratory endpoint and evaluated in a 
longitudinal design for all patients entered in this study.
PRO questionnaires must be filled out at the Screening visit; on Day 1 of 
every treatment cycle before other assessments are performed or study drugs 
are administered; and at the End-of-Treatment visit. The questionnaire will 
be handed out to the patients by the investigator or a study nurse prior to
seeing the doctor for clinical evaluations. Patients will be asked to fill out the 
questionnaires as completely and accurately as possible. The CRFs will 
include a question on whether the PRO forms have been filled in and if not, 
the reason why. Data collection procedures should be followed using the 
EORTC guidelines.
Missing data may hamper assessment of PRO in clinical trials. This may be 
because centers do not collect the questionnaires at the appropriate time 
(unit non-response), and because patients may miss questions within the 
questionnaires (item non-response). The latter problem occurs less than 2% 
on average and should not be a problem. The former problem will be 
minimized by ensuring that participating centers are properly informed and 
motivated about PRO assessment. During the study, compliance with 
completing PRO questionnaires will be investigated at each time point.


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9.4.
Medical Resource Utilization
MRU data associated with medical encounters related to MCL or adverse 
effects of the treatment will be collected for all patients during the study. 
Specifically, MRU is evaluated based on the number of medical care 
encounters such as hospital admissions, reason, type, duration, type of 
adverse events involved, outpatient visits, diagnostic tests and procedures, 
and concomitant medications. The MRU data will be used to conduct 
economic analyses.
9.5.
Pharmacogenomics Evaluations
There are 2 parts to the pharmacogenomics component of this study. This 
section of the study is to help identify patient populations that are more or 
less likely to respond to VcR-CAP or R-CHOP through the evaluation of a 
defined set of biomarkers including:
Correlations of somatic mutations in specific proteasome subunits from 
paraffin embedded tissue or fresh tissue or bone marrow (additional genes 
associated with response to drug treatment may also be evaluated).
Evaluation of Ki-67, NF-kB and PSMA5,and other protein prognostic 
markers of disease or drug activity in paraffin embedded tissue or fresh 
tissue or bone marrow (e.g., p27, p53, cyclin D1, CTAG1B, CYCLIN A, B, 
E, P21, ICAM, VCAM, BID, BCL-XL, BAK, BCL2, ROS, BAX, 
CASPASES, CHK-1, PSMB8, LMP1, IL-32, PERK, GAS-5, P2RY5, 
CCNB1IP1, CR2, PTB, AKT1, CD40, JUN, eIF, and Noxa/Mcl-1, 
STK17A, STK17B, CSEIL, DRAK1, DRAK2, TOSO, TNFRSFS, 
TNFS4, TANK, TRAF5, TRAF6, DED, ALK, Topoisomerase II, 
Repp86, IL10R, SPARC, CDC14A, RAS family, FADD, DAXX, RIPK1, 
RAIDD, PRAD1, BCL1)
Samples will be collected from patients who give separate written informed 
consent for this component of the study (where local regulations permit) 
(Attachment 5). This will allow for biomarker research, as described. If 
sufficient sample is available, a portion of the embedded paraffin tissue 
required for the central review of diagnosis of MCL will be utilized for the 
analyses. If there is insufficient tissue sample available, patients can 
optionally consent to undergo a biopsy to obtain a fresh tissue sample or to 
provide a 5 mL sample of bone marrow. Whole blood (10 mL) and three 
5 mL serum samples will be collected from patients that optionally consent 
to these collections. Results of the exploratory analyses will be presented in a 


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separate report. Details of the analyses will be presented in the Statistical 
Analysis Plan.  
9.5.1.
Analyses Related to the Trial (Part 1)
Patients will be asked to consent to the pharmacogenomics and biomarker 
tests described below. 
9.5.1.1.
Somatic Mutational Status of Tissue
If sufficient sample is available, a portion of the embedded paraffin tissue 
sample required for central review will be utilized. If there is insufficient
tissue sample available, patients can optionally consent to undergo a biopsy 
to obtain a fresh tissue or to provide a 5 mL sample of bone marrow. Purified 
DNA from these tissues will be examined to detect abnormalities (mutations, 
deletions, amplifications) in selected genes. 
Genetic variability in drug target genes may influence drug binding and 
subsequently, response to treatment. Suspected drug target genes including 
PSMB1, 2, 5, 6, 8 and 9 may be analyzed in tissue of all patients in order to 
determine any associations with response within this clinical trial. 
In addition, other genes (such as those listed in Attachment 6) may be 
analyzed in the MCL population through a candidate gene approach with 
sufficient single nucleotide polymorphism (SNP)/mutation coverage in 
relation to PFS, disease response, duration of response, and OS with the goal 
of identifying a “classifier” that will associate with response to drug 
treatment. Suspected target genes and genes that have been involved in the 
signaling pathways affected by VELCADE will be included in the gene set. 
Prognostic markers of MCL will also be included. Other genes may be 
analyzed on identifiable samples if these genes are hypothesized to be 
relevant to VELCADE or the indications for which it is developed between 
the time that the clinical protocol has been issued and the samples have been 
made non-identifiable. DNA extracted from tissue or bone marrow samples 
will be utilized for these analyses. 
9.5.1.2.
Analysis of Whole Blood Samples
Genetic variability in drug target genes may influence drug binding and 
subsequently, patient response. For example, the efficacy of rituximab has 
been shown to be significantly associated with germline genetic variants in 
the FcReceptor 3A (FCGR3A/FCGR2A) gene, indicating that functions of 


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non-neoplastic cells can play a prominent role in FL.29, 30 Suspected drug 
target genes for VELCADE (PSMB1, 2, 5, 7, 8, and 9) and CHOP may be 
analyzed by genotyping of DNA extracted from lymphocytes found in whole 
blood collected from the patients.
Genetic variability in absorption, distribution, metabolism, and elimination 
(ADME) genes may also have implications in terms of patient-to-patient 
response, drug-drug interactions, and safety outcomes. Drug metabolism 
studies in preclinical animal models, in vitro systems, and in human liver 
microsomes indicate an important contribution of CYP2C19 and CYP3A and 
to a lesser extent CYP2D6, to clearance of VELCADE. These and the 
following candidate ADME genes will only be genotyped if considered 
appropriate depending on clinical trial results, developments in the scientific 
literature, and availability of assays designed to detect polymorphisms within 
these genes: 
ABCB1 (MDR1), ABCB4 (MDR3), ABCC1 (MRP1), ABCC2 (MRP2), 
ADH, AHR, ALDH, ARNT, CYP1A1, CYP1A2, CYP1B1, CYP2A6, 
CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4, CYP3A5, 
CYP4B1, EPHX1, EPHX2, FMO1-4, GSTM1, GSTP2, GSTT1, MEH, 
MPO, NAT1, NAT2, NFE2L2, NR1I2 (PXR), SULT1A1, SULT1A2, 
SULT2A1 TPMT, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, 
UGT1A8, UGT1A9, UGT2B15, UGT2B4, UGT2B7.
9.5.1.3.
Biomarkers
If sufficient sample is available, a portion of the embedded paraffin tissue 
sample required for central review will be utilized. If there is insufficient 
tissue sample available, patients can optionally consent to undergo a biopsy 
to obtain a fresh tissue or to provide a 5 mL sample of bone marrow. These 
samples will be subjected to immunohistochemical analysis to quantify the 
levels of Ki-67, p27, p65 subunit of NF-kB and PSMA5 prognostic proteins. 
Other markers may also be analyzed including p53, cyclin D1, and markers 
of NF-kB activation. Clinical or preclinical studies have also implicated the 
following molecules in the efficacy of VELCADE: CTAG1B, CYCLIN A, B, 
E, P21, NFKB, ICAM, VCAM, BID, BCL-XL, BAK, BCL2, ROS, BAX, 
CASPASES, CHK-1, PSMA5, PSMB8, LMP1, IL-32, PERK, GAS-5, P2RY5, 
CCNB1IP1, CR2, PTB, AKT1, CD40, JUN, eIF, and Noxa/Mcl-1, STK17A, 
STK17B, CSEIL, DRAK1, DRAK2, TOSO, TNFRSFS, TNFS4, TANK, 


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TRAF5, TRAF6, DED, ALK, Topoisomerase II, Repp86, IL10R, SPARC, 
CDC14A, RAS family, FADD, DAXX, RIPK1, RAIDD, PRAD1, and BCL1. 
The protein levels of these or related biomarkers may also be evaluated and 
correlated with clinical outcomes. 
Patients will be asked to optionally provide a serum sample before dosing in 
Cycles 1, 2, and 3 for serum protein analyses to look at the effects of study 
treatment on circulating levels of prognostic markers such as VEGF and 
bFGF as well as candidate response markers. Additional analyses may 
include mass spectrometry or other protein based evaluation of differences 
between serum samples from patients sensitive and insensitive to drug 
treatment. These additional analyses will proceed only if considered 
appropriate depending on clinical trial results, developments in the scientific 
literature, and availability of assays to reliably detect differences in clinical 
samples. 
9.5.2.
Pharmacogenomics and Biomarker Samples
Pharmacogenomics and biomarker sample collections will be applicable only 
for those countries where the health authorities have approved of this testing. 
The following samples will be taken for pharmacogenomics and biomarker 
analysis from patients who gave informed consent for this part of the study. 
If sufficient sample is available, a portion of the embedded paraffin tissue 
sample required for central review will be utilized. If there is insufficient 
tissue sample available, patients can optionally consent to undergo a biopsy 
to obtain a fresh tissue or to provide a 5 mL sample of bone marrow. A 
whole blood sample will be collected from all patients that optionally 
consent. Serum samples will be collected from patients who optionally 
consent to serum protein analyses.
Refer to the Time and Events Schedule for a complete list of procedures to 
be performed.
9.5.3.
DNA Storage for Future Analyses (Part 2)
Patients will be asked to consent to storage of DNA samples from whole 
blood, bone marrow or embedded tissue or fresh tissue samples for optional 
future testing of genes related to VELCADE, MCL or other similar cancers 
that may be treated with VELCADE. This analysis will include genes listed 
within this protocol and others that are later found to be relevant to the drug 


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or cancer. These markers can add value in characterizing any observed 
outcomes not foreseen in the clinical development. Analysis of variants 
within these genes may help to guide future development decisions for this 
compound. The DNA samples and relevant clinical data will be held in a 
non-identifiable format, in which case no link will be made between the 
genetic information and an individual patient.
9.6.
Safety Evaluations
All patients who receive treatment will be considered evaluable for toxicity. 
All adverse events, with the exception of progression of MCL, will be 
reported from the time a signed and dated informed consent form is obtained 
until 30 days following the last dose of study drug or until the start of a 
subsequent systemic anti-lymphoma therapy, if earlier. Adverse events 
reported after 30 days following the last dose of study drug should also be 
reported if considered related to study drug, and all instances of second 
primary malignancy should be reported for the full duration of a subject’s 
participation in the study, regardless of onset date or relationship to study 
drug.
All Grade 3 or 4 adverse events considered related to study drug must be 
followed until recovery to Grade 0 or 1. Neuropathic and cardiac adverse 
events of Grade 2 or higher will be followed until improvement to Grade 0 
or 1. The unresolved aforementioned events will be followed for a maximum 
of 6 months. 
The study will include the following evaluations of safety and tolerability 
according to the time points provided in the Time and Events Schedule:
Adverse Events
All adverse events will be recorded, with the details of the duration and the 
severity of each episode, the action taken with respect to the study drug, 
investigator’s evaluation of its relationship to the study drug, and the patient 
outcome. The intensity (severity) of adverse events will be assessed using 
NCI CTCAE Version 3.0. 
All serious adverse events (life-threatening, resulting in death, prolonged 
hospitalization, resulting in persistent disability, congenital anomaly/birth 
defect) must be reported to the IRB for review and also to the Sponsor within 
24 hours by FAX.


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Specific details on adverse event reporting are provided in Section 12.
Clinical Laboratory Tests
All laboratory tests should be performed at the laboratory facilities 
associated with the investigational site. Laboratory certificates or 
accreditation and normal ranges of the laboratory facility at the site must be 
submitted before the enrolment of any patient at the site. 
If the patient has their laboratory assessments conducted at a laboratory 
facility other than the one associated with the investigational site, the 
investigator must submit laboratory certificates or accreditation and normal 
ranges for that facility as well.
Blood samples for serum chemistry and hematology will be collected. The 
investigator must review the laboratory report, document this review, and 
any clinically relevant changes in laboratory values must be recorded in the 
adverse event section of the CRF. For example, laboratory abnormalities 
leading to an action regarding study drug (dose change, temporary stop, 
delay of the start of a cycle or permanent stop) or the start of concomitant 
therapy should be reported. For each laboratory abnormality reported as an 
adverse event, the following laboratory values should be reported in the 
laboratory section of the CRF: the value indicative of the onset of each 
toxicity grade; the most abnormal value observed during the adverse event 
and the value supporting recovery to Grade 0 or 1 or to baseline values.


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The following tests will be performed:

Hematology Panel
-hemoglobin
- ANC and absolute lymphocyte 
count (ALC)
-platelet count
-white blood cell (WBC) count 

Serum Chemistry Panel 
-sodium
-alanine aminotransferase (ALT)
-potassium
-LDH
-blood urea nitrogen (BUN)/urea
-total bilirubin
-creatinine
-albumin
-aspartate aminotransferase (AST)
-calcium
-alkaline phosphatase
-phosphate
-glucose
-uric acid

Hepatitis B Screening
-hepatitis B surface antigen
-hepatitis B core antibody
Please see Time and Events Schedule for exact time points of these and other 
assessments. Also included are -2 microglobulin and bicarbonate, which are 
measured only at screening. During short-term follow-up, only LDH will be 
measured.
Serum/urine pregnancy test for women of childbearing potential only
Electrocardiogram (ECG)/Echocardiogram or Multiple Uptake Gated 
Acquisition (MUGA) scans
Twelve-lead ECGs will be recorded at a paper speed of 25 mm/sec so that 
the different ECG intervals (RR, PR, QRS, QT) can be measured manually. 
The ECG will be recorded until 4 regular consecutive complexes are 
available.
ECG interval estimates can be measured either manually or taken from the 
automated ECG recorder. ECGs will be recorded at the times specified in the 
Time and Events schedule.
Echocardiogram or MUGA scans will be performed as mandatory at 
screening but thereafter optionally according to clinical need. The purpose is 
to document baseline ventricular and septal parameters as well as baseline 
ventricular function. Any follow-up test method should be the same as the 
screening method.


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Vital Signs
Pulse and blood pressure will be recorded at the times specified in the Time 
and Events Schedule.
Physical Examination
A complete physical examination will be conducted at the times specified in 
the Time and Events Schedule. During treatment cycles, the patient will 
undergo a limited examination, which will include any symptom related 
examinations required.
10.
PATIENT COMPLETION/WITHDRAWAL
10.1. Completion
A patient will be considered as having completed the study Treatment Phase 
if he/she has completed all assessments at the End-of-Treatment visit of the 
Treatment Phase.
Completion of the posttreatment follow-up phases will occur after the patient 
has completed all of the required follow-up assessments or has been lost to 
follow-up and is censored.
10.2. Discontinuation of Treatment
If a patient must be discontinued from treatment before the end of the 
prescribed treatment regimen, this will not result in automatic withdrawal of 
the patient from the study. 
A patient should be discontinued from study treatment if:
The patient experiences overt disease progression or relapse
The investigator believes that for safety reasons (i.e., adverse event) it is 
in the best interest of the patient to stop treatment
The patient becomes pregnant
The patient refuses further study drug
A serious protocol violation has occurred, as determined by the principal 
investigator or the sponsor
The reason(s) a patient discontinues treatment will be recorded on the CRF. 
If a patient discontinues treatment before the end of the treatment phase, an 
end of treatment assessment must be obtained within 30 days after the last 
dose of study drug and follow-up continued for scheduled assessments.


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10.3. Withdrawal From the Study
A patient will be withdrawn from the study for any of the following reasons:
Lost to follow-up
Withdrawal of consent
Death
In case a patient is lost to follow-up, every possible effort must be made by 
the study site personnel to contact the patient and determine the reason for 
discontinuation. The measures taken to follow-up must be documented.
When a patient withdraws before completing the study, the reason for 
withdrawal must be documented in the CRF and in the source documents. 
Study drug assigned to the withdrawn patient will not be re-assigned to 
another patient. Patients who withdraw will not be replaced.
If a patient discontinues treatment before the end of the Treatment Phase, 
end-of-treatment and follow-up assessments will be obtained.
A patient who withdraws from the main part of the study will have the 
following options regarding pharmacogenomics research:
The DNA extracted from the patient's blood, bone marrow or fresh or 
paraffin embedded tissue will be retained and used in accordance with the 
patient's original pharmacogenomics informed consent
The patient may withdraw consent for pharmacogenomics research, in 
which case the DNA sample/s will be destroyed and no further testing 
will take place. To initiate the sample destruction process, the investigator 
must notify the sponsor site contact to request sample destruction. The 
sponsor site contact will, in turn, contact the pharmacogenomics 
representative for sample destruction. Upon request, the investigator will 
receive written confirmation from the sponsor that the sample has been 
destroyed
Withdrawal From Pharmacogenomics Research Only
The patient may also withdraw consent for pharmacogenomics research 
while remaining in the clinical study. If a patient withdraws consent for 
pharmacogenomics research, any DNA extracted from the patient’s samples 
will be destroyed. The sample destruction process will proceed as described 
above. After the clinical study is over, the sample will be made 
non-identifiable and therefore will not be destroyed. If the sample has 


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already undergone conversion to the non-identifiable format, the sponsor 
will notify the investigator in writing.
11.
STATISTICAL METHODS
11.1. Sample Size Determination
The sample size calculation for the study population is based on the 
following assumptions. The median PFS of Treatment Arm B (R-CHOP) is 
18 months.36 Assuming that treatment Arm A (VcR-CAP) can improve the 
median PFS by 40%, i.e. from 18 months to 25 months, a total number of 
295 events (PD or death) provides 80% power (α=0.05, 2-sided) to detect 
such improvement. Assuming a 24 month accrual and 18 month follow-up, a 
total of 486 patients is needed for the study (243/arm). 
If 280 PFS events are observed in the subset of subjects with a centrally 
confirmed diagnosis of MCL, the study can achieve approximately 80% 
power to detect a hazard ratio of 1.4 in this subset of patients with a 2-sided 
log-rank test (α=0.05).
11.2. Study Populations
Intent-to-treat (ITT) Population
The intent-to-treat (ITT) population is defined as all patients who are 
randomized to treatment. Patients in this population will be analyzed 
according to the treatment to which they were randomized
Per-protocol (PP) Population
The per-protocol (PP) population is defined as all patients who are 
randomized to treatment and undergo at least 1 postbaseline disease 
assessment. Patients in this population will be analyzed according to the 
treatment to which they were randomized.
Safety Population
The safety population is defined as all patients who receive at least one dose 
of study drug. The safety population will be analyzed according to the 
treatment actually received.
Biomarker Population
The biomarker population is defined as patients whose biomaterial is 
available and who have consented to participate in the study’s biomarker and 
pharmacogenomics evaluations or future research.


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11.3. Efficacy Analyses
Stratified log-rank test will be used to compare PFS between the 2 treatment 
arms in the primary efficacy analysis.
For the secondary efficacy endpoints, the OS, 18-month survival, TTP, and 
TNT, will be compared using stratified log-rank test. The Kaplan-Meier 
method will be used to estimate the distribution of PFS, OS, 18-month 
survival, and TTP for each treatment.
Long-term follow-up will continue until June 2017. 
The ORR and overall CR rate will be obtained and comparison of the rates 
will 
be 
performed 
between 
2 
treatment 
arms 
using 
the 
Cochran-Mantel-Haenszel (CMH) chi-square test. The 95% confidence 
interval for the difference of response rate between 2 treatment arms will be 
given.
The duration of response and treatment-free interval will be summarized 
descriptively. There will be no formal comparison of these endpoints 
between treatment groups because they are not statistically comparable.
For all efficacy endpoints, the primary analysis is to be performed in the ITT 
population. A sensitivity analysis will be performed in the subset of subjects 
with a centrally confirmed diagnosis of MCL. Approximately 280 events are 
expected in this subset of subjects at the time of the final analysis (295 PFS 
events in total), which can provide around 80% power to detect a hazard 
ratio of 1.4 using a 2-sided log-rank test (α=0.05).
11.4. Patient-Reported Outcomes Analyses
Patient-reported outcome assessments using the EORTC QLQ-C30, the 
EQ5D, and BFI will be analyzed to determine if response to the treatment 
and side effects of the treatment are accompanied by measurable changes in 
the PROs. The analyses will be performed on summary scores as well as on 
subscales and individual symptoms, with specific analytical methods 
outlined in a formal statistical analysis plan developed prior to database lock. 
The primary analytical focus for the PRO will be the global health 
status/quality of life subscale of the EORTC QLQ-C30. The change in PRO 
scores between baseline and each postbaseline assessment will be described 
overall and according to the response to treatment. The secondary PRO 


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analytical focus including the remaining EORTC QLQ-C30 subscales and 
individual item scores, and the BFI item scores. The change in scores will be 
tabulated. 
The EORTC QLQ-C30 questionnaire will be scored according to the 
algorithm described in the EORTC QLQ-C30 scoring manual. All scales and 
single items are scored on categorical scales and linearly transformed to 
0-100 scales where:
A high score for a symptom scale or item represents a high level of 
symptoms or problems.
A high score for a functional scale represents a high or healthy level of 
functioning.
A high score for the global health status/QoL represents high QoL.
The nine items of the BFI are measured on 0-10 numeric rating scales, with 
higher scores representing greater severity of fatigue and interference with 
daily functioning. A global fatigue score can be obtained by averaging all the 
items on the BFI. 
The analysis of the PRO scores will be performed as a repeated-measures 
analysis using all available time points. The analysis will use mixed model 
analysis of variance.
In PROs, if necessary, missing data will be imputed using the last 
observation carried forward (LOCF) method. For PROs, if a multi-item 
subscale has a missing item, then the average of the remaining items will be 
used as the Scale score, as long as at least half the items in that Scale are 
present. For example, for Fatigue in EORTC QLQ-30, if Item 12 is missing, 
the average score of Items 10 and 18 will be used.
11.5. Pharmacogenomics Analyses
The pharmacogenomics exploratory statistical analysis will be performed 
1) at the time of the third interim analysis, if required; and 2) at the 
completion of the trial in order to inform subsequent lymphoma trials.
Impact of Somatic Tumor Mutations in 100-Gene Set on Efficacy
For a gene with well-characterized, simple mutational spectra in tumors 
(e.g., p53), mutational status will be expressed as a categorical variable 
(mutated/not mutated) using standard, well-established gene-specific 


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classification schemes. For genes that do not have well-characterized 
mutational spectra, the impact of individual mutations and haplotypes (e.g., 
combinations of mutations) will be examined. The impact of mutational 
status, individual mutations, or haplotypes, as appropriate, will be tested 
using standard categorical tests or standard survival methods, depending on 
the endpoint, with modifications to allow for haplotyping testing, if required. 
Analyses will be performed within each treatment group and race.
Analysis of Whole Blood Samples
For genes with well-established genotype-to-phenotype mapping, the impact 
of predicted phenotype on response will be examined. For genes that do not 
have well-established genotype-to-phenotype mapping, the impact of the 
mutations taken individually and in haplotypes will be examined. The impact 
of predicted phenotype, individual mutations, or haplotypes, as appropriate, 
will be tested using standard categorical tests or standard survival methods, 
depending on the endpoint, with modifications to allow for haplotyping 
testing, if required. Analyses will be performed within each treatment group 
and race.
Impact of Changes in Protein Levels of Key Genes in Tumor Cells and 
Efficacy-Related Endpoints
Protein levels of prognostic markers such as p21cip1 and p27kip1 quantified 
by immunohistochemistry (IHC) and fluorescence in situ hybridization 
(FISH) will be measured as scores on an ordinal scale. The impact of protein 
expression level on response endpoints will be tested using standard 
categorical tests or survival analysis methods, as appropriate. The 
relationship between protein expression patterns (patterns of proteins, 
peptides, or small molecule components) in serum to clinical outcome will 
also be explored before and after treatment. Changes from baseline in protein 
levels after treatment will be categorized as increased, no change, or 
decreased, and tabulated against the response-related endpoints. Response 
related endpoints will be summarized by change from baseline using 
descriptive statistics and graphics, if appropriate. Impact of change from 
baseline will be tested using standard categorical or survival methods, as 
appropriate. Analyses will be performed within each treatment group.


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11.6. Medical Resource Utilization Analyses
Frequencies of hospitalization, outpatient visits, reasons, types, durations, 
types of adverse events if involved, blood product transfusions, antibiotic 
use, and other concomitant medication will be calculated and tabulated.
11.7. Safety Analyses
All safety analyses will use data for the safety population. The safety 
parameters to be evaluated are the incidence, intensity, and type of adverse 
events, clinically significant changes in the patient’s physical examination 
findings, vital signs measurements, and clinical laboratory results. Exposure 
to investigational product and reasons for discontinuation of study treatment 
will be tabulated.
Adverse Events
Detailed tabulations of safety data will be provided for all patients who 
receive study drug. The original terms used in the CRFs by investigators to 
identify adverse events will be coded using the Medical Dictionary for 
Regulatory 
Activities 
Terminology 
(MedDRA) 
dictionary. 
Treatment-emergent adverse events are adverse events that occur after the 
first dose of study drug, through the Treatment Phase, and for 30 days 
following the last dose of study drug; any event that is considered 
study-drug-related regardless of the start date of the event; or any event that 
is present at baseline but worsens in severity or is subsequently considered 
drug-related by the investigator. The number and percent of patients with 
treatment-emergent adverse events will be summarized according to 
intensity (NCI CTCAE, Version 3.0) and drug relationship as well as 
categorized by System Organ Class and preferred term by treatment group.
Clinical Laboratory Tests
Laboratory data will be summarized according to the type of laboratory test. 
Descriptive statistics will be calculated for each laboratory analyte at 
baseline and at each scheduled time point. The laboratory data for patients 
with any post baseline results outside the reference range will be 
summarized, when appropriate, by use of the NCI-CTCAE Version 3.0.
Vital Signs and Physical Examination
Changes in vital signs and physical examination parameters will be 
summarized over time and any abnormal values will be tabulated.


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11.8. Interim Analyses
There will be 3 interim analyses planned in the study. 
The first interim analysis will occur after the first 100 patients have been 
randomized into the study and will assess the safety and concordance rate of 
the diagnosis of MCL when central review is compared with the investigator 
assessment of the diagnosis. The concordance rate of the diagnosis of MCL 
when central review is compared with the investigator assessment of the 
diagnosis will also be reviewed at 50% accrual. This may be used to 
recalculate the sample size to ensure an adequate number of PFS events 
(approximately 280) in those subjects with a centrally confirmed MCL 
diagnosis at the time of the final analysis (295 PFS events in total). Based on
publications the concordance rate of the diagnosis of MCL between central 
and investigator review of pathology is estimated at 91%.37
If the observed concordance rate is 95% (95% CI: 89%, 98%), the sample 
size for the study will not be changed. If the observed difference is less than 
95%, the sample size may be adjusted to provide adequate PFS events 
(approximately 280) in those subjects with a centrally confirmed MCL 
diagnosis at the time of the final analysis (295 PFS events in total). There is 
no alpha adjustment for the first 2 interim analyses since no efficacy 
analyses will be performed. 
The first interim analysis will also review the safety data collected to date. 
Safety data will be reviewed after at least one cycle for the first 100 treated 
patients, irrespective of whether they complete treatment within that first 
cycle.
The second interim analysis will review the safety data and be performed 
after 100 patients per arm have either completed or discontinued study 
treatment.
The third interim analysis has been planned for this study after at least 
148 events have occurred in the ITT population. If, at the third interim 
analysis, pre-specified boundaries for PFS are met then the study will be 
terminated and superiority of the experimental arm (VcR-CAP) will be 
declared over the comparator arm (R-CHOP). If the observed hazard ratio 
(R-CHOP vs VcR-CAP) for PFS in the third interim is equal to or less than 
1.03 (a value of >1 favoring VcR-CAP), then the study may be terminated 


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due to futility. There will also be a review of the safety data at the third 
interim analysis.
The type I error adjustment for the interim is based on O’Brien-Fleming 
spending function. Assuming that 148 events are observed at the third 
interim analysis, the alpha allocated for the interim is 0.003 (2-sided) and for 
the final analysis is 0.049 (2-sided). 
If pre-specified boundaries are not met at the third interim stage, the final 
analysis of the study will occur after 295 events in patients have been 
observed in the ITT population.
11.9. Independent Data Monitoring Committee
An IDMC will be formed and constituted according to regulatory agency 
guidelines (such as United States Food and Drug Administration [FDA] 
guidelines) to evaluate safety data and results of the prospectively defined 
interim analyses of efficacy. The IDMC will meet following completion of 
the interim analysis. The review will consist of a review of the concordance 
rate of histological review, efficacy data, and safety data. Detailed 
information regarding the composition of the IDMC and detailed IDMC 
procedures will be documented in the IDMC charter.
11.10. Independent Radiology Review 
An Independent Radiology Review body will review the results of the study 
mandated radiological procedures. 
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information 
from clinical studies are crucial for the protection of patients, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The 
sponsor has established Standard Operating Procedures (SOPs) in 
conformity with regulatory requirements worldwide to ensure appropriate 
reporting of safety information; all clinical studies conducted by the sponsor 
or its affiliates will be conducted in accordance with those procedures. 


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12.1. Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study 
patient administered a pharmaceutical product. An adverse event does not 
necessarily have a causal relationship with the treatment. An adverse event 
can therefore be any unfavorable and unintended sign (including an 
abnormal finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product. (Definition per International Conference 
on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition, or abnormal results of diagnostic 
procedures, including laboratory test abnormalities.
Note: The sponsor collects adverse events once the signed and dated 
informed consent form has been obtained.
Serious Adverse Event
A serious adverse event as defined by ICH is any untoward medical 
occurrence that at any dose meets any of the following conditions:
Results in death
Is life-threatening
(The patient was at risk of death at the time of the event. It does not refer 
to an event that hypothetically might have caused death if it were more 
severe.)
Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization
Results in persistent or significant disability/incapacity, or
Is a congenital anomaly/birth defect
Note: Medical and scientific judgment should be exercised in deciding 
whether expedited reporting is also appropriate in situations other than those 
listed above. For example, important medical events may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the outcomes listed in 
the definition above. Any adverse event is considered a serious adverse event 
if it is associated with clinical signs or symptoms judged by the investigator 
to have a significant clinical impact.


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Unlisted (Unexpected) Adverse Event
An unlisted adverse event, the nature or severity of which is not consistent 
with the applicable product reference safety information. For an 
investigational product, the expectedness of an adverse event will be 
determined by whether or not it is listed in the Investigator's Brochure. For a 
comparator product with a marketing authorization, the expectedness of an 
adverse event will be determined by whether or not it is listed in the SmPC.
Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the 
attribution is possible, probable, or very likely by the definitions listed in 
Section 12.1.2.
12.1.2.
Attribution Definitions
Not related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, 
e.g., concomitant drug(s), concomitant disease(s), or the relationship in time 
suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative 
explanation, 
e.g., 
concomitant 
drug(s), 
concomitant 
disease(s), 
is 
inconclusive. The relationship in time is reasonable; therefore, the causal 
relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in 
time is suggestive (e.g., confirmed by dechallenge). An alternative 
explanation is less likely, e.g., concomitant drug(s), concomitant disease(s).
Very likely
An adverse event that is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, e.g., concomitant 
drug(s), concomitant disease(s). The relationship in time is very suggestive 
(e.g., it is confirmed by dechallenge and rechallenge).


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12.2. Procedures
12.2.1.
All Adverse Events
All adverse events, with the exception of progression of MCL, will be 
reported from the time a signed and dated informed consent form is obtained 
until 30 days following the last dose of study drug or until the start of a 
subsequent systemic anti-lymphoma therapy, if earlier. Resolution 
information after 30 days following the last dose of study drug should also 
be provided. Adverse events occurring after 30 days following the last dose 
of study drug should also be reported if considered related to study drug, and 
all instances of second primary malignancy will be collected for the full 
duration of a subject’s participation in the study, regardless of onset date and 
relationship to study drug. Serious adverse events, including those
spontaneously reported to the investigator within 30 days after the last dose 
of study drug, must be reported using the Serious Adverse Event Report 
Form. The sponsor will evaluate any safety information that is spontaneously 
reported by an investigator beyond the time frame specified in the protocol.
PD or relapse will not be reported as an adverse event, however, unexpected 
clinical signs or symptoms must be reported, even if they are eventually 
attributable to PD or relapse.
All events that meet the definition of a serious adverse event will be reported 
as serious adverse events, regardless of whether they are protocol-specific 
assessments.
All adverse events, regardless of seriousness, severity, or presumed 
relationship to study therapy, must be recorded using medical terminology in 
the source document and the CRF. Whenever possible, diagnoses should be 
given when signs and symptoms are due to a common etiology (e.g., cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as 
“upper respiratory infection”). Investigators must record in the CRF their 
opinion concerning the relationship of the adverse event to study therapy. All 
measures required for adverse event management must be recorded in the 
source document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of adverse 
events to the regulatory authorities. The sponsor will also report to the 
investigator (and the head of the investigational institute where required) all 


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serious adverse events that are unlisted and associated with the use of the
drug. The investigator (or sponsor where required) must report these events 
to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol unless otherwise required and 
documented by the IEC/IRB.
Patients (or their designees, if appropriate) must be provided with a “study
card” indicating the name of the investigational study drug, the study
number, the investigator’s name, a 24-hour emergency contact number, and, 
if applicable, excluded concomitant medications.
12.2.2.
Serious Adverse Events
All serious adverse events occurring during clinical studies must be reported 
to the appropriate sponsor contact person by investigational staff within 
24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the 
sponsor using the Serious Adverse Event Report Form, which must be 
completed and signed by a member of the investigational staff, and 
transmitted to the sponsor within 1 working day. The initial report of a 
serious adverse event should be made by facsimile (fax) or may be made by
telephone report in exceptional circumstances.
All serious adverse events that have not resolved by the end of the study, or 
that have not resolved upon discontinuation of the patient’s participation in 
the study, must be followed until any of the following occurs:
The event resolves
The event stabilizes
The event returns to baseline, if a baseline value is available
The event can be attributed to agents other than the study drug or to 
factors unrelated to study conduct
When it becomes unlikely that any additional information can be obtained 
(patient or health care practitioner refusal to provide additional 
information, lost to follow-up after demonstration of due diligence with 
follow-up efforts)
The cause of death of a patient in a clinical study, whether or not the event is 
expected or associated with the investigational agent, is considered a serious 
adverse event. Any event requiring hospitalization (or prolongation of 


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hospitalization) that occurs during the course of a patient’s participation in a 
clinical study must be reported as a serious adverse event, except 
hospitalizations for the following:
A standard procedure for protocol treatment administration will not be 
recorded as a serious adverse event (hospitalization or prolonged 
hospitalization for a complication of study treatment will be reported as a 
serious adverse event)
The administration of blood or platelet transfusion (hospitalization or 
prolonged hospitalization for a complication of the transfusion will be 
reported as a serious adverse event)
A procedure for a protocol/ disease related investigations (e.g., surgery, 
scans, endoscopy, sampling for laboratory tests, bone marrow sampling) 
(hospitalization or prolonged hospitalization for a complication of the 
procedure performed will be reported as a serious adverse event)
Prolonged hospitalization for technical, practical or social reasons in 
absence of an adverse event
Surgery or procedure planned before entry into the study (must be 
documented in the CRF) 
12.2.3.
Pregnancy
While pregnancy, in itself, is not an adverse event, all initial reports of 
patient pregnancy must be reported to the sponsor by the investigational staff 
within 24 hours of their knowledge of the event using a Serious Adverse 
Event Report Form (see Section 12.2.2, Serious Adverse Events) or 
Pregnancy Notification Form. Any patient who becomes pregnant during the 
study must be promptly withdrawn from treatment within the study. Because
the study drug may have an effect on sperm, or if the effect is unknown, 
pregnancies in partners of male patients included in the study will be reported 
by the investigational staff within 24 hours of their knowledge of the event 
using the pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any 
postnatal sequelae in the infant will be required.
12.3. Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who 
should be contacted regarding safety issues or questions regarding the study 
are listed on the Contact Information page(s), which will be provided as a 
separate document.


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13.
STUDY DRUG INFORMATION
13.1. Physical Description of Study Drug(s)
VELCADE for Injection is an antineoplastic agent available for i.v. use only. 
Each single-dose vial contains 3.5 mg of bortezomib as a sterile lyophilized 
powder in a 10 mL glass vial, and inactive ingredient: 35 mg mannitol.
Cyclophosphamide injection is supplied in vials of 1 g. Each vial contains 
cyclophosphamide monohydrate equivalent to 1000 mg anhydrous 
cyclophosphamide.
Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate 
for i.v. infusion administration in single use vials. The product is formulated 
for i.v. infusion administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL 
sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for 
Injection. 
Prednisone is supplied as scored tablets containing either 5 mg or 20 mg of 
active product.
Doxorubicin injection for intravenous administration is supplied in a vial 
containing 25 mL of sterile solution. Each vial contains 50 mg of active 
product at a concentration of 2 mg/mL.
Vincristine is supplied as a lyophilized powder or as United States 
Pharmacopeia (USP), sterile, preservative–free, single use only, solution 
available for intravenous use in 2 mL vial. Each vial contains 1 mg of active 
product.
13.2. Packaging
VELCADE will be provided as a sterile lyophilized powder in a single-use 
10 mL glass vial. Each vial contains the equivalent of 3.5 mg of VELCADE 
in the form of a mannitol boronic ester. Each vial is secured into a blister 
package. Blisters will be placed into a carton. Each carton will be labeled 
with a clinical label.
Cyclophosphamide is supplied in commercially packaged vials. Two vials 
will be labeled with a clinical label and placed into a carton. Each carton will 
be labeled with a clinical label.


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Rituximab is supplied in the commercially-packaged vial. Vials may contain 
either 10 mL or 50 mL of active solution. Each carton will be labeled with a 
clinical label.
Prednisone 5 mg and 20 mg tablets are supplied in the commercially 
packaged blister containing 10 tablets. Each blister is secured into a child 
resistant wallet. Each child resistant wallet will be labeled with a clinical 
label.
Doxorubicin is supplied as individual packaged vials. Each vial will be 
labeled with a clinical label and placed into a carton. Each carton will be 
labeled with a clinical label. Doxorubicin will be supplied as a 0.2% 
injection containing 2 mg/ml doxorubicin hydrochloride. Each vial will 
contain 50 mg doxorubicin hydrochloride in a 25 mL solution.
Vincristine is supplied as individual packaged vials. Each vial will be labeled 
with a clinical label and placed into a carton. Each carton will be labeled 
with a clinical label.
13.3. Labeling
Study drug labels will contain information to meet the applicable regulatory 
requirements. The investigational products will be labeled as open-label 
material.
Each vial, blister, and carton of VELCADE will contain a study specific 
label with a unique identification number.
Each vial and carton of cyclophosphamide will contain a study specific label 
with a unique identification number.
Each vial and carton of rituximab will contain a study specific label with a 
unique identification number.
Each blister card of prednisone will contain a study specific label with a 
unique identification number.
Each vial and carton of doxorubicin will contain a study specific label with a 
unique identification number.
Each vial and carton of vincristine will contain a study specific label with a 
unique identification number.


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13.4. Preparation and Handling
VELCADE
Vials containing lyophilized VELCADE for Injection should be stored below 
30ºC. Vials should be stored in their carton to protect from light. 
VELCADE is cytotoxic. As with all cytotoxic drugs, caution is required 
when preparing and handling VELCADE. 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.
VELCADE will be supplied in sterile, single-use vials containing 3.5 mg of 
VELCADE. Aseptic technique must be strictly observed throughout the 
reconstitution and handling of VELCADE since no preservative is present. 
Each vial of VELCADE for Injection should be reconstituted within 8 hours 
before dosing, with 3.5 mL of normal (0.9%) saline, sodium chloride 
injection, so that the reconstituted solution contains VELCADE at a 
concentration of 1 mg/mL. Dissolution is completed in approximately 
10 seconds. The reconstituted solution is clear and colorless, with a final pH 
of 5 to 6. Reconstituted VELCADE should be administered promptly and in 
no case more than 8 hours after reconstitution. In case of skin contact, wash 
the affected area immediately and thoroughly with soap and water and 
diluted hydrogen peroxide for 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.
Cyclophosphamide
Cyclophosphamide should be stored below 25ºC. Store in the supplied 
container. After reconstitution, store at 2 to 8ºC and protect from light. 
Cyclophosphamide is a cytotoxic agent. As with all cytotoxic agents, caution 
is required when preparing and handling cyclophosphamide. Cytotoxic 
agents 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.
Refer 
to 
the 
approved 
package 
insert 
for 
the 
preparation 
of 
cyclophosphamide.


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Rituximab 
Store vials in a refrigerator (2° to 8°C). Keep the container in the outer 
carton in order to protect from light.
The prepared infusion solution of MabThera is physically and chemically 
stable for 24 hours at 2° to 8°C and subsequently 12 hours at room 
temperature. From a microbiological point of view, the prepared infusion 
solution should be used immediately. If not used immediately, in-use storage 
times and conditions prior to use are the responsibility of the user and would 
normally not be longer than 24 hours at 2° to 8°C, unless dilution has taken 
place in controlled and validated aseptic conditions.
Refer to the approved package insert for the preparation of rituximab.
Prednisone
Prednisone should be stored at room temperature below 30ºC.
Doxorubicin 
Store between 2º to 8ºC. Protect from light. Doxorubicin is a cytotoxic agent. 
As with all cytotoxic agents, caution is required when preparing and 
handling. Cytotoxic agents should only be handled by staff specially trained 
in the safe handling of such preparations. Cytotoxic preparations must not be 
handled by pregnant employees. Careful and ample precautions must be 
observed in the removal of material used for reconstituting cytotoxic 
medications. 
It is necessary to avoid any contact with the liquid. During preparation, it is 
necessary to use a strictly aseptic working method; the protection measures 
are the use of gloves, an oral mask, safety glasses, and protective clothing. 
The use of a vertical laminar hood is recommended. It is advisable to wear 
gloves during the administration of the product.
Doxorubicin will be administered as an intravenous infusion over 1 to 3 hours 
because bolus injections (1 to 2 minutes) cause higher peak plasma 
concentrations and therefore are probably more cardiotoxic.
Refer to the approved package insert for the preparation of doxorubicin.


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Vincristine 
Store vials in a refrigerator (2° to 8°C). Vincristine is a cytotoxic agent. As 
with all cytotoxic agents, caution is required when preparing and handling 
vincristine. Cytotoxic agents should only be handled by staff specially 
trained in the safe handling of such preparations. Cytotoxic preparations 
must not be handled by pregnant employees. Careful and ample precautions 
must be observed in the removal of material used for reconstituting cytotoxic 
medications. 
The use of gloves and other appropriate protective clothing is recommended.
Vincristine can be diluted in physiological saline solution (0.9% wt/vol 
sodium chloride) to a concentration of 0.01 - 1 mg/ml.
Vincristine will be administered intravenously as a bolus injection of at least 
1 minute.
For additional information refer to the approved package insert for 
vincristine.
13.5. Drug Accountability
The clinical investigator is responsible for ensuring that all study drug 
received at the site is inventoried and accounted for throughout the study. 
The dispensing of study drug to the patient, and the return of study drug from 
the patient (if applicable), must be documented on the drug accountability 
form. Patients or their legally acceptable representative, where applicable, 
must be instructed to return all original containers, whether empty or 
containing study drug. Study drug returned by study patients will be stored 
and disposed of according to the sponsor’s instructions. Site staff must not 
combine contents of the study drug containers.
Study drug must be handled strictly in accordance with the protocol and the 
container label and will be stored in a limited access area or in a locked 
cabinet under appropriate environmental conditions. Unused study drug, and 
study drug returned by the patient (if applicable), must be available for 
verification by the sponsor’s site monitor during on-site monitoring visits.
The return to the sponsor of unused study drug, or used returned study drug 
for destruction, will be documented on the Drug Return Form. When the site 


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is an authorized destruction unit and study drug supplies are destroyed on 
site, this must also be documented on the Drug Return Form.
Hazardous materials such as used ampoules, needles, syringes and vials 
containing hazardous liquids, should be disposed of immediately in a safe 
manner and therefore will not be retained for drug accountability purposes. 
The immediate destruction of these drug supplies should be documented in 
the drug accountability records on site.
Study drug should be dispensed under the supervision of the investigator, a 
qualified member of the investigational staff, or by a hospital/clinic 
pharmacist. Study drug will be supplied only to patients participating in the 
study. Returned study drug must not be dispensed again, even to the same 
patient. Study drug may not be relabeled or reassigned for use by other 
patients. The investigator agrees neither to dispense the study drug from, nor 
store it at, any site other than the study sites agreed upon with the sponsor.
Patients will be given diary cards to complete for the prednisone dosing at 
home on days 2-5. The patients must bring these to the site on every visit so 
that the diary cards can be checked by study site personnel for compliance.
14.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
A copy of the current Investigator Brochure for VELCADE
A copy of the SmPC for all study medications
A copy of the NCI CTCAE Version 3.0
15.
ETHICAL ASPECTS
15.1. Study-Specific Design Considerations
All patients will receive an active drug combination.
All participating patients will receive full supportive care and will be 
followed closely for safety and efficacy throughout the trial. Efficacy 
assessments will occur according to the internationally accepted response 
criteria. Safety assessments will occur through regular clinic visits including 
laboratory analyses. An IDMC will follow safety and efficacy during the 
trial at regular intervals and in a pre-specified interim analysis.


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IEC/IRB approval for the pharmacogenomics research component of the 
clinical study and for the pharmacogenomics informed consent form must be 
obtained. IEC/IRB approval can be obtained for the protocol independent of 
approval for pharmacogenomics research.
All information, including but not limited to information regarding 
VELCADE or the sponsor’s operations (e.g., patent application, formulas, 
manufacturing processes, basic scientific data, prior clinical data, and 
formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomics research 
data, generated as a result of this study, are considered confidential and 
remains the sole property of the sponsor. The investigator agrees to maintain 
this information in confidence and use this information only to accomplish 
this study, and will not use it for other purposes without the sponsor’s prior 
written consent.
The results of the study will be reported in a Clinical Study Report generated 
by the sponsor and will contain all data from all investigational sites. Results 
of any pharmacogenomics analyses performed after the Clinical Study 
Report has been issued will be reported in a separate report and will not 
require a revision of the Clinical Study Report. Study patient identifiers will 
not be used in publication of pharmacogenomics results. Any work created 
in connection with performance of the study and contained in the data that 
can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work.
The total blood volume will be approximately 180 mL during the Treatment 
Phase and 15 mL in each study visit in short-term follow-up.
15.2. Regulatory Ethics Compliance
15.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical study is 
performed in accordance with the protocol, current ICH guidelines on Good 
Clinical Practice (GCP), and applicable regulatory and country-specific 
requirements.


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Good Clinical Practice is an international ethical and scientific quality 
standard for designing, conducting, recording, and reporting studies that 
involve the participation of human patients. Compliance with this standard 
provides public assurance that the rights, safety, and well being of study 
patients are protected, consistent with the principles that originated in the 
Declaration of Helsinki, and that the clinical study data are credible.
15.2.2.
Independent Ethics Committee or Institutional 
Review Board (IEC/IRB)
Before the start of the study, the investigator (or sponsor where required) will 
provide the IEC/IRB with current and complete copies of the following 
documents:
Final protocol and, if applicable, amendments
Sponsor-approved informed consent form (and any other written materials 
to be provided to the patients)
Investigator’s Brochure (or equivalent information) and amendments
Sponsor-approved patient recruiting materials
Information on compensation for study-related injuries or payment to 
patients for participation in the study, if applicable
Investigator’s curriculum vitae or equivalent information (unless not 
required, as documented by IEC/IRB)
Information regarding funding, name of the sponsor, institutional 
affiliations, other potential conflicts of interest, and incentives for patients
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval 
of the final protocol, amendments (if any), the informed consent form, 
applicable recruiting materials, and patient compensation programs, and the 
sponsor has received a copy of this approval. This approval letter must be 
dated and must clearly identify the IEC/IRB and the documents being 
approved.
Approval for the pharmacogenomics research component of the clinical 
study and for the pharmacogenomics informed consent form must be 
obtained from the IEC/IRB. Approval for the protocol can be obtained 
independent of approval for pharmacogenomics research.


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During the study the investigator (or sponsor where required) will send the 
following documents to the IEC/IRB for their review and approval, where 
appropriate:
Protocol amendments
Revision(s) to informed consent form and any other written materials to 
be provided to patients
If applicable, new or revised patient recruiting materials approved by the 
sponsor
Revisions to compensation for study-related injuries or payment to 
patients for participation in the study, if applicable
Investigator’s Brochure amendments or new edition(s)
Summaries of the status of the study at intervals stipulated in guidelines 
of the IEC/IRB (at least annually)
Reports of adverse events that are serious, unlisted, and associated with 
the investigational drug
New information that may adversely affect the safety of the patients or the 
conduct of the study
Deviations from or changes to the protocol to eliminate immediate 
hazards to the patients
Report of deaths of patients under the investigator's care
Notification if a new investigator is responsible for the study at the site
Any other requirements of the IEC/IRB
For protocol amendments that increase patient risk, the amendment and 
applicable informed consent form revisions must be submitted promptly to 
the IEC/IRB for review and approval before implementation of the 
change(s).
At least once a year, the IEC/IRB will be asked to review and re-approve this 
clinical study. This request should be documented in writing.
At the end of the study, the investigator (or sponsor where required) will 
notify the IEC/IRB about the study completion.


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15.2.3.
Informed Consent
Each patient (or a legally acceptable representative) must give written 
consent according to local requirements after the nature of the study has been 
fully explained. The consent form must be signed before performance of any 
study-related activity. The consent form that is used must be approved by 
both the sponsor and by the reviewing IEC/IRB. The informed consent 
should be in accordance with principles that originated in the Declaration of 
Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor policy.
Before entry into the study, the investigator or an authorized member of the 
investigational staff must explain to potential patients or their legally 
acceptable representatives the aims, methods, reasonably anticipated 
benefits, and potential hazards of the study, and any discomfort participation 
in the study may entail. Patients will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. 
They will be informed that choosing not to participate will not affect the care 
the patient will receive for the treatment of his/her disease. Patients will be 
told that alternative treatments are available if they refuse to take part and 
that such refusal will not prejudice future treatment. Finally, they will be told 
that the investigator will maintain a patient identification register for the 
purposes of long-term follow-up if needed and that their records may be 
accessed by health authorities and authorized sponsor staff without violating 
the confidentiality of the patient, to the extent permitted by the applicable 
law(s) or regulations. By signing the informed consent form the patient or 
legally acceptable representative is authorizing such access, and agrees to 
allow his or her study physician to recontact the patient for the purpose of 
obtaining consent for additional safety evaluations, if needed, or to obtain 
information about his or her survival status.
The patient or legally acceptable representative will be given sufficient time 
to read the informed consent form and the opportunity to ask questions. After 
this explanation and before entry into the study, consent should be 
appropriately recorded by means of either the patient's or his/her legally 
acceptable representative's dated signature. After having obtained the 
consent, a copy of the informed consent form must be given to the patient.


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Patients will be asked to consent to participate in a pharmacogenomics
research component of the study (where local regulations permit). After 
informed consent for the clinical study is appropriately obtained, the patient 
or his/her legally acceptable representative will be asked to sign and 
personally date a separate pharmacogenomics informed consent form 
indicating agreement to participate in pharmacogenomics and biomarker 
research. A copy of the signed pharmacogenomics informed consent form 
will be given to the patient. Refusal to participate will not result in 
ineligibility for the clinical study.
If the patient or legally acceptable representative is unable to read or write, 
an impartial witness should be present for the entire informed consent 
process (which includes reading and explaining all written information) and 
should personally date and sign the informed consent form after the oral 
consent of the patient or legally acceptable representative is obtained.
When prior consent of the patient is not possible and the patient's legally 
acceptable representative is not available, enrollment procedures should be 
described in the protocol with documented approval/favorable opinion by the 
IEC/IRB to protect the rights, safety, and well being of the patient and to 
ensure compliance with applicable regulatory requirements. The patient or 
legally acceptable representative must be informed about the study as soon 
as possible and give consent to continue.
15.2.4.
Privacy of Personal Data
The collection and processing of personal data from patients enrolled in this 
study will be limited to those data that are necessary to investigate the 
efficacy, safety, quality, and utility of the investigational study drug(s) used 
in this study.
These data must be collected and processed with adequate precautions to 
ensure confidentiality and compliance with applicable data privacy 
protection laws and regulations. Appropriate technical and organizational 
measures to protect the personal data against unauthorized disclosures or 
access, accidental or unlawful destruction, or accidental loss or alteration 
must be put in place. Sponsor personnel whose responsibilities require access 
to personal data agree to keep the identity of study patients confidential.


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The informed consent obtained from the patient (or his/her legally acceptable 
representative) includes explicit consent for the processing of personal data 
and for the investigator to allow direct access to his or her original medical 
records for study-related monitoring, audit, IRB/IEC review, and regulatory 
inspection. This consent also addresses the transfer of the data to other 
entities and to other countries.
The patient has the right to request through the investigator access to his/her 
personal data and the right to request rectification of any data that are not 
correct or complete. Reasonable steps should be taken to respond to such a 
request, taking into consideration the nature of the request, the conditions of 
the study, and the applicable laws and regulations.
For those patients who gave consent to store DNA samples for future genetic 
research (Part 2), samples and corresponding relevant clinical data will be 
made nonidentifiable by the removal of personal identifiers. Samples will be 
stored until used up. Only research related to the drug or the indications for 
which the drug is developed will be done on stored samples.  For data 
generated on identifiable samples (Part 1), the sponsor will provide the 
individual raw data, through the investigator, to patients who submit a 
written request. The sponsor cannot make decisions as to the significance of 
any findings resulting from this pharmacogenomics research, and cannot, 
therefore, provide genetic counseling. Genotypic data generated on 
nonidentifiable samples (Part 2) cannot be returned to individual patients.
15.2.5.
Country Selection
Unless explicitly addressed as a specific ethical consideration in 
Section 15.1, Study-Specific Ethical Considerations, this study will only be 
conducted in those countries where the intent is to register for marketing 
authorization.
16.
ADMINISTRATIVE REQUIREMENTS
16.1. Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a 
formal amendment. All protocol amendments must be issued by the sponsor, 
and signed and dated by the investigator. Protocol amendments must not be 
implemented without prior IEC/IRB approval, or when the relevant 
competent authority has raised any grounds for non-acceptance, except when 


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necessary to eliminate immediate hazards to the patients, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant 
competent authority. When the change(s) involves only logistic or 
administrative aspects of the study, the IRB (and IEC where required) only 
needs to be notified.
During the course of the study, in situations where a departure from the 
protocol is unavoidable, the investigator or other physician in attendance will 
contact the appropriate sponsor representative by fax or telephone 
(see Contact Information pages provided separately). If possible, this contact 
will be made before implementing any departure from the protocol. In all 
cases, contact with the sponsor must be made as soon as possible to discuss 
the situation and agree on an appropriate course of action. The data recorded 
in the CRF and source documents will reflect any departure from the 
protocol, and the source documents will describe this departure and the 
circumstances requiring it.
16.2. Regulatory Documentation
16.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate 
regulatory authorities in each respective country, if applicable. A study may 
not be initiated until all local regulatory requirements are met.
16.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment 
of study drug to the investigational site:
Protocol and amendment(s), if any, signed and dated by the investigator
A copy of the dated and signed written IEC/IRB approval of the protocol, 
amendments, informed consent form, any recruiting materials, and if 
applicable, patient compensation programs. This approval must clearly 
identify the specific protocol by title and number and must be signed by 
the chairman or authorized designee.


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Name and address of the IEC/IRB including a current list of the IEC/IRB 
members and their function, with a statement that it is organized and 
operates according to GCP and the applicable laws and regulations. If 
accompanied by a letter of explanation, or equivalent, from the IEC/IRB, 
a general statement may be substituted for this list. If an investigator or a 
member of the investigational staff is a member of the IEC/IRB, 
documentation must be obtained to state that this person did not 
participate in the deliberations or in the vote/opinion of the study.
Regulatory authority approval or notification, if applicable
Signed and dated statement of investigator (e.g., Form FDA 1572), if 
applicable
Documentation of investigator qualifications (e.g., curriculum vitae)
Completed investigator financial disclosure form from the investigator
Signed and dated clinical trial agreement, which includes the financial 
agreement
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment 
of the first patient:
Completed 
investigator 
financial 
disclosure 
forms 
from 
all 
subinvestigators
Documentation of subinvestigator qualifications (e.g., curriculum vitae)
Photocopy of the site signature log, describing delegation of roles and 
responsibilities at the start of the study
Name and address of any local laboratory conducting tests for the study, 
and a dated copy of current laboratory normal ranges for these tests
Local laboratory documentation demonstrating competence and test 
reliability (e.g., accreditation/license), if applicable.
16.3. Patient Identification, Enrollment, and Screening Logs
The investigator agrees to complete a patient identification and enrollment 
log to permit easy identification of each patient during and after the study. 
This document will be reviewed by the sponsor site contact for 
completeness.
The patient identification and enrollment log will be treated as confidential 
and will be filed by the investigator in the trial center file. To ensure patient 
confidentiality, no copy will be made. All reports and communications 


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relating to the study will identify patients by initials and assigned number 
only.
The investigator must also complete a patient-screening log, which reports 
on all patients who were seen to determine eligibility for inclusion in the 
study.
16.4. Source Documentation
At a minimum, source documentation must be available for the following to 
confirm data collected in the CRF: patient identification, eligibility, and 
study identification; study discussion and date of informed consent; dates of 
visits; results of safety and efficacy parameters as required by the protocol; 
record of all adverse events; concomitant medication; study drug; and date of 
study completion, and reason for early discontinuation if applicable. 
It is recommended that the author of an entry in the source documents be 
identifiable.
At a minimum, the type and level of detail of source data available for a 
study patient should be consistent with that commonly recorded at the site as 
a basis for standard medical care. Specific details required as source data for 
the study will be reviewed with the investigator before the study and will be 
described in the monitoring guidelines (or other equivalent document).
16.5. Case Report Form Completion
Case report forms are provided for each patient in printed or electronic 
format. 
Electronic Data Capture (eDC) will be used for this study. The study data 
will be recorded directly into the electronic CRF or transcribed by study 
personnel from the source documents onto an electronic CRF, and 
transmitted in a secure manner to the sponsor within 2 days of the patient’s 
visit. The electronic file will be considered as the CRF. Worksheets may be 
used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the patients’ source documentation.
All data relating to the study must be recorded in CRFs prepared by the 
sponsor. Data must be entered into CRFs in English. Designated site 
personnel must complete CRFs as soon as possible after a patient visit, and 


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the forms should be available for review at the next scheduled monitoring 
visit.
Every effort should be made to ensure that all subjective measurements (e.g., 
pain scale information or other questionnaires) to be recorded in the CRF are 
completed by the same individual who made the initial baseline 
determinations. The investigator must verify that all data entries in the CRFs 
are accurate and correct.
All CRF entries, corrections, and alterations must be made by the 
investigator or other authorized study-site personnel. If necessary, queries 
will be generated in the eDC tool. The investigator or an authorized member 
of the investigational staff must adjust the eCRF (if applicable) and complete 
the query.
If corrections to a CRF are needed after the initial entry into the CRF, this 
can be done in 3 different ways:
Site personnel can make adjustments in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool)
Site manager (SM) can generate a query (field Data Correction Form 
[DCF]) for resolution by the investigational staff
Clinical data manager (CDM) can generate a query for resolution by the 
investigational staff 
PRO questionnaires will be provided as printed forms. All printed forms 
must be filled out legibly in black ballpoint pen or typed. The appropriate 
pages must be signed and dated by the investigator. Corrections to PROs 
must be made in such a way that the original entry is not obscured. 
Correction fluid or tape must NOT be used. The correct data must be 
inserted, dated, and initialed by the investigator or an authorized member of 
the investigational staff. The investigational staff must not write on No 
Carbon Required (NCR) copies of questionnaires left at the investigational 
site once the original is transmitted to the sponsor. Completed questionnaires 
will be continuously submitted according to the sponsor’s instructions and 
reviewed by the sponsor to determine their acceptability. If necessary, DCFs 
will be generated and transmitted to the study site. The investigator or an 
authorized member of the investigational staff must complete, sign, and date 
the DCFs.


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16.6. Data Quality Assurance
Steps to be taken to ensure the accuracy and reliability of data include the 
selection of qualified investigators and appropriate study centers, review of 
protocol procedures with the investigator and associated personnel before the 
study, and periodic monitoring visits by the sponsor. Written instructions 
will be provided for collection, preparation, and shipment of blood, plasma, 
and urine samples. 
Guidelines for CRF completion will be provided and reviewed with study 
personnel before the start of the study. The sponsor will review CRFs for 
accuracy and completeness during on-site monitoring visits and after 
transmission to the sponsor; any discrepancies will be resolved with the 
investigator or designee, as appropriate. After upload of the data into the 
clinical study database they will be verified for accuracy. 
16.7. Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will 
maintain all CRFs and all source documents that support the data collected 
from each patient, as well as all study documents as specified in ICH/GCP 
Section 8, Essential Documents for the Conduct of a Clinical Trial, and all 
study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or 
premature destruction of these documents.
Essential documents must be retained until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or until at 
least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of 
the sponsor to inform the investigator/institution as to when these documents 
no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons 
withdraws from the responsibility of keeping the study records, custody must 
be transferred to a person who will accept the responsibility. The sponsor 
must be notified in writing of the name and address of the new custodian.


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Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory 
authority to review any documentation relating to this study, the investigator 
must permit access to such reports.
16.8. Monitoring
The sponsor will perform on-site monitoring visits as frequently as 
necessary. The monitor will record dates of the visits in a study center visit 
log that will be kept at the site. The first post-initiation visit will usually be 
made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the CRFs with the hospital or 
clinic records (source documents). The nature and location of all source 
documents will be identified to ensure that all sources of original data 
required to complete the CRF are known to the sponsor and investigational 
staff and are accessible for verification by the sponsor site contact. If 
electronic records are maintained at the investigational site, the method of 
verification must be discussed with the investigational staff. 
Direct access to source documentation (medical records) must be allowed for 
the purpose of verifying that the data recorded in the CRF are consistent with 
the original source data. Findings from this review of CRFs and source 
documents will be discussed with the investigational staff. The sponsor 
expects that, during monitoring visits, the relevant investigational staff will 
be available, the source documentation will be accessible, and a suitable 
environment will be provided for review of study-related documents. The 
monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
16.9. Study Completion/Termination
16.9.1.
Study Completion
The study is considered completed with the last visit of the last patient 
participating in the study. The final data from the investigational site will be 
sent to the sponsor (or designee) following completion of the final patient 
visit at that site, in the time frame specified in the Clinical Trial Agreement.


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16.9.2.
Study Termination
The sponsor reserves the right to close the investigational site or terminate 
the study at any time. Investigational sites will be closed upon study 
completion. An investigational site is considered closed when all required 
documents and study supplies have been collected and a site closure visit has 
been performed.
The investigator may initiate site closure at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended 
termination.
Reasons for the early closure of an investigational site by the sponsor or 
investigator may include but are not limited to:
Failure of the investigator to comply with the protocol, the sponsor’s 
procedures, or GCP guidelines
Inadequate recruitment of patients by the investigator
16.10. On-Site Audits
Representatives of the sponsor’s clinical quality assurance department may 
visit the site at any time during or after completion of the study to conduct an 
audit of the study in compliance with regulatory guidelines and company 
policy. These audits will require access to all study records, including source 
documents, for inspection and comparison with the CRFs. Patient privacy 
must, however, be respected. The investigator and staff are responsible for 
being present and available for consultation during routinely scheduled site 
audit visits conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any 
regulatory body either as part of a national GCP compliance program or to 
review the results of this study in support of a regulatory submission. The 
investigator should immediately notify the sponsor if they have been 
contacted by a regulatory agency concerning an upcoming inspection.
16.11. Use of Information and Publication
All information, including but not limited to information regarding 
VELCADE or the sponsor’s operations (e.g., patent application, formulas, 
manufacturing processes, basic scientific data, prior clinical data, 
formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomics research 


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data, generated as a result of this study, are considered confidential and 
remain the sole property of the sponsor. The investigator agrees to maintain 
this information in confidence and use this information only to accomplish 
this study, and will not use it for other purposes without the sponsor’s prior 
written consent.
The investigator understands that the information developed in the clinical 
study will be used by the sponsor in connection with the continued 
development of VELCADE, and thus may be disclosed as required to other 
clinical investigators or regulatory agencies. To permit the information 
derived from the clinical studies to be used, the investigator is obligated to 
provide the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated 
by the sponsor and will contain all data from all investigational sites. Results 
of any pharmacogenomics analyses performed after the Clinical Study 
Report has been issued will be reported in a separate report and will not 
require a revision of the Clinical Study Report. Study patient identifiers will 
not be used in publication of pharmacogenomics results. Any work created 
in connection with performance of the study and contained in the data that 
can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of 
Medical Journal Editors guidelines, the sponsor shall have the right to 
publish such primary (multicenter) data and information without approval 
from the investigator. The investigator has the right to publish study 
site-specific data after the primary data are published. If an investigator 
wishes to publish information from the study, a copy of the manuscript must
be provided to the sponsor for review at least 60 days before submission for 
publication or presentation. Expedited reviews will be arranged for abstracts, 
poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an 
additional 60 days to allow for filing of a patent application. In the event that 
issues arise regarding scientific integrity or regulatory compliance, the 
sponsor will review these issues with the investigator. The sponsor will not 
mandate modifications to scientific content and does not have the right to 


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suppress information. The investigator will recognize the integrity of a 
multicenter study by not publishing data derived from the individual site 
until the combined results from the completed study have been published in 
full, within 12 months after conclusion, abandonment, or termination of the 
study at all sites, or the sponsor confirms there will be no multicenter study 
publication. Authorship of publications resulting from this study will be 
based on the guidelines on authorship, such as those described in the 
Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 
which state that the named authors must have made a significant contribution 
to the design of the study or analysis and interpretation of the data, provided 
critical review of the paper, and given final approval of the final version. 


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Lymphoma. J Clin Oncol 2007; 25 (5):579-586.
25. Rosenwald A, Wright G, Wiestner A et al. The proliferation gene expression signature 
is a quantitative integrator of oncogenic events that predicts survival in mantle cell 
lymphoma. Cancer Cell 2003; 3 (2):185-197  
26. Chiarle R, Budel LM, Skolnick J et al. Increased proteasome degradation of 
cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in 
mantle cell lymphoma. Blood 2000; 95 (2): 619-26. 
27. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms 
independently predict response to rituximab in patients with follicular lymphoma. J Clin 
Oncol. 2003; Nov 1;21(21):3940-7. 
28. Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-CD20 
monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene, Blood 
2002:Feb1:99(3):754-758.
29. Mulligan G, Kim S, Stec J, et al. Pharmacogenomic analyses of myeloma samples from 
bortezomib (VELCADE) Phase II clinical trial. ASH 2002 Abstract 1519.
30. Mulligan, G, Mitsiades B, Bryant F, et al. Pharmacogenomics (PGx) Research in the 
APEX Randomized Multicenter International Phase 3 Trial Comparing Bortezomib and 
High-Dose Dexamethasone (Dex) ASH 2005 Abstract
31. The EuroQol Group. EuroQol-a New Facility for the Measurement of Health-Related 
Quality of Life. Health Policy 1990;16:199-208.
32. Brooks R. EuroQol: the Current State of Play. Health Policy 1996;37:53-72.
33. Dolan 
P. 
Modeling 
Valuations 
for 
EuroQol 
Health 
States. 
Med 
Care 
1997;35:1095-1108.
34. Roset M, Badia X, Mayo NE. Sample Size Calculations in Studies Using the EuroQol 
5D. Qual Life Res 1999;8:539-549.
35. Kind P, Hardman G, Macran S. UK Population Norms for EQ-5D. York Centre for 
Health Economics. Discussion Paper. 1999 Nov;172.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
147
36. Howard OM, Gribben JG, Neuberg DS et al.  Rituximab and CHOP Induction Therapy 
for Newly Diagnosed Mantle-Cell Lymphoma: Molecular Complete Responses Are Not 
Predictive of Progression-Free Survival. J Clin Oncol 2002; 20 (5): 1288-1294
37. LaCasce A, Niland J, Kho ME et al. Potential Impact of Pathologic Review on Therapy 
in Non-Hodgkin’s Lymphoma (NHL): Analysis from the National Comprehensive 
Cancer Network (NCCN) NHL Outcomes Project. ASH 2005 abstract 2816.
38. Mendoza TR, Wang XS, Cleeland CS et al. The Rapid Assessment of Fatigue Severity 
in Cancer Patients: Use of the Brief Fatigue Inventory. Cancer 1999;85:1186-96.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
148
ATTACHMENTS


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
149
Attachment 1:
ECOG Performance Status
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking 
hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.
5
Dead.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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150
Attachment 2:
Creatinine Clearance Calculation
Creatinine clearance for men and women will be calculated according to the Cockcroft-Gault formula 
as follows:
In men:









dL
mg
creatinine
kg
weight
age
/
72
140



        In women:
           








85
.0
/
72
140




dL
mg
creatinine
kg
weight
age
Note: 
Age (in years), weight (in kg), serum-creatinine (in mg/dL) 
72 (normalized to 72 kg body weight and a body surface of 1.73 m2)


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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151
Attachment 3:
Body Surface Area Calculation
BSA should be calculated using a standard nomogram. An example nomogram follows:


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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152
Attachment 4:
FACT/GOG-Neurotoxicity Questionnaire, Version 4.0
By circling one (1) number per line, please indicate how true each statement has been 
for you during the past 7 days.
ADDITIONAL CONCERNS
Not
at all
A little
bit
Some-
what
Quite
a bit
Very
much
I have numbness or tingling in my hands………
0
1
2
3
4
I have numbness or tingling in my feet…………
0
1
2
3
4
I feel discomfort in my hands………………….
0
1
2
3
4
I feel discomfort in my feet……………………
0
1
2
3
4
I have joint pain or muscle cramps……………
0
1
2
3
4
I feel weak all over……………………………
0
1
2
3
4
I have trouble hearing…………………………
0
1
2
3
4
I get a ringing or buzzing in my ears…………
0
1
2
3
4
I have trouble buttoning buttons………………
0
1
2
3
4
I have trouble feeling the shape of small objects
when they are in my hand………………………
0
1
2
3
4
I have trouble walking…………………………
0
1
2
3
4


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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153
Attachment 5:
Pharmacogenomics Sample Collection and Shipment Procedure
Supplies and Preparation of Pharmacogenomics Whole Blood Samples
The central laboratory will provide the investigational site with prelabeled EDTA collection tubes. 
Detailed information is provided in the laboratory manual from the central laboratory.
Pharmacogenomics Whole Blood samples should be prepared as follows: 

Invert the tube 10 to 15 times immediately after collection, to prevent coagulation.

DO NOT centrifuge sample.

Blood samples collected and shipped within 24 hours can be shipped at ambient temperature 
(see sample shipment below).

When there is a delay of more than 24 hours between collection and shipment, samples should be 
stored at 4C at the investigational site for at most 5 calendar days, and shipped in ambient or 
cooled condition (but not on dry ice). Freezing of the blood should be avoided.
Pharmacogenomics Whole Blood Sample Shipment 

Once collected, the blood samples should be shipped within 24 hours to the central laboratory. 
Detailed information will be provided in the laboratory manual from the central laboratory. In 
general, the following guidelines should be adhered to:

If possible, ambient/cooled shipment should be arranged with other clinical study samples. If this is 
not possible, a separate shipment for these blood samples should be organized, using the courier 
recommended by the central laboratory.

Notify courier at least 24 hours in advance of the planned shipment. Provide courier with the 
appropriate account number to be used, if applicable.

DO NOT package the samples in dry ice.

Label the package with the study number and all other information required by the central 
laboratory.

Include a return address (which includes the investigator’s name) on the outside of each shipping 
container.

Comply with all courier regulations for the shipment of biological specimens (include all 
paperwork).

Retain all documents indicating date, time, and signature/s of person/people making the shipment, 
in the study files.

The blood samples should be shipped to the name and address indicated in the central laboratory 
manual.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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154
Attachment 5: (Continued)
Pharmacogenomics Sample Collection and Shipment Procedure

The central laboratory provides a biweekly electronic update of the sponsor specific DNA 
repository to:
Dr. Stephan Francke
Johnson & Johnson Pharmaceutical Research & Development
Department of Pharmacogenomics
1000 Route 202
Raritan, NJ 08869
Tel: (908) 218-6596
Fax: (908) 429-0695
Email: sfranck1@prdus.jnj.com

The central laboratory forwards extracted DNA samples either on request of the Department of 
Pharmacogenomics or at the end of the study to the address above.
*NOTE: If there are changes regarding the courier or location to which samples are shipped during the 
course of the clinical study, written notification will be provided to the investigator and will not require 
(a) protocol amendment(s).
Paraffin Embedded Tissue (including bone marrow samples), Fresh Tissue
Paraffin embedded or fresh tissue samples will be labeled with the specimen type, the study number, 
Case Report Form identification number (CRF ID #) and date of collection. No personal identifiers 
(name, initials, address, etc.) will be written on the tubes. A form will accompany each tissue sample 
being shipped and will be used to record the following information: the study number, CRF ID #, date 
of collection and comments. Forms will be provided as part of study specific materials (see Section 
14.0).

Confirm that patient has a paraffin embedded tissue sample. Determine location of contact person. 
Determine if site is able to generate slides or if they prefer to send the entire paraffin embedded 
block or fresh tissue sample.

Send the paraffin embedded sample from the primary biopsy or resection specimen using the kit 
provided. 

All lymph blocks should be sent to the address specified by the central laboratory.

If the tissue block from the primary biopsy or tissue resection specimen cannot be sent, please 
prepare ten 6-micron slides and send to the address specified by the central laboratory. Please see 
the laboratory manual for specimen processing labeling and shipping instructions. Please also 
prepare ten, 15-micron sections and place in an Ependorf tube if the tumoral content is greater than 
80%, alternatively ten, 10 micron sections are placed on uncharged uncoated glass slides if the 
tumoral content is less than 80%. Send the samples to the address specified by the central 
laboratory.
Pharmacogenomics Tissue Sample Shipment
Notify courier at least 24 hours in advance of the planned shipment. Provide courier with the 
appropriate account number to be used, if applicable.
DO NOT package the paraffin embedded tissue block in dry ice.
Label the package with the study number and all other information required.
Include a return address on the outside of each shipping container. Send to the address specified by the 
central laboratory.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
155
Attachment 5: (Continued)
Pharmacogenomics Sample Collection and Shipment Procedure
The central laboratory will send the paraffin blocks and samples for IHC to the following address:
Dr. Stephan Francke
Johnson & Johnson Pharmaceutical Research & Development
Department of Pharmacogenomics
1000 Route 202
Raritan, NJ 08869
Tel: (908) 218-6596
Fax: (908) 429-0695
Email: sfranck1@prdus.jnj.com
The central laboratory will send the samples for somatic analyses to the following address:
Dr. Stephan Francke
Johnson & Johnson Pharmaceutical Research & Development
Department of Pharmacogenomics
1000 Route 202
Raritan, NJ 08869
Tel: (908) 218-6596
Fax: (908) 429-0695
Email: sfranck1@prdus.jnj.com
Comply with all courier regulations for the shipment of biological specimens (include all paperwork).
Retain all documents indicating date, time and signature/s of person/people making the shipment, in 
the study files.
Serum for Protein Analysis

One 5 mL blood sample should be drawn into a serum separator (red top) tube at each of the 
3 specified visits. 

Protocol number, CRF ID #, and date of collection will identify the tubes. No personal identifiers 
(name, initials, address etc.) are to be placed on the tube. 

The sample should be spun down accordingly to separate serum and plasma. 

The sample is to be aliquoted into two 2 mL Sarstedt tubes. The 2 tubes are to be labeled with the 
protocol number, patient ID, CRF ID #, date of collection and type of tube. 

Once collected, sample should be shipped frozen within 24 hours to the central laboratory.

Samples are to be stored at –70C and shipped on dry ice. Storage at –20C may be permitted, if 
required.

The central laboratory will ship serum samples to the address specified above. 


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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156
Attachment 6:
Candidate Gene List for Part 1 of Pharmacogenomics
AKT1, ALK, ALOX5, ATM, ATR, BAD, BAK1, BAX, BCL1, BCL2, BCL2A1, BCL2L1, 
BIK, BIRC2, BIRC3, BIRC4, CASP3, CASP7, CASP8, CASP9, CASP12P1, CCNA2, 
CCNB1, CCND1, CCNE1, CDC14A, CD40, CDC28, CDKN1A ( p21Cip1), CDKN1B 
(p27Kip1), CDKN2B, CHUK, CSEIL, CTAG2, CTNNB1, DAXX, DED, DRAK1, 
DRAK2, E2F1, EIF2AK2, FADD, FAS, FASLG, FCGR2A, FOS, HRAS, HSPB1, 
HSPCA, ICAM1, IFI44, IGF1, IGF1R, IGFBP3, IB, IKBKB, IKBKG (IKK), IL1A, 
IL6, IL10R, IL32, IRS1, JAK2, JUN, KRAS, MAPK, MAPKAPK2, MAPK8, MAP3K1, 
MAP3K14, MCL1, MDM2, MKI67, MYC, MYCN, NFKB1, NFKB1A, NFKB2, 
NOLC1, NOXA, NUDT6, PARP1, PRAD1, PRKDC, PSMA5, PSMB1, PSMB2, 
PSMB5, PSMB6, PSMC6, PSMB8, PSMB9, PSMB10, PSMD9 (p27), PTGS2, 
PTTG1, RASGRF1, RAF1, RAIDD, RAS family, REL, RELA, Repp86, RIPK1, SELE, 
SPARC, SPP1, STAT3, STIP1, STK17A, STK17B, TANK, TAP1, TAT, TNF, 
TNFRSFS, TNFS4, Topoisomerase II, TOSO,  TP53, TRAF5, TRAF6,  TTF1, 
VCAM1, VEGF.


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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157
Attachment 7:
Health Questionnaire


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
158
Attachment 7: (Continued)
Health Questionnaire


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
159
Attachment 7: (Continued)
Health Questionnaire 


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
160
Attachment 8:
EORTC QLQ-C30


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
161
Attachment 8: (Continued)
EORTC QLQ-C30


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
162
Attachment 9:
Brief Fatigue Inventory


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
FINAL – 3 February 2014
163
Attachment 10:
Calculating the International Prognostic Index for MCL
Score 1 for each of the following:
Age > 60years
MCL Stage III or IV at diagnosis
EGCO performance status >1
More than one extranodal site involvement
LDH above normal limits
Score range will be 0 - 5


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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164
Attachment 11:
American Joint Committee on Cancer, NHL Staging System
Stage I
Involvement of a single lymph node region or localized involvement 
of a single extralymphatic organ or site
Stage II
Involvement of two or more lymph node regions on the same side of 
the diaphragm or localized involvement of a single associated 
extralymphatic organ or site and its regional nodes with or without 
other lymph node regions on the same side of the diaphragm
Stage III
Involvement of lymph node regions on both sides of the diaphragm 
(III) that may also be accompanied by localized involvement of an 
extralymphatic organ or site , by involvement of the spleen or both
Stage IV
Disseminated 
(multifocal) 
involvement 
of 
one 
or 
more 
extralymphatic organs with or without associated lymph node 
involvement, or isolated extralymphatic organ involvement with 
distant (no regional) nodal involvement


VELCADE: Clinical Protocol 26866138-LYM-3002 – Amendment INT-6
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165
Attachment 12:
New York Heart Association 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.
LAST PAGE

SAP_000.pdf: 
 
1
 
 
Johnson & Johnson Pharmaceutical Research & Development 
 
Millennium Pharmaceuticals, Inc.
 
Statistical Analysis Plan
 
A Randomised, Open-Label, Multicentre Phase 3 Study of the Combination of 
Rituximab, Cyclophosphamide, Doxorubicin, VELCADE, and Prednisone  
(VcR-CAP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and 
Prednisone (R-CHOP) in Patients With Newly Diagnosed Mantle Cell Lymphoma 
who are not Eligible for a Bone Marrow Transplant 
 
Protocol 26866138-LYM-3002; Phase 3
 
JNJ-26866138 (VELCADE* [Bortezomib] for Injection) 
 
 
* VELCADE is the exclusive trademark of Millennium Pharmaceuticals, Inc., registered 
in the United States and internationally. 
Issue/Report Date: 
8 January 2014 
Prepared by: 
Janssen Research & Development, LLC  
Document No.: 
EDMS-ERI-28105966:2.0 
 
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice 
(GCP). 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential 
and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to 
whom the information is disclosed must be informed that the information is privileged or confidential and may not be 
further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you 
that is indicated as privileged or confidential. 


JNJ-26866138 (VELCADE* [Bortezomib] for Injection) 
Statistical Analysis Plan LYM-3002 
 
2
TABLE OF CONTENTS 
1. 
INTRODUCTION .......................................................................................................... 4 
1.1. 
Trial Objectives ............................................................................................................. 4 
1.2. 
Study Design ................................................................................................................ 4 
1.3. 
Statistical Hypotheses for Trial Objectives ................................................................... 6 
1.4. 
Sample Size Justification .............................................................................................. 7 
1.5. 
Randomization and Blinding ......................................................................................... 7 
2. 
GENERAL ANALYSIS DEFINITIONS ......................................................................... 8 
2.1. 
Imputation of Missing Data ........................................................................................... 8 
2.1.1. 
Missing/Partial Dates in Screening Visit ....................................................... 8 
2.1.2. 
Missing/Partial Dates in Adverse Events/Concomitant 
Therapies/Subsequent Therapies ................................................................ 8 
2.1.3. 
Missing/Partial Dates in Death ..................................................................... 9 
2.2. 
Analysis Sets .............................................................................................................. 10 
2.2.1. 
Efficacy Analysis Set(s) .............................................................................. 10 
2.2.1.1. 
Primary Efficacy Analysis Set ................................................................. 10 
2.2.1.2. 
Secondary Efficacy Analysis Set ............................................................ 10 
2.2.1.2.1. 
Per-Protocol Analysis Set ....................................................................... 10 
2.2.1.2.2. 
Response Evaluable Population ............................................................. 10 
2.2.1.2.3. 
Biomarker Population .............................................................................. 10 
2.2.2. 
Safety Analysis Set .................................................................................... 10 
2.3. 
Definition of Subgroups .............................................................................................. 10 
2.4. 
Other General Definitions ........................................................................................... 11 
2.4.1. 
Treatment Groups ...................................................................................... 11 
2.4.2. 
Individual Study Start (Day 1), Study Day and Month ................................ 12 
2.4.3. 
End of Follow-up and Length of Follow-up ................................................ 12 
2.4.4. 
Treatment Start, Treatment End, and Time on Study Treatment .............. 12 
2.4.5. 
Number of Treatment Cycles ..................................................................... 13 
2.4.6. 
Properties of Treatment Cycles .................................................................. 13 
2.4.7. 
Dose Intensity and Relative Dose Intensity ............................................... 14 
2.4.8. 
Age and Age Categories ............................................................................ 15 
2.4.9. 
Baseline Values .......................................................................................... 15 
2.4.10. 
Categories of Extranodal Sites of Disease ................................................ 15 
2.4.11. 
Category of International Prognosis Index (IPI) ......................................... 15 
2.4.12. 
Stage of MCL at Diagnosis ........................................................................ 16 
2.4.13. 
Creatinine Clearance and Its Category ...................................................... 16 
2.4.14. 
Time since Initial Diagnosis ........................................................................ 16 
2.4.15. 
Relationship of Adverse Events to Study Medication ................................ 16 
2.4.16. 
Study Medication-Related Death ............................................................... 17 
2.4.17. 
Dose Discontinuation of A Specific Study Drug Due to Adverse Events ... 17 
2.4.18. 
Adverse Events Leading to Treatment Discontinuation, and Study 
Medication-Related Treatment Discontinuation ......................................... 17 
2.4.19. 
Linking of Adverse Events .......................................................................... 17 
2.4.20. 
Concomitant Medication During Treatment ............................................... 18 
2.4.21. 
Categories of Body Surface Area ............................................................... 18 
2.4.22. 
Censoring Reasons for PFS ...................................................................... 18 
2.4.23. 
Censoring Reasons for Overall Survival .................................................... 19 
3. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW ............... 19 
4. 
SUBJECT INFORMATION ........................................................................................ 20 
4.1. 
Demographics and Baseline Characteristics .............................................................. 20 
4.2. 
Disposition Information ............................................................................................... 21 
4.3. 
Extent of Exposure ..................................................................................................... 22 
4.4. 
Protocol Deviations ..................................................................................................... 22 


JNJ-26866138 (VELCADE* [Bortezomib] for Injection) 
Statistical Analysis Plan LYM-3002 
 
3
4.5. 
Concomitant Medications ........................................................................................... 22 
4.6. 
Subsequent Therapies for MCL.................................................................................. 23 
5. 
EFFICACY .................................................................................................................. 23 
5.1. 
Analysis Specifications ............................................................................................... 23 
5.1.1. 
Level of Significance .................................................................................. 23 
5.1.2. 
Data Handling Rules .................................................................................. 23 
5.1.3. 
Definitions for Some Efficacy Variables ..................................................... 24 
5.1.3.1. 
Tumor Assessment by Independent Radiology Review Committee 
(IRC) ........................................................................................................ 24 
5.1.3.2. 
Date of Progression ................................................................................ 24 
5.1.3.3. 
Complete Response Assessment ........................................................... 25 
5.1.3.4. 
Tumor Assessment by Investigator......................................................... 25 
5.1.3.5. 
Best Overall Response ........................................................................... 25 
5.2. 
Primary Efficacy Endpoint(s) ...................................................................................... 25 
5.2.1. 
Definition .................................................................................................... 25 
5.2.2. 
Analysis Methods ....................................................................................... 26 
5.3. 
Major Secondary Endpoints ....................................................................................... 27 
5.3.1. 
Definition .................................................................................................... 27 
5.3.2. 
Analysis Methods ....................................................................................... 29 
5.4. 
Other Efficacy Variables ............................................................................................. 30 
5.4.1. 
Definition .................................................................................................... 30 
5.4.2. 
Analysis Methods ....................................................................................... 30 
6. 
SAFETY ...................................................................................................................... 31 
6.1. 
Adverse Events .......................................................................................................... 31 
6.1.1. 
All Adverse Events ..................................................................................... 31 
6.1.2. 
Adverse Events of Clinical Interest ............................................................ 33 
6.1.2.1. 
Peripheral Neuropathies ......................................................................... 33 
6.1.2.2. 
Cardiac Rhythm and Conduction Abnormalities ..................................... 34 
6.1.2.3. 
Heart Failure ........................................................................................... 34 
6.1.2.4. 
Pericardial Disease ................................................................................. 35 
6.1.2.5. 
Acute Diffuse Infiltrative Pulmonary Disease .......................................... 35 
6.1.2.6. 
Reactivation of Hepatitis B ...................................................................... 35 
6.1.2.7. 
Acute Hypersensitivity ............................................................................. 36 
6.1.2.8. 
Central Nervous System Disorders ......................................................... 36 
6.1.2.9. 
Herpes Zoster Infection ........................................................................... 36 
6.1.2.10. 
Thrombocytopenic Bleeding Events ....................................................... 37 
6.1.2.11. 
Neutropenic Sepsis and Infections Events ............................................. 38 
6.1.3. 
Death .......................................................................................................... 38 
6.2. 
Clinical Laboratory Tests ............................................................................................ 39 
6.3. 
Vital Signs and Physical Examination Findings .......................................................... 39 
6.4. 
Electrocardiogram and ECHO/MUGA Scans ............................................................. 40 
7. 
PATIENT-REPORTED OUTCOMES (PRO) ENDPOINTS ........................................ 40 
7.1. 
Definition ..................................................................................................................... 40 
7.2. 
Analysis Methods ....................................................................................................... 40 
8. 
BIOMARKER EVALUATIONS ................................................................................... 42 
8.1. 
Definition ..................................................................................................................... 42 
8.2. 
Analysis Methods ....................................................................................................... 42 
REFERENCES ........................................................................................................................ 43 
ATTACHMENT ........................................................................................................................ 44 
 
 
 


JNJ-26866138 (VELCADE* [Bortezomib] for Injection) 
Statistical Analysis Plan LYM-3002 
 
4
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables 
and statistical methods for the analysis of efficacy and safety.  
1.1. 
Trial Objectives 
Primary Objective 
To determine which regimen of chemotherapy rituximab, cyclophosphamide, doxorubicin, 
VELCADE, and prednisone  (VcR-CAP) or rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone (R-CHOP) provides greater benefit in newly diagnosed mantle 
cell lymphoma (MCL) subjects with Stage II, III, or IV disease, as assessed by significant 
prolongation of progression-free survival (PFS). 
Secondary Objectives 
The secondary objectives are: 
 To determine time to progression (TTP) 
 To determine the duration of response (DoR), time to next treatment (TNT), and 
treatment-free interval  
 To determine overall response (complete response [CR]+CR unconfirmed 
[CRu]+partial response [PR]) and CR rates (CR+CRu) 
 To determine overall survival (OS) 
 To determine the 18-month survival rate 
 To evaluate the safety of VcR-CAP compared to R-CHOP 
Exploratory Objectives 
 To evaluate patient-reported outcomes (PROs) utilizing the European Organisation for 
Research and Treatment of Cancer quality of life questionnaire (EORTC-QLQ-C30), 
EQ-5D, and Brief Fatigue Inventory (BFI) instruments 
 To evaluate medical resource utilization (MRU) information which may be used in 
future economic evaluation models 
 To identify subject populations that are more or less likely to respond to VcR-CAP or 
R-CHOP through the evaluation of biomarker analyses 
 
1.2. 
Study Design 
This is a randomized, open-label, multicenter, prospective study to compare the efficacy 
and safety of the combination of VcR-CAP to that of R-CHOP in subjects who have newly 
diagnosed MCL and who are ineligible for bone marrow transplantation. 


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At least 486 subjects will be randomized into 1 of 2 arms (Treatment Arm A or Treatment 
Arm B) in a 1:1 ratio taking into account the following stratification factors: International 
Prognostic Index (IPI) and stage of disease at diagnosis. 
Treatment Arm A (VcR-CAP): rituximab 375 mg/m2 intravenous (IV) on Day 1, 
cyclophosphamide 750 mg/m2 IV on Day 1, doxorubicin 50 mg/m2 IV on Day 1, 
VELCADE 1.3 mg/m2 IV on Days 1, 4, 8 and 11, and prednisone 100 mg/m2 per os (PO) 
on Day 1 to Day 5 of a 21-day (3-week) cycle for 6 cycles (or 8 cycles if a response is first 
documented at the Cycle 6 assessment). 
Treatment Arm B (R-CHOP): rituximab 375 mg/m2 IV on Day 1, cyclophosphamide 
750 mg/m2 IV on Day 1, doxorubicin 50 mg/m2 IV on Day 1, vincristine 1.4 mg/m2 
(maximum total of 2 mg) IV on Day 1, and prednisone 100  mg/m2 PO on Day 1 to Day 5 
of a 21-day (3-week) cycle for 6 cycles (or 8 cycles if a response is first documented at the 
Cycle 6 assessment). 
The study will include a Screening Phase, a Treatment Phase, a Short-term Follow-up 
Phase, and a Long-term Follow-up Phase. The Screening Phase will be up to 28 days 
(56 days for bone marrow evaluation) prior to randomization. The Treatment Phase will 
extend from randomization until 6 cycles of treatment have been given (or 2 cycles beyond 
a response documented in Cycle 6). The Short-term Follow-up Phase will extend from the 
End-of-Treatment Phase to progressive disease (PD; or relapse if subject achieves a CR or 
CRu), initiation of alternate antineoplastic therapy, decision by the subject to completely 
withdraw from the study and refuse any further study related procedure, or death. Subjects 
who are withdrawn from the study treatment due to adverse events, or reasons other than 
above and are willing to continue study follow-up procedures can be followed as per 
protocol for PD or death. 
The Long-term Follow-up Phase will be used to assess survival and will document when 
the subject has died.  
Three interim analyses are planned for this study. The first interim analysis will occur after 
the first 100 subjects have been randomized into the study and will assess safety and the 
concordance rate of the diagnosis of MCL when central review is compared with the 
investigator assessment of the diagnosis. The concordance rate of the diagnosis of MCL 
will also be reviewed in a blinded manner at 50% accrual. This may be used to recalculate 
the sample size to ensure an adequate number of PFS events (approximately 280) in those 
subjects with a centrally confirmed MCL diagnosis at the time of the final analysis (295 
PFS events in total). A review of these data will occur by the IDMC. 


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A second interim analysis for safety will occur after 100 subjects in each arm (200 subjects 
in total) have either completed the study treatment or discontinued the study treatment, 
which allows sufficient exposure for review of cumulative toxicity. 
The third interim analysis is planned after at least 148 events have occurred. If, at the time 
of the third interim analysis, the pre-specified superiority boundaries for PFS are met, then 
the study will be terminated and superiority of the experimental arm (VcR-CAP) will be 
declared over the comparator arm (R-CHOP). If the pre-specified futility boundaries for 
PFS are met, then the study will be terminated due to futility. 
If pre-specified boundaries are not met at the time of the third interim analysis, the final 
analysis of the study will occur after 295 events have been observed in the ITT population. 
An Independent Data Monitoring Committee (IDMC) has been commissioned for this 
study. 
1.3. 
 Statistical Hypotheses for Trial Objectives 
The primary statistical hypothesis is that there is no difference between the two treatment 
groups (Treatment Group A: VcR-CAP, and Treatment Group B: R-CHOP) with regard to 
PFS. 
Secondary statistical hypotheses are as follows: 
1) There is no difference between the two treatment groups with respect to TTP 
2) There is no difference between the two treatment groups with respect to TNT; 
3) There is no difference between the two treatment groups with respect to the 
complete response (CR+CRu) rate; 
4) There is no difference between the two treatment groups with respect to OS;  
5) There is no difference between the two treatment groups with respect to overall 
response (CR+CRu+PR) rate (ORR); 
6) There is no difference between the two treatment groups with respect to 18-month 
survival rate. 
7) There is no difference between the two treatment groups with respect to treatment 
free interval 


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Exploratory hypotheses include: 
There is no difference between the two treatment groups with respect to the PRO 
endpoints as defined in Section 7. 
There is no difference between the two treatment groups within each biomarker 
subgroup as defined in Section 8. 
Analysis of DoR will be descriptive instead of inferential. This is due to the fact that the 
analyses can only be performed on subsets of subjects determined by a post-randomization 
outcome.  
1.4. 
Sample Size Justification 
The sample size calculation for the study population is based on the following assumptions. 
The median PFS of Treatment Arm B (R-CHOP) is 18 months. Assuming that Treatment 
Arm A (VcR-CAP) can improve the median PFS by 40%, i.e. from 18 months to 25 
months, a total number of 295 events (PD or death) provides 80% power (alpha = 0.05, 
two-sided) to detect such improvement. Assuming a 24-month accrual and 18-month 
follow-up, 486 subjects in total are needed for the study (243/arm). 
1.5. 
Randomization and Blinding 
Subjects will be assigned in a 1:1 ratio to 1 of the 2 treatment groups based on a computer-
generated randomization schedule prepared by the sponsor before the study. The sponsor 
and the investigational sites will be blinded to all data reviewed by the IDMC. 
Permuted blocks central randomization will be implemented in conducting this study. The 
randomization will be stratified by two stratification factors: IPI (0-1, 2, 3, and 4-5) and 
stage of disease at diagnosis (II, III, and IV) per the American Joint Committee on Cancer 
NHL staging system. The stratified randomization minimizes the imbalance in the 
distribution of treatment numbers within the levels of each individual stratification factors. 
The IPI is the total score of the following risk factors (score 1 for each positive factor):  age 
>60 years, MCL Stage III or IV at diagnosis, Eastern Cooperative Oncology Group 
(ECOG) performance status score >1, >1 extranodal site involvement, and lactate 
dehydrogenase (LDH) above normal limits. For stratification, the scores will then be 
categorized (low [0-1 factor], low-intermediate [2 factors], high-intermediate [3 factors] 
and high [4-5 factors]). 
The stage of disease at diagnosis will also be used for stratification and will be assessed 
using the American Joint Committee on Cancer NHL staging system (see Attachment 11 
of Protocol 26866138LYM3002). 


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2. 
GENERAL ANALYSIS DEFINITIONS 
2.1. 
Imputation of Missing Data 
Unless otherwise specified, no data imputation will be applied for missing values and all 
available data for all subjects will be presented. For PRO data, missing elements may be 
substituted with the average of non-missing items per the published methods of analysis 
using well-established scaling programs, and missing scores will be handled using 
statistical techniques as outlined in the section for PRO data. 
2.1.1. 
Missing/Partial Dates in Screening Visit 
The following rules apply to dates recorded in the screening visits except for prior therapies 
(excluding prior systemic therapies for MCL). 
 If only the day-component is missing, the first day of the month will be used if the year 
and the month are the same as those for the first treatment. Otherwise, the 15th will be 
used unless it is later than the first treatment. 
 If only a year is present, and it is the same as the year of the first treatment, 15 January 
will be used unless it is later than the first treatment, in which case the date of 1 January 
will be used. 
 If only a year is present, and it is not the same as the year of the first treatment, 15 June 
will be used, unless other data indicate that the date is earlier. For instance, the 
diagnosis date of MCL should be used to impute missing month/day of the start dates 
for prestudy systemic therapy for MCL if the diagnosis date is later than 15 June. 
2.1.2. 
Missing/Partial Dates in Adverse Events/Concomitant 
Therapies/Subsequent Therapies 
Every effort will be made to avoid missing/partial dates in on-study data. In case that the 
resolution date of a resolved adverse event, or the stop date of a concomitant therapy is 
missing, the following rules are to be used unless conflicting data exists: if month and year 
are present and the day of the month is missing, the last day of the month is imputed. If 
only a year is present, 31 December will be used. After imputation, the imputed dates will 
be compared against the date of death, if available. If the date is later than the date of death, 
the date of death will be used as the imputed date instead. 
In case that the onset date of an adverse event is missing completely or partially, the 
following imputation rules will be used. 
1) When month and year are present and the day of the month is missing, 
 If the onset month and year are the same as the month and year of first treatment 
with study drug, the day of first treatment or the day-component of the resolution 
date are imputed, whichever is earliest. 


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 If the onset month and year are not the same as the month and year of first treatment 
with study drug, the first day of the month is imputed. 
2) When only a year is present, or no components of the onset date are present,  
 If the imputed resolution date is available, the later of the imputed resolution date 
(possibly imputed) and the date of first treatment will be used. 
 If the imputed resolution date is missing, and the onset-year is the same as the year 
of first treatment with study drug, then the date of first treatment with study drug is 
used. 
 Otherwise if only a year is present, 1 January of that year is imputed.  
3) If none of the previous rules can be applied, then the date of first treatment with study 
drug is imputed as the onset date. 
The imputation rules for missing/partial start dates of concomitant therapies will be the 
same as the above with the exception as follows. 
For prior therapy data recorded in the concomitant medication page, no imputation will be 
done for start dates. 
The imputation rules for missing/partial start dates of subsequent therapies will be the same 
as the above with the exception as follows. 
1) When month and year are present and the day of the month is missing, 
 If the month and year of the start date are the same as the month and year of 
treatment termination, the day of treatment termination visit or the day-component 
of the stop date is imputed, whichever is earliest. 
 If the start month and year are not the same as the month and year of treatment 
termination visit, the first day of the month is imputed. 
2) When only a year is present, or no components of the start date are present, the date will 
not be imputed. 
2.1.3. 
Missing/Partial Dates in Death 
If month and year are present and the day of the month is missing, the last day of the month 
is imputed.  


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2.2. 
Analysis Sets 
2.2.1. 
Efficacy Analysis Set(s) 
2.2.1.1. 
Primary Efficacy Analysis Set 
The primary efficacy analysis set is the intent-to-treat (ITT) population, which includes all 
randomized subjects. 
2.2.1.2. 
Secondary Efficacy Analysis Set 
2.2.1.2.1. 
Per-Protocol Analysis Set 
The per-protocol (PP) population is defined as all subjects who are randomized to treatment 
who meet all inclusion and exclusion criteria, who received at least 1 dose of study drug, 
and undergo at least one post-baseline disease assessment (post-baseline tumor assessment 
by independent radiology reviewers [IRC]). Subjects in this population will be analyzed 
according to the treatment to which they were randomized. The analyses using the PP 
population will be considered as sensitivity analyses. 
2.2.1.2.2. 
Response Evaluable Population 
The response-evaluable population is defined as all subjects in the ITT population who 
receive at least 1 dose of study drug, have at least 1 measurable tumor mass (greater than 
1.5 cm in the longest dimension and greater than 1.0 cm in the short axis) at baseline, and 
have at least 1 post-baseline tumor assessment by IRC, before any subsequent anti-
lymphoma treatment. 
2.2.1.2.3. 
Biomarker Population 
The biomarker population is defined as subjects who are randomized to treatment (ITT), 
whose biomaterial is available, who have consented to participate in the study’s biomarker 
and pharmacogenomic evaluations or future research, and have biomarker data generated 
for the biomarker evaluation.  
2.2.2. 
Safety Analysis Set 
The safety population, which includes all randomized subjects who receive at least 1 dose 
of study drug, will be used in the safety analyses.  
2.3. 
Definition of Subgroups 
In general, the following subgroup analyses are to be performed for efficacy and safety. 
Additional subgroup analyses will also be performed for selected efficacy and/or safety 
endpoints, which are described in Sections 5 and 6. 


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Subgroup 
Definition of Group 
Analysis 
Type 
IPI risk 
low [0-1 factor], low-intermediate [2 factors], high-
intermediate [3 factors], high [4-5 factors] 
E, S 
Sex 
Male, Female 
E, S 
Race 
White, Non-White 
E, S 
Region 
European Union, North America Region, Rest of World 
E, S 
Age 
65, >65   
E, S 
Stage of Disease at 
Diagnosis 
II, III, IV 
E, S 
LDH  
Normal, Elevated 
E 
White Cell Count 
(WBC) 
<6.7, 6.7-<10, 10-<15, >=15 
E 
ECOG 
0: asymptomatic, 1: symptomatic, Fully Ambulatory, 2: 
symptomatic, in Bed<50% of the Day 
 E 
Renal Function 
(mL/min) 
Baseline creatinine clearance: Renal impairment (<=60), 
Normal renal function (>60) 
S 
Liver Function 
Baseline ALT and AST<1.5*ULN, ALT/AST>=1.5*ULN 
S 
E= efficacy (primary, secondary endpoints); S= Safety (adverse events)  
 
In order to demonstrate applicability of study results to the US population, a 
US/Canada/Western Europe subset will be created where Western Europe includes 
Austria, Belgium, France, Germany, Italy, Portugal, and Spain. Summary data for 
demographics, baseline disease characteristics, key efficacy endpoints (progression free 
survival by IRC and Investigator, progression free survival for US/Canada subset, time to 
tumor progression, overall survival, best overall response), and treatment-emergent 
adverse events will be generated for the US/Canada/Western Europe subset. 
2.4. 
Other General Definitions 
Unless specified otherwise, the dates used in the derivations are those obtained after 
applying the rules specified in Section 2.2. 
2.4.1. 
Treatment Groups 
There are two variables for treatment group identification (Treatment Group A: VcR-CAP 
or Treatment Group B: R-CHOP). The first variable identifies the treatment group to which 
a subject is randomized. All randomized subjects will have a nonmissing value for this 
variable. 
The second variable denotes the actual treatment received. This variable is derived from 
the dosing data of the study medication. A subject is in the VcR-CAP group if the subject 
receives at least one dose of VELCADE; otherwise, the actual treatment group is R-CHOP. 
Those subjects without any dose of the study medications (VELCADE, rituximab, 
cyclophosphamide, doxorubicin, vincristine, or prednisone) will have this variable set as 
missing. 


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2.4.2. 
Individual Study Start (Day 1), Study Day and Month 
Individual Study Start (Day 1) is the day of randomization.  
Study day is equal to the date of procedure minus the date of randomization plus one.  
A month is defined as 365.25/12 days. 
2.4.3. 
End of Follow-up and Length of Follow-up 
The end of follow-up is either the date of death or the end of survival follow-up, defined 
as the maximum date of the following study evaluations: randomization, vital signs, ECOG 
performance status, CT scans (neck, chest, abdomen, and pelvis), dates of assessable 
lesions or new lesions, physical examination, bone marrow evaluations, labs (hematology, 
chemistry), study drug administration, subsequent therapy, investigator-assessed PD, 
relapse from CR/CRu, investigator determined response, and survival follow-up. 
Length of follow-up (in months) equals to the end of follow-up minus study start, then 
divided by 365.25/12. 
2.4.4. 
Treatment Start, Treatment End, and Time on Study Treatment 
Treatment start is the date of first dose of study medication (dose>0 for any of the study 
drugs: VELCADE, rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone). Treatment end is the date of the last dose of the study medication (dose >0 for 
any of the six drugs: VELCADE, rituximab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone).  Time (weeks) on study treatment equals treatment end minus treatment 
start plus 1, then divided by 7. 
For subjects randomized to VcR-CAP, the start date of VELCADE is the date of first 
nonzero dose of VELCADE, and the stop date of VELCADE is the date of last nonzero 
dose of VELCADE. Time (in weeks) on VELCADE equals the stop date minus the start 
date plus 1, then divided by 7. Note that time on VELCADE can only be determined for 
subjects who have received at least one dose of VELCADE. 
For subjects randomized to R-CHOP, the start date of vincristine is the date of first nonzero 
dose of vincristine, and the stop date of vincristine is the date of last nonzero dose of 
vincristine. Time (in weeks) on vincristine equals the stop date minus the start date plus 1, 
then divided by 7. Note that time on vincristine can only be determined for subjects who 
have received at least one dose of vincristine. 
The start date of rituximab is the date of first nonzero dose of rituximab, and the stop date 
of rituximab is the date of last nonzero dose of rituximab. Time (in weeks) on rituximab 
equals the stop date minus the start date plus 1, then divided by 7. 


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The start date of cyclophosphamide is the date of first nonzero dose of cyclophosphamide, 
and the stop date of cyclophosphomide is the date of last nonzero dose of 
cyclophosphamide. Time (in weeks) on cyclophosphamide equals the stop date minus the 
start date plus 1, then divided by 7. 
The start date of doxorubicin is the date of first nonzero dose of doxorubicin, and the stop 
date of doxorubicin is the date of last nonzero dose of doxorubicin. Time (in weeks) on 
doxorubicin equals the stop date minus the start date plus 1, then divided by 7. 
The start date of prednisone is the date of first nonzero dose of prednisone, and the stop 
date of prednisone is the date of last nonzero dose of prednisone. Time (in weeks) on 
prednisone equals the stop date minus the start date plus 1, then divided by 7. 
2.4.5. 
Number of Treatment Cycles 
The first treatment cycle is the first cycle in which a subject receives any nonzero dose of 
the study drugs (VELCADE, rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone). The last treatment cycle is the last cycle in which a subject receives any 
nonzero dose of the study drugs. Number of treatment cycles equals the last cycle number 
minus the first cycle number plus 1.  
For each of the study drugs (VELCADE, rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone), the first (or last) treatment cycle on this drug is the first (or 
last) cycle in which a subject receives any nonzero dose of the study drug, and the number 
of cycles on this study drug equals the last cycle minus the first cycle plus 1. 
Note that number of cycles on rituximab, cyclophosphamide, doxorubicin, or prednisone 
can be determined for all treated subjects, while the number of cycles on VELCADE can 
only be determined for subjects randomized to receive VcR-CAP, and the number of cycles 
on vincristine can only be determined for subjects randomized to receive R-CHOP. 
2.4.6. 
Properties of Treatment Cycles 
For each treatment cycle, the following variables are to be derived.  
 Cycle delay (5 days)  to flag if this cycle is delayed for at least 5 days (date of Day 
1 in the current cycle – date of Day 1 in the previous cycle is 26 days) and checked 
on the case report form (CRF) by investigator as cycle delayed. 
 Reasons for cycle delay (5 days)  to record reasons for cycle delay of at least 5 days 
as captured in CRF (AE or Other).  
 Cycle start  the date of the first dose of any of the study drugs (including zero doses). 
 Cycle stop  For cycles other than the last one, cycle end is defined as the day before 
the start of the next cycle; for the last cycle, it is defined as the visit date of the end of 


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treatment visit (or the cycle start plus 20 days in case that the end of treatment visit is 
not performed yet). 
 Dose reduction  to flag if the dose of the study medication is reduced (each drug has 
its own flag[s]). For VELCADE, a dose is considered reduced if a nonzero dose is 
marked as reduced on the CRF and the prescribed dose is lower than the previous non-
zero dose level. For rituximab, a nonzero dose is considered as reduced if it is >25% 
lower than the prescribed dose. For other drugs, a dose is considered as reduced if a 
non-zero dose is marked on the CRF as reduced. Dose adjustment due to BSA change 
is not counted as dose reduction as long as the prescribed dose is not lower than the 
protocol specified level. For Prednisone, due to the tapering regimen, dose after DAY 
5 in each cycle is not used in dose reduction consideration. 
 Dose withholding  to flag if the dose of the study medication is withheld at least once 
(one flag for each drug), excluding those due to schedule changes for VELCADE. A 
dose not given due to schedule change will not be counted as withholding for 
VELCADE. The number of withheld doses will be recorded for VELCADE and 
prednisone. 
 Schedule change  to flag if a schedule change of VELCADE is initiated within the 
cycle, i.e., if the VELCADE dose schedule is changed from twice weekly to once 
weekly. Note: this is applicable only for those subjects randomized to receive VcR-
CAP.  
 Dose modification  to flag if the dose of the study medication is modified (delayed, 
reduced or withheld, schedule change [for VELCADE only]) at least once (one flag for 
each drug).   
 Number of doses  to record the number of nonzero actual doses given (one variable 
for each drug). 
 Total dose (mg)  to record the sum of nonzero doses (one variable for each drug). 
 Total doses (mg/m2)  to record the sum of nonzero doses per m2 (one variable for 
each drug), which equals the total dose (mg) divided by body surface area in that cycle. 
When the BSA is not available for the cycle of interest, the most recent value is to be 
used. 
 
2.4.7. 
Dose Intensity and Relative Dose Intensity 
Dose intensity (mg/m2/cycle) will be calculated separately for the study drugs (VELCADE, 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) by cycle and 
overall. 
For each of the study drugs, the dose intensity equals the sum of total dose (mg/m2) 
received in all cycles divided by the number of cycles on that drug.  
The dose intensity per cycle is equal to the sum of the total dose (mg/m2) received in that 
cycle.  


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The overall planned dose intensity is equal to the sum of the planned total dose (mg/m2) in 
all cycles divided by the number of cycles received.  
The planned dose intensity per cycle is equal to the sum of the planned total dose (mg/m2) 
in the cycle. When a subject receives all scheduled doses in a cycle, the planned dose 
intensity per cycle for VELCADE is 1.3*4=5.2 (mg/m2/cycle); for rituximab, is 375*1=375 
(mg/m2/cycle); for doxorubicin, is 50*1=50(mg/m2/cycle); for cyclophosphamide, is 
750*1=750 (mg/m2/cycle); for vincristine, is 1.4*1=1.4 (mg/m2/cycle); for prednisone, is 
100*5=500 (mg/m2/cycle).  
The relative dose intensity is the ratio of the dose intensity and the planned dose intensity. 
2.4.8. 
Age and Age Categories 
Age will be calculated at the date of randomization. Integer values are used. The following 
categories of age will be adopted: 65 years, >65 years. 
2.4.9. 
Baseline Values 
The baseline value is defined as the value collected at the time closest to, but prior to, the 
date of first dose (inclusive). If a subject is not dosed, the date of randomization will be 
used.  
In case that laboratory values from both the central lab and local lab are available before 
randomization, the values from central lab will be used as baseline, even if the sample date 
of central lab result is prior to that of local lab value.  
2.4.10. 
Categories of Extranodal Sites of Disease 
Two categories will be used for the number of extranodal sites: 1 or >1.  
2.4.11. 
Category of International Prognosis Index (IPI) 
The IPI will be assessed according to the following risk factors: age, stage of disease, 
performance status, number of extranodal sites, and LDH level. A subjects’s IPI ranges 
from 0-5 and equals the number of the following applicable conditions: 
 Age >60 years 
 MCL stage III or IV at diagnosis 
 ECOG performance status score >1 at baseline 
 More than one extranodal site involvement at baseline 
 Baseline LDH > normal limits 
IPI at baseline will be classified into the following categories: low (0-1 factor), 
low-intermediate (2 factors), high-intermediate (3 factors) and high (4-5 factors). 


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Categories of IPI are also used to determine the appropriate stratum in which a subject is 
to be randomized. Since evaluations at screening may be used to determine the 
stratification, a separate variable is used to capture the value used in randomization. 
2.4.12. 
Stage of MCL at Diagnosis 
The staging of MCL at diagnosis is to be assessed using the American Joint Committee on 
Cancer NHL staging system. Those subjects with Stages II, III, or IV disease are eligible 
for this study. 
Stage of MCL disease is also used to determine the appropriate stratum in which a subject 
is to be randomized. A separate variable is used to capture the value used in randomization. 
2.4.13. 
Creatinine Clearance and Its Category 
Creatinine clearance is to be calculated using the following formulae.  
For male subjects,  
Creatinine clearance = (140 - Age [yrs]) * Weight [kg] / 72 / (Serum 
creatinine/88.4) 
For female subjects, 
Creatinine clearance = 0.85 * (140 – Age [yrs]) * Weight [kg] / 72 / (Serum 
creatinine /88.4). 
Integer values will be used. When available, creatinine clearance values are divided into 3 
categories: 30 mL/min, 31-60 mL/min, and >60 mL/min. 
2.4.14. 
Time since Initial Diagnosis  
Time since initial diagnosis is defined for all subjects and is calculated from the date of 
diagnosis to the date of randomization (month). 
2.4.15. 
Relationship of Adverse Events to Study Medication 
For each adverse event, its relationship to each of the six study medications is determined 
by the investigator and recorded on the CRF.  
An adverse event that occurs in the VcR-CAP arm is considered as related to study 
medication if it is possibly, probably or very likely related to any one or combinations of 
the five study drugs (VELCADE, rituximab, cyclophosphamide, doxorubicin, and 
prednisone). The category of the relationship to study medication is to be the maximum of 
the relationship to the five individual study drugs (“Very Likely”>“Probable”> 
“Possible”> “Doubtful”> “Not Related”). 


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An adverse event that occurs in the R-CHOP arm is considered as related to study 
medication if it is possibly, probably or very likely related to any one or combinations of 
the five study drugs (rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone). The category of the relationship to study medication is to be the maximum of 
the relationship to the five individual study drugs. 
An adverse event that occurs in the VcR-CAP-treated subjects is considered as related to 
VELCADE if it is possibly, probably or very likely related to VELCADE. 
2.4.16. 
Study Medication-Related Death 
A death is considered as related to study medication if the cause is recorded as adverse 
event, at least one of which is related to study medication.  
2.4.17. 
Dose Discontinuation of A Specific Study Drug Due to Adverse 
Events 
The dose of a specific drug (VELCADE, rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone) may be discontinued due to adverse events while at least one 
of the other study drugs may be continuing. Such dose discontinuations will have Action 
Taken Regarding Trial Med being “permanently stopped” for the study drug of interest. 
The cycle in which the dose is discontinued is to be the cycle in which the last nonzero 
dose of this study drug is given. 
2.4.18. 
Adverse Events Leading to Treatment Discontinuation, and Study 
Medication-Related Treatment Discontinuation 
The CRF collects adverse events that lead to discontinuation of any of the six study drugs. 
For an adverse event to be considered as the reason for treatment discontinuation, the 
following two conditions must be met: 
1) The action taken regarding trial medication due to this adverse event should be 
“permanently stopped” for at least one of the study drugs; and  
2) This subject should be indicated by the investigator to have discontinued study 
treatment due to adverse events. 
A subject is considered as discontinued due to study medication-related adverse events if 
(1) the reason for treatment discontinuation is adverse event, and (2) at least one of the 
adverse events leading to treatment discontinuation, as defined above, should be related to 
study medication. 
2.4.19. 
Linking of Adverse Events 
To analyze new onsets of adverse events, overlapping/adjacent adverse event records of 
the same preferred term may need to be linked. This is due to the AE collection procedure 


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as follows. For an adverse event recorded on the CRF, whenever a feature of the adverse 
event changes (e.g., changes in grade/seriousness/action taken), a new adverse event record 
will be entered to reflect the change. For example, if the toxicity of an AE changes, the 
altered toxicity must be recorded on a new line. Resolved date and Onset date must not 
overlap from 1 line to another for more than 1 day. For the first degree of toxicity, the 
Resolved date must be filled. A new line should list the same AE, a new Onset date, and 
the new degree of toxicity. All the adverse event records of the same preferred term from 
the same subject are to be linked by the onset date and the resolution date. If a resolved 
event is followed by another event of the same preferred term with the onset date within 1 
day of the resolution date of the previous record, these 2 records should be linked together 
and considered as 1 event. 
2.4.20. 
Concomitant Medication During Treatment 
Concomitant medications administered during study treatment include those concomitant 
medication records that are indicated in the CRF as not being prior therapy, and have the 
onset date, possibly imputed, no earlier than treatment start and no later than the treatment 
end. 
2.4.21. 
Categories of Body Surface Area 
Three categories of body surface area are of interest: <1.5 m2, 1.5-2 m2, and >2 m2. 
2.4.22. 
Censoring Reasons for PFS 
Those subjects who are censored for PFS will be classified into the following categories: 
subsequent therapy, lost to follow-up, missed tumor assessments before death, and study 
cut-off.  
The Censoring reasons for PFS are defined as below: 
1) Subsequent therapy: if subsequent therapy is started before PFS events (i.e., PD or 
death).  
2) Lost to follow-up: if the reason for end of data collection is lost to follow-up, 
subject choice, or other. 
3) Missed tumor assessments before death: if a subject died more than 6-month after 
last adequate tumor assessment. 
4) Date of clinical cut-off/study closed by sponsor: for subjects without PD at the 
time of clinical cut-off/ study closed by sponsor for analysis. 
Refer to the Table 1 in Section 5.2.1 for more details of censoring method. 


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2.4.23. 
Censoring Reasons for Overall Survival 
Those subjects who are censored for OS will be classified into the following categories:  
1) Lost to follow-up: the reason for end of data collection is lost to follow-up, subject 
choice, or other. 
2) Study cut-off: subjects who are still alive as of the date of clinical cut-off. 
 
3. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW 
An Independent Data Monitoring Committee (IDMC) has been commissioned for this 
study. There will be three interim analyses planned in the study.  
The first interim analysis will occur after the first 100 subjects have been randomized into 
the study and will assess the safety and concordance rate of the diagnosis of MCL when 
central review is compared to the investigator assessment of the diagnosis.  
The concordance rate of the diagnosis of MCL will also be reviewed at 50% accrual in a 
blinded manner. If the observed concordance rate is 95% (95% CI: [91%, 97%]), the 
sample size for the study will not be changed. If the observed difference is less than 95%, 
the sample size may be adjusted to provide adequate events (approximately 280) in those 
subjects with a centrally confirmed MCL diagnosis for the final analysis (295 PFS events 
in total). There is no alpha adjustment for the 1st interim analysis since no efficacy analyses 
will be performed.  
The first interim analysis will also review the safety data collected to date. Safety data will 
be reviewed after at least one cycle for the first 100 treated subjects, irrespective of whether 
they complete treatment within that first cycle. 
The second interim analysis will review the safety data and will be performed after 
100 subjects per arm have either completed or discontinued study treatment, which allows 
sufficient exposure for review of cumulative toxicity. 


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The third interim analysis has been planned for this study after at least 148 events have 
occurred. If, at the interim analysis, pre-specified boundaries for PFS are met then the study 
may be terminated and superiority of the experimental arm (VcR-CAP) will be declared 
over the comparator arm (R-CHOP). If the observed hazard ratio (R-CHOP vs. VcR-CAP) 
for PFS in the third interim analysis is equal to or less than 1.03 (a value of >1 favoring 
VcR-CAP), then the study may be terminated due to futility. The conditional power would 
be <30% with the observed hazard ratio (HR) 1.03 at the third interim analysis and the 
future HR of 1.4, which suggests low probability of success at the end of the study. There 
will also be a review of the safety data at the third interim analysis. 
The stopping boundary for the interim is to be calculated using the observed number of 
PFS events at the data cutoff using the O’Brien-Fleming spending function. The alpha 
allocated for the interim is 0.003 (2-sided) with 148 events, and is 0.049 (2-sided) for the 
final analysis.  
If pre-specified boundaries are not met at the interim stage, the final analysis of the study 
will occur after 295 events. 
4. 
SUBJECT INFORMATION 
4.1. 
Demographics and Baseline Characteristics 
All demographic and baseline characteristic variables will be summarized for both the ITT 
and the PP populations. 
Subject enrollment will be summarized by region, country, and investigator. Also to be 
summarized is subject eligibility by meeting inclusion/exclusion criteria. 
Stratification factors used in randomization (IPI category and stage of disease at baseline) 
will be tabulated. The stratified logrank test and stratified cox model use the stratification 
factors in randomization.  
Demographic and baseline characteristic data will be summarized, including sex, age, race, 
ECOG performance status score, weight, height, and body surface area (m2).   
The following categories of disease characteristics at baseline will be summarized: 
1) Diagnosis information of MCL: including confirmed diagnosis by central review 
(Yes, No, or indeterminate), stage of disease at diagnosis, type of histology, 
cellularity, over-expression of cyclin D1 in association with CD20 and CD5 (Yes 
or No), and chromosome translocation t(11; 14)  (Yes or No). 


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2) Disease characteristics at baseline: including IPI at baseline, bone marrow aspirate 
results (Positive, Negative, Indeterminate, or Not Evaluable), bone marrow biopsy 
results (Positive, Negative, Indeterminate, or Not Evaluable), baseline LDH 
(absolute value and category [>ULN, ULN], and reason for transplantation 
ineligibility. 
Baseline IPI score and baseline stage of disease will be derived or obtained from CRF. 
These baseline derived stratification factors will be tabulated and they will be used in the 
subgroup analyses.  
Two panels of baseline clinical laboratory tests will be summarized: hematology and serum 
chemistry. Descriptive summaries for creatinine clearance and categories of creatinine 
clearance will be provided. Frequencies of CTC grade are to be provided for the following 
laboratory tests at baseline:  
Hematology: hemoglobin, WBC, absolute neutrophil count (ANC), absolute lymphocyte 
count (ALC), and platelets. 
Chemistry: aspartate transaminase (AST), alanine transaminase (ALT), bilirubin, 
creatinine, alkaline phosphatase, glucose, albumin, bicarbonate, magnesium, LDH, urea, 
blood urea nitrogen, uric acid, electrolytes (sodium, potassium, calcium, and phosphate), 
and creatinine clearance. 
Medical history will be summarized. The findings (normal or abnormal [clinically 
significant or clinically insignificant]) will also be summarized for baseline 12-lead ECGs, 
and ECHO/MUGA scans. 
4.2. 
Disposition Information 
A CONSORT-type flow chart of subject disposition will be provided for the intent-to-treat 
population.  
The number of subjects discontinuing and completing the study treatment will be reported 
for the intent-to-treat population. The reasons for discontinuation as indicated by the 
investigators will be summarized by the number of subjects reporting. Those subjects who 
discontinue study treatment due to adverse events will be further tabulated by relationship 
to study medication. The number and percentage of subjects in the safety population and 
the per-protocol populations will also be reported. 
Descriptive statistics (mean, standard deviation, median, and range) will be provided for 
study duration (in weeks) as well as length of follow-up (in months) for the intent-to-treat 
and the per-protocol populations. 


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4.3. 
Extent of Exposure 
All extent-of-exposure summaries are to be presented for the safety population. 
Frequency of subjects who receive at least a certain number of treatment cycles will be 
tabulated by the number of cycles. Number of treatment cycles will be summarized along 
with time on study treatment, and dose intensity for the study drugs. 
Summaries will be provided for number of doses and total doses of study drug (mg/m2) by 
cycle. Also to be presented by cycle are the number and percentage of subjects on 
treatment, and the number and percentage of subjects with cycle delays (>5 days). For each 
of the study drugs, the following summaries are to be reported: number of subjects dosed, 
number of subjects with dose reduced, dose withheld, schedule change (only applicable to 
subjects treated with VELCADE), and any change in dosing (reduced, withheld, schedule 
change [VELCADE only]).  
Reasons for dose modifications will be summarized by cycle as well as across the study 
for each of the following changes: cycle delay, dose reduction, dose withholding, and 
schedule change (VELCADE only).  
For each type of the dose changes mentioned above, adverse events leading to these 
changes in doses of study treatment will be summarized for each of the study drugs.  
Adverse events leading to the discontinuation of VELCADE will be summarized in a 
separate summary. In this summary, the incidences of the following AEs are to be reported: 
AEs leading to the discontinuation of VELCADE alone, AEs leading to the discontinuation 
of VELCADE and at least one other study drug, and AEs leading to the discontinuation of 
study treatment. 
4.4. 
Protocol Deviations   
Major protocol deviations will be summarized by types of deviations.  
4.5. 
Concomitant Medications  
Concomitant medications will be coded using the latest version of the WHO Drug 
Dictionary. The concomitant therapies will be provided by therapeutic class, 
pharmacological class, and preferred term. A summary of all concomitant medications will 
be summarized, including the ones that (1) started prior to study treatment and continued 
during study treatment (2) started during study treatment. A separate summary will be 
provided for concomitant therapies started during study treatment.  
 


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4.6. 
Subsequent Therapies for MCL 
Subsequent therapies for MCL, including antineoplastic agents and other systemic 
therapies such as steroids, will be summarized by pharmacological class and preferred 
term. In addition, the number and percentage of subjects who receive VELCADE as 
subsequent therapy will be presented. These summaries are to be provided for both the ITT 
and the PP populations. 
Best responses to subsequent anti-lymphoma therapies will be tabulated. 
5. 
EFFICACY 
5.1. 
Analysis Specifications 
5.1.1. 
Level of Significance 
All tests will be 2-sided. The primary population is the ITT population, with sensitivity 
analyses to be performed on the centrally confirmed MCL population and PP populations. 
The primary hypothesis is to be tested at the 0.05 significance level (overall). The 
significance level at an interim analysis is to be determined by the observed number of 
events at the time of the interim analysis per the O’Brien-Fleming spending function. 
The secondary hypotheses are to be tested sequentially at the nominal 0.05 significance 
level. The order of these hypotheses is as follows: 1) TTP, 2) TNT, 3) CR rate and 4) OS. 
A secondary hypothesis will be tested if and only if the primary hypothesis is rejected along 
with all the secondary hypotheses that precede it.  
OS will be analyzed regardless of what happened to the other endpoints in the hierarchical 
test.  
For exploratory modeling, main effects other than the treatment group in a proposed model 
will be tested at the 0.05 significance level, while interactions will be examined at the 0.10 
significance level. Non-significant interaction terms will be removed from the model. 
The clinical cutoff of the third interim analysis was 5 July 2011. At the time of clinical cut-
off, there were 173 PFS events. Based on the original design with an O’Brien-Fleming 
spending function (the Lan-DeMets approach) and a total of 295 events, an alpha allocated 
for the 3rd interim analysis is 0.006 (2-sided), and for the final analysis is 0.048 (2-sided).  
5.1.2. 
Data Handling Rules 
Unless specified otherwise, missing values for efficacy criteria will be handled using the 
last-observation-carried forward method. Baseline values of efficacy criteria will not be 
carried forward. 


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5.1.3. 
Definitions for Some Efficacy Variables  
5.1.3.1. 
Tumor Assessment by Independent Radiology Review 
Committee (IRC) 
Tumor assessment by radiological images (computed tomography [CT] scans) is the 
primary efficacy evaluation.  All radiological images will be collected and reviewed 
centrally by Perceptive Informatics, an Independent Radiology Review committee (IRC).  
The radiological images will be collected at baseline, Cycles 2, 4, 6 (and 8, if applicable), 
End-of-Treatment, and thereafter every 6 weeks for 18 weeks and every 8 weeks until 
PD/initiation of alternate therapy/withdrawal. With the approval of Amendment INT-3, 
when the subject is recorded to have an event of PD, a repeat CT scan to confirm PD must 
be undertaken at least 30 days after the scan that was used to determine PD. In the event a 
subject starts subsequent anti-lymphoma treatment, it is strongly recommended that this 
repeat CT scan be performed before the subject starts treatment. The repeat CT scan must 
be done using i.v. and oral contrast and must be of the neck, chest, abdomen, and pelvis. If 
the subject is intolerant of i.v. contrast agents, the scan may be performed with only oral 
contrast. 
The IRC will consist of a minimum of 3 board certified radiologists assigned to 
Study LYM-3002. Two primary radiologists will independently read each case (double 
read) with a third radiologist serving as adjudicator, when necessary. 
The primary radiologists will independently interpret imaging studies for subjects enrolled 
in the study, using modified International Workshop to Standardize Response Criteria for 
non-Hodgkin’s Lymphoma (IWRC) [Cheson 2007]). Detailed criteria for response 
categories can be found in the attachment to this SAP. The radiologists will be blinded to 
treatment assignment.  
The IRC primary radiologists will assess study imaging to determine overall tumor 
response at each timepoint (CR, CRu, PR, SD, or PD). The adjudicator will evaluate cases 
where disagreement exists between the primary radiologists and will choose one of the 
primary reviewer’s assessments as the final assessment. The IRC primary radiologists will 
review all timepoints available for each subject in a sequential fashion.  
5.1.3.2. 
Date of Progression 
For analyses based on the IRC tumor assessment, the date of progression will be the earliest 
date of PD from imaging studies. 
For analyses based on the investigator’s tumor assessment, the date of progression will be 
the earliest date of PD from imaging study (collected on Evaluation of Response page on 


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CRF) or date of PD other than imaging study (collected on PD page of CRF), whichever is 
first reported.   
5.1.3.3. 
Complete Response Assessment 
Overall complete response refers to CR and CRu, defined by meeting the requirements for 
CR/CRu per the modified IWRC criteria (Attachment) . 
A CR must meet the CR criteria based on radiological imaging study, and subsequently 
verified by the laboratory tests with normal LDH and negative bone marrow at screening 
or at the time of the radiological CR (from central pathology laboratory 
Phenopath/Covance). A CRu is CRu based on radiological imaging study, and 
subsequently verified by laboratory tests with normal LDH and negative bone marrow at 
screening or normal LDH and negative/indeterminate bone marrow at the time of the 
radiological CRu.  
Radiological overall complete response refers to radiological CR/CRu verified or not 
verified by LDH and bone marrow. Radiological CR/CRu is defined by CR/CRu meeting 
all the criteria for CR/CRu based on radiological imaging studies, but subsequent 
verification by LDH and bone marrow findings is not required. The date of radiological 
CR/CRu is the first date that CR/CRu is documented (tumor assessment per IRC) based on 
radiological imaging study. 
5.1.3.4. 
Tumor Assessment by Investigator 
Tumor assessment will be performed by investigators locally based on radiological images 
and using the same modified IWRC criteria.  Overall tumor assessment by the investigators 
at each timepoint is collected in the CRF.  In addition, tumor assessment of PD can also be 
done based on clinical evidence other than radiological images, which is collected in the 
CRF.  Analyses for investigator tumor assessment are secondary analyses. 
5.1.3.5. 
Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression or the start of subsequent anti-neoplastic therapy.  
5.2. 
Primary Efficacy Endpoint(s) 
5.2.1. 
Definition  
The primary endpoint is PFS, which is defined as the interval between the date of 
randomization and the date of PD or death, whichever is first reported, in the ITT population. 
Subjects who withdraw from the study (i.e., withdrawal of consent, lost to follow-up) or start 
anti-neoplastic therapy without documented PD will be censored at the time of the last 
adequate (CT scan available) disease assessment. Subjects who complete the study, have not 


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progressed, and are still alive at the cut-off date of the final analysis will be censored at the 
last adequate disease assessment. For PD documented between scheduled evaluations, the 
actual date of PD will be used, not the date of the next scheduled evaluation. For death no 
more than 6-month after last disease assessment, the date of the event will be the date of 
death. For death more than 6-month after last disease assessment, the PFS will be censored 
at the last adequate disease assessment. The censoring method is summarized in Table 1.  
Table 1:  Censoring Method 
Situation 
Date of Progression or Censoring
Outcome 
No baseline tumor assessments 
Randomization
Censored 
Progression documented between 
scheduled visits 
Earliest date of radiological assessment 
documenting progression 
PFS event   
No progression  
Date of last visit with adequate assessment
Censored 
New anticancer treatment started 
Date of last visit with adequate assessment 
(prior to subsequent anticancer treatment)
Censored 
Death before first PD assessment 
Date of death
PFS event 
Death between adequate 
assessment visits 
Date of death 
PFS event 
Death within 6-month after last 
disease assessment 
Date of death 
PFS event 
Death more than 6-month after last 
disease assessment 
Date of last visit with adequate assessment 
Censored 
 
The primary analysis for PFS will be based on IRC assessment of PD. Progression-free 
survival derived from investigator data will be evaluated and used as supportive evidence. 
Sensitivity analysis on PFS using IRC alternative assessments of transient fluid collection 
or transient lesion as basis for PD will be performed. 
The primary analysis for PFS will also be conducted among the subjects with centrally 
confirmed MCL. 
Sensitivity analysis for PFS will be conducted by not censoring a subject who started 
subsequent antineoplastic therapy without documented PD. Sensitivity analysis for PFS 
will also be conducted by censoring a subject whose PD is after more than one missing 
adequate disease assessment and censoring date is the last adequate disease assessment 
before PD. 
5.2.2. 
Analysis Methods 
The Kaplan-Meier method will be used to estimate the distribution of overall PFS for each 
treatment group. The primary treatment comparison is based on a stratified log-rank test. 
Hazard ratio and its 95% confidence interval are to be estimated based on a stratified Cox’s 


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model with treatment as the explanatory variable. Stratification factors include 
International Prognostic Index (IPI: 0-1, 2, 3, and 4-5) and stage of disease at diagnosis (II, 
III, and IV). The sensitivity analyses for PFS among centrally confirmed MCL subjects, 
for PFS without censoring subsequent therapy, and for PFS censoring after more than one 
missing adequate disease assessment will be performed similarly. 
The unstratified log-rank test will also be performed as a sensitivity analysis.  
The subgroup analyses for PFS will be done as specified in Section 2.3. 
A Cox’s regression model will be used in sensitivity analyses. It is intended to estimate the 
effect size of VcR-CAP vs. R-CHOP after accounting for prognostic factors. The following 
prognostic factors will be included in the analysis: age (>65, 65), sex, race (white, non-
white), baseline ECOG performance status (1, >1), baseline extranodal site involvement 
(1, >1), baseline LDH (normal, above normal limits), and WBC (normal, above normal 
limits),  together with stage of disease at diagnosis (II and III vs. IV).  
Concordance rate between investigator PD and IRC PD will be provided.  Agreement on 
PD status includes PD by both IRC and investigator or no PD by both of them. In addition, 
PD by both IRC and investigator will be categorized into sub categories of complete 
agreement, agreement with later date, or agreement with early date.  Disagreement on PD 
status includes PD by investigator but not IRC and PD by IRC but not investigator. 
The total number of PD events adjudicated will be given. For subjects without PD, the 
main reason for censoring will also be tabulated.  
5.3. 
Major Secondary Endpoints 
5.3.1. 
Definition 
Time to Progression 
Time to Progression is defined as the duration from the date of randomization until the date 
of first documented evidence of PD or relapse for subjects who experience CR or CRu on 
this study. Death due to PD will be considered as an event if the date of death is within 6-
month after last disease assessment, otherwise, death will be censored at the date of last 
disease assessment. Subjects who withdraw from the study (i.e., withdrawal of consent, 
lost to follow-up) or start subsequent therapy or die of causes other than PD will be 
censored at the time of the last disease assessment. 


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Overall Response Rate (ORR) 
Overall Response Rate is defined as the proportion of subjects who achieve CR, CRu, or 
PR relative to the response evaluable population. Disease response and progression will be 
evaluated according to the modified IWRC.   
Complete Response (CR/CRu) Rate 
Complete response rate is defined as the proportion of subjects who achieve CR or CRu 
relative to the response evaluable population.   
Radiological complete response rate is defined as the proportion of subjects who achieve 
radiological CR or radiological CRu relative to the response evaluable population.   
Time to Next Antilymphoma Treatment  
Time (days) to next anti-lymphoma treatment is measured from the date of randomization 
to the start date of new anti-lymphoma treatment.  Death due to disease progression prior 
to subsequent therapy is considered as an event.  Otherwise, time to next anti-lymphoma 
treatment is censored at the date of death or the last date known to be alive.  
Overall Survival (OS) 
Overall survival is measured from the date of randomization to the date of the subject’s 
death. If the subject is alive or the vital status is unknown, OS will be censored at the date 
that the subject is last known to be alive. 
Duration of Response and Duration of Complete Response 
Duration of radiological response (CR, CRu, or PR) will be calculated from the date of 
initial documentation of a response to the date of first documented evidence of PD or death 
due to PD.  Responders who withdraw from the study (i.e., withdrawal of consent, lost to 
follow-up) or who start subsequent anti-neoplastic therapy without documented PD will be 
censored at the time of the last adequate (CT scan available) disease assessment. 
Responders who complete the study, have not progressed, and who are still alive at the cut-
off date of the final analysis will be censored at the last adequate disease assessment. For 
death due to PD  more than 6-month after last disease assessment, the duration will be 
censored at the last adequate disease assessment before PD or death.    
Duration of complete response (CR, CRu) will be calculated from the date of initial 
documentation of a complete response to the date of first documented evidence of PD or 
death due to PD.  Subjects who have a complete response without disease progression or 
death due to PD will be censored in the same way as in duration of response.  


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5.3.2. 
Analysis Methods 
Time to Progression 
The analysis method will be similar to that used for the primary PFS. The analysis of TTP 
is considered sensitivity analyses for PFS. 
Response-Related Endpoints 
The number and percentage of subjects in the following response categories will be 
presented by treatment group: complete response (CR), unconfirmed complete response 
(CRu), overall complete response (CR+CRu), partial response (PR), overall response 
(CR+CRu+PR), stable disease (SD), and progressive disease (PD). 
Overall Response Rate (ORR) 
Overall 
response 
rate 
is 
to 
be 
presented 
by 
treatment 
group. 
Stratified 
Cochran-Mantel-Haenszel (CMH) test will be used to test treatment difference.  The 
Mantel-Haenszel estimate of odds ratio and its 95% confidence interval are to be presented 
as well. 
Both ORR based on IRC assessment (primary) and on investigator assessment (supportive) 
will be evaluated and analyzed for the response evaluable population.  
Complete Response (CR/CRu) Rate 
Both complete response rate and radiological complete response rate are to be presented 
by treatment group. Stratified CMH test will be used to test treatment difference. The 
Mantel-Haenszel estimate of odds ratio and its 95% confidence interval are to be presented 
as well. 
Analyses will be based on the response evaluable population. 
Time to Next Antilymphoma Treatment  
The Kaplan-Meier method will be used to estimate the distribution of time to next 
anti-lymphoma treatment for each treatment group. The primary treatment comparison is 
based on a stratified log-rank test. The hazard ratio and its 95% confidence interval are to 
be estimated based on the Cox’s regression model.  
Overall Survival (OS) 
The Kaplan-Meier method will be used to estimate the distribution of OS for each treatment 
group. The primary treatment comparison is based on a stratified log-rank test. Hazard ratio 
and its 95% confidence interval are to be estimated based on a stratified Cox’s model with 
treatment as the explanatory variable. Stratification factors include International Prognostic 
Index (IPI: 0-1, 2, 3, and 4-5) and stage of disease at diagnosis (II, III, and IV).  


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In addition, the probability of survival at 18 months and 3-year after randomization, based 
on Kaplan-Meier estimates, will be presented for the 2 treatment groups, along with their 
95% confidence interval. 
Duration of Response and Duration of Complete Response 
The Kaplan-Meier method will be used to descriptively summarize duration of response 
and duration of complete response. 
5.4. 
Other Efficacy Variables 
5.4.1. 
Definition 
Time to Response   
Time (days) to response is measured from the date of randomization to the date of initial 
response (CR, CRu, or PR). Those subjects without response (CR/CRu/PR) will be 
censored either at PD or at the last efficacy assessment before the start of subsequent 
therapy. 
Rate of Durable Response  
A durable response is defined as a response (CR, CRu, PR) with a duration 6 months.  
The rate of durable response is the proportion of subjects who achieve durable response 
relative to the response evaluable population.   
Duration of Treatment Free Interval  
Duration (days) of treatment free interval is measured from the date of last dose plus 1 to 
the start date of the new treatment.  
Death due to disease progression prior to subsequent therapy is considered as an event.  
Otherwise, treatment-free interval is censored at the date of death or the last date known to 
be alive. 
5.4.2. 
Analysis Methods 
Time to Response   
The Kaplan-Meier method will be used to estimate the cumulative distribution over time 
for time to response in the response evaluable population. The stratified log-rank test will 
be used to compare the 2 treatment groups.  In addition, descriptive summaries are to be 
provided for time to response for responding subjects (CR/CRu/PR). 
Rate of Durable Response  
For rate of durable response, the analysis method will be similar to the one used for ORR. 
For subjects who don’t have durable response, numbers of subjects whose best response is 
worse than PR,  numbers of subjects whose best response are better or equal PR with 


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censored value and duration <6 months,  and numbers of subjects whose best response are 
better or equal PR with event and duration <6 months will be given separately. 
Duration of Treatment Free Interval  
The Kaplan-Meier method will be used to descriptively summarize the duration of the 
treatment-free interval.    
Subsequent Anti-Lymphoma Therapy 
Frequency tabulation will be given, indicating how many subjects in each group started 
subsequent therapy.  
6. 
SAFETY 
Safety of the treatment arms will be compared using the incidence and severity of adverse 
events, laboratory test results, ECG/echo or MUGA results, vital sign measurements, 
physical examination results, mortality, and ECOG performance status.  
Safety analyses will be performed by the treatment actually received. That is, those subjects 
who are randomized to VcR-CAP but never receive VELCADE will be analyzed in the R-
CHOP group (Treatment Arm B), and those who are randomized to R-CHOP but 
mistakenly receive at least one dose of VELCADE will be analyzed in the VcR-CAP group 
(Treatment Arm A). 
MRU data will be analyzed in a separate report. 
6.1. 
Adverse Events 
Treatment-emergent adverse events are defined as any adverse event that occurs on or after 
administration of the first dose of study medication (VELCADE, rituximab,  
cyclophosphamide, doxorubicin, vincristine, and prednisone) and through the End of 
Treatment visit to 30 days after the last dose of study drug, any event that is considered 
drug-related (very likely, probably or possibly related) regardless of the start date of the 
event, or any event that is present at baseline but worsens in intensity or is subsequently 
considered drug-related by the investigator.   
The most recent MedDRA dictionary will be used to code the investigator’s adverse event 
terms. Adverse event tables will summarize subject incidence by treatment group actually 
received. The severity of adverse events will be assessed using NCI CTC v3.0. 
6.1.1. 
All Adverse Events 
The incidence of treatment-emergent adverse events will be summarized.  The following 
tabulations will also be presented: 


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 Overview of treatment-emergent adverse events 
 Incidence of treatment-emergent adverse events, especially the most commonly 
reported events (i.e., those events reported by at least 10% of subjects) by MedDRA 
SOC and preferred term. 
 Incidence of treatment-emergent adverse events by SOC, high level term, and preferred 
term. 
 Incidence of treatment-emergent adverse events considered by the investigator to be 
related to study medication, by SOC and preferred term. 
 Incidence of treatment-emergent adverse events by relationship to study medication. 
 Incidence of treatment-emergent adverse events by CTC toxicity grade.  
 Incidence of treatment-emergent adverse events by CTC toxicity grade and relationship 
to study medication. 
 Incidence of AEs leading to withdrawal from treatment by SOC and preferred term 
 Incidence of AEs leading to dose reduction, dose withholding, and cycle delay by SOC 
and preferred term 
 Incidence of treatment-emergent adverse events leading to death by system organ class 
and preferred term. 
 Incidence of AEs leading to the discontinuation of VELCADE alone, AEs leading to 
the discontinuation of VELCADE and at least one other study drug, and AEs leading 
to the discontinuation of study treatment. 
 
Incidence of treatment-emergent adverse events (overview, all events, Grade 3, and 
serious) will also be summarized by Cycles 1, 2-3, 4-6, vs. >6. In case a subject experiences 
multiple adverse events of the same preferred term during the study, all new onsets will be 
summarized. For treatment-emergent adverse events with CTC toxicity grade of 3 or 
higher, the following summaries are to be produced. 
 Incidence of Grade 3 treatment-emergent adverse events, by SOC and preferred term.   
 Incidence of Grade 3 treatment-emergent adverse events considered by the 
investigator to be related to study medication, by SOC and preferred term. 
 Incidence of Grade 3 treatment-emergent adverse events by relationship to study 
medication. 
For treatment-emergent serious adverse events, the following summaries are to be 
produced. 
 Incidence of treatment-emergent serious adverse events, by SOC and preferred term.   
 Incidence of treatment-emergent serious adverse events considered by the investigator 
to be related to study medication, by SOC and preferred term. 


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 Incidence of treatment-emergent serious adverse events by relationship to study 
medication. 
Analyses of adverse events leading to treatment discontinuation are specified in 
Section 2.4.18. 
6.1.2. 
Adverse Events of Clinical Interest 
Unless specified otherwise, the adverse events in this section are treatment-emergent ones. 
6.1.2.1. 
Peripheral Neuropathies 
Definition 
Peripheral neuropathies (PN) refer to the adverse events in the high level term of peripheral 
neuropathies NEC. 
All the PN event records of the same preferred term from the same subject are to be linked 
by the onset date and the resolution date. If a resolved event is followed by another event 
of the same preferred term with the onset date within 1 day of the resolution date of the 
previous record, these 2 records should be linked together and considered as 1 event. 
A PN event is considered as resolved if its final outcome is resolved with no subsequent 
PN event of the same preferred term occurring on the resolution date or the day before and 
after. 
A PN event is considered as improved if the event improves from the maximum grade. 
That is, all the grades recorded after the maximum grade is less than the maximum grade. 
Time to first onset of peripheral neuropathy events (any grade, grade 2, and grade 3) is 
measured from the first dosing date to the initial onset date of event. 
Time to improvement and time to resolution are to be defined for each PN event. 
Time to resolution is defined as the number of days from the initial onset date (inclusive) 
to the resolution date for resolved events. Those events that are not resolved will be 
censored at the date of last study drug dose plus 30 days for Grade 1 events (or the data 
cut-off if earlier) and the date of last study drug dose plus 180 days for Grade >=2 events 
(or the data cut-off if earlier). This is in line with the protocol specifications on adverse 
event reporting, indicating that unresolved neuropathic adverse events Grade 2 or higher 
should be followed for a maximum of 6 months, while general adverse events are reported 
until 
at 
least 
30 
days 
following 
last 
dose 
of 
study 
medication 
(Protocol 26866138LYM3002, Section 9.6) 


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For improved events, time to improvement is defined as the number of days from the initial 
onset date (inclusive) of the maximum grade to the first onset date that the toxicity grade 
is below the maximum grade with no higher grade thereafter, or the resolution date, 
whichever occurs first. For those events that stay at the maximum grade until the end of 
follow-up, time to improvement will be censored at the date of last study drug dose plus 
180 days if the maximum grade is at least 2, and the date of last study drug dose plus 
30 days for Grade 1 events. 
Method 
The incidence of treatment-emergent peripheral neuropathies will be summarized by high 
level term and preferred term.  
Kaplan-Meier estimates of probability of developing peripheral neuropathy events (any 
grade, grade 2, and grade 3) will be presented for time to the first onset in the two 
treatment arms, and for cumulative VELCADE dose up to the first onset in the VcR-CAP 
arm. Subjects without any peripheral neuropathy events will be censored at 30 days after 
last dose, or at total VELCADE dose received in these analyses.  
Furthermore, time to improvement and time to resolution of peripheral neuropathy events 
will be summarized by outcome (improvement or resolution) using the Kaplan-Meier 
method. This analysis is event based, thus 1 subject could contribute multiple observations 
if the subject has more than 1 PN event. 
6.1.2.2. 
Cardiac Rhythm and Conduction Abnormalities 
Definition 
Cardiac rhythm and conduction abnormalities include adverse events in the following high 
level terms (HLTs): cardiac conduction disorders, cardiac signs and symptoms NEC 
(palpitations only), rate and rhythm disorders NEC, supraventricular arrhythmias, 
ventricular arrhythmias, and cardiac arrest. 
Method 
The incidence of treatment-emergent adverse events associated with cardiac rhythm and 
conduction abnormalities will be tabulated.  
6.1.2.3. 
Heart Failure 
Definition 
This endpoint refers to those adverse events coded to the following preferred terms: acute 
left ventricular failure, acute pulmonary oedema, acute right ventricular failure, cardiac 
asthma, cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure 
congestive, cardiac failure high output, cardiogenic shock, cardiopulmonary failure, 


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cardiorenal syndrome, chronic left ventricular failure, chronic right ventricular failure, cor 
pulmonale,  cor pulmonale acute, cor pulmonale chronic, ejection fraction decreased, 
hepatic congestion, hepatojugular reflux, left ventricular failure, low cardiac output 
syndrome, neonatal cardiac failure, pulmonary oedema, pulmonary oedema neonatal, 
ejection fraction decreased, and diastolic dysfunction. 
Method 
Incidence of treatment-emergent heart failure events will be summarized. 
6.1.2.4. 
Pericardial Disease 
Definition 
Pericardial disease includes adverse events in the high level group term (HLGT) of 
“Pericardial disorders” and high level term of noninfectious pericarditis.  
Method 
The incidence will be presented. 
6.1.2.5. 
Acute Diffuse Infiltrative Pulmonary Disease 
Definition 
This endpoint refers to those adverse events coded to the following preferred terms:  acute 
interstitial pneumonitis, acute respiratory distress syndrome, allergic granulomatous 
angiitis, alveolar proteinosis, alveolitis, alveolitis allergic, alveolitis necrotising, 
bronchiolitis, organising pneumonia, diffuse alveolar damage, diffuse panbronchiolitis, 
eosinophilic pneumonia, eosinophilic pneumonia acute, eosinophilic pneumonia chronic, 
idiopathic pneumonia syndrome, idiopathic pulmonary fibrosis, interstitial lung disease, 
loeffler’s syndrome, lower respiratory tract inflammation, lung induration, lung 
infiltration, acute lung injury, necrotising bronchiolitis, obliterative bronchiolitis, 
pneumonitis, progressive massive fibrosis, pulmonary eosinophilia, pulmonary fibrosis, 
pulmonary necrosis, pulmonary toxicity, pulmonary alveolar haemorrhage, pulmonary 
haemorrhage, and non-cardiogenic pulmonary oedema. 
Method 
The incidence will be presented. 
6.1.2.6. 
 Reactivation of Hepatitis B  
Definition 
Reactivation of Hepatitis B includes adverse events in the following preferred terms: 
Hepatitis B, Acute hepatitis B, Hepatitis acute, Asymptomatic viral hepatitis, Chronic 
hepatitis B, Hepatitis post transfusion, Hepatitis Viral.  


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Prophylactic use of anti-virals of hepatitis B includes lamivudine, entecavir, entecavir 
monohydrate, thymalfasin, with prophylaxis checked in the CRF. 
Method 
The incidence will be presented. The incidence of hepatitis B by prophylactic use of anti-
virals of hepatitis B will be tabulated. 
6.1.2.7. 
Acute Hypersensitivity 
Definition 
This endpoint refers to those adverse events coded to the following preferred terms:   
allergic oedema, anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, 
anaphylactoid shock, angioedema, circumoral oedema, drug hypersensitivity, eyelid 
oedema, face oedema, hypersensitivity, laryngeal oedema, laryngotracheal oedema, lip 
oedema, lip swelling, oedema mouth, periorbital oedema, small bowel angioedema, tongue 
oedema, type I hypersensitivity, type IV hypersensitivity reaction, swelling face, infusion 
site urticaria, and urticaria. 
Method 
The incidence will be presented. Incidence of study drug related treatment-emergent acute 
hypersensitivity adverse events will be tabulated by study drugs. Listing of treatment-
emergent acute hypersensitivity adverse events will be provided. 
6.1.2.8. 
Central Nervous System Disorders  
Definition 
This endpoint refers to those adverse events coded to the following preferred terms: 
Leukoencephalopathy, Progressive multifocal leukoencephalopathy, Posterior reversible 
encephalopathy syndrome, Guillain-Barre Syndrome, Encephalitis and Encephalopathy. 
Method 
The incidence will be presented. 
6.1.2.9. 
Herpes Zoster Infection 
Definition 
This endpoint refers to those adverse events coded to the following preferred terms:  
Encephalitis herpes, Herpes zoster multi-dermatomal, Herpes ophthalmic, Herpes zoster 
ophthalmic, Herpes sepsis, Herpes zoster oticus, Herpes zoster, Keratitis herpetic, Herpes 
zoster disseminated, Meningitis herpes, Herpes zoster infection neurological, 
Meningoencephalitis herpetic. 


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Prophylactic use of anti-virals of herpes zoster includes aciclovir, valaciclovir, famciclovir, 
valaciclovir hydrochloride, aciclovir sodium, with prophylaxis checked in the CRF. 
Method 
The incidence will be presented. The incidence by prophylactic use of anti-virals of herpes 
zoster will be tabulated. 
6.1.2.10. 
Thrombocytopenic Bleeding Events 
Definition 
This endpoint refers to the adverse events with the following preferred terms: 
Abdominal wall haematoma, Abdominal wall haemorrhage, Acute haemorrhagic 
conjunctivitis, Adrenal haematoma, Adrenal haemorrhage, Anal haemorrhage, Anal ulcer 
haemorrhage, Application site haematoma, Application site haemorrhage, Basal ganglia 
haemorrhage, Bloody discharge, Brain stem haematoma, Brain stem haemorrhage, Brain 
stem microhaemorrhage, Breast haematoma, Breast haemorrhage, Bronchial haemorrhage, 
Catheter site haematoma, Catheter site haemorrhage, Central nervous system haemorrhage, 
Cerebellar haematoma, Cerebellar haemorrhage, Cerebellar microhaemorrhage, Cerebral 
haematoma, Cerebral haemorrhage, Cerebral microhaemorrhage, Cerebrovascular 
accident, Cervix haematoma uterine, Cervix haemorrhage uterine, Choroidal haematoma, 
Choroidal haemorrhage, Ciliary body haemorrhage, Colonic haematoma, Conjunctival 
haemorrhage, Corneal bleeding, Cystitis haemorrhagic, Duodenitis haemorrhagic, Ear 
haemorrhage, Enterocolitis haemorrhagic, Epistaxis, Exsanguination, Extradural 
haematoma, Extravasation blood, Eye haemorrhage, Eyelid bleeding, Gastric 
haemorrhage, 
Gastroduodenal 
haemorrhage, 
Gastroduodenitis 
haemorrhagic, 
Gastrointestinal haemorrhage, Gastrointestinal ulcer haemorrhage, Genital haemorrhage, 
Gingival bleeding, Haemarthrosis, Haematemesis, Haematochezia, Haematocoele, 
Haematoma, 
Haematosalpinx, 
Haematotympanum, 
Haemoptysis, 
Haemorrhage, 
Haemorrhage intracranial, Haemorrhage urinary tract, Haemorrhagic anaemia, 
Haemorrhagic cerebral infarction, Haemorrhagic disorder, Haemorrhagic stroke, Intestinal 
haematoma, Intestinal haemorrhage, Intracranial haematoma, Intracranial tumour 
haemorrhage, Intraocular haematoma, Intraventricular haemorrhage, Iris haemorrhage, 
Lacrimal haemorrhage, Large intestinal haemorrhage, Large intestinal ulcer haemorrhage, 
Lower gastrointestinal haemorrhage, Melaena, Meningorrhagia, Mesenteric haematoma, 
Mesenteric haemorrhage, Mouth haemorrhage, Ocular retrobulbar haemorrhage, 
Oesophageal haemorrhage, Oesophagitis haemorrhagic, Optic disc haemorrhage, Optic 
nerve sheath haemorrhage, Ovarian haematoma, Ovarian haemorrhage, Pelvic haematoma, 
Pelvic haematoma obstetric, Pelvic haemorrhage, Penile haematoma, Penile haemorrhage, 
Perineal haematoma, Periorbital haematoma, Periorbital haemorrhage, Pituitary 


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haemorrhage, Prostatic haemorrhage, Putamen haemorrhage, Renal haematoma, Renal 
haemorrhage, Retinal haemorrhage, Retinopathy haemorrhagic, Scleral haemorrhage, 
Scrotal haematocoele, Scrotal haematoma, Spermatic cord haemorrhage, Spinal cord 
haemorrhage, 
Spinal 
epidural 
haemorrhage, 
Spinal 
haematoma, 
Subarachnoid 
haemorrhage, Subdural haematoma, Subdural haemorrhage, Subretinal haematoma, 
Testicular haemorrhage, Thalamus haemorrhage, Traumatic intracranial haemorrhage, 
Ureteric 
haemorrhage, 
Urethral 
haemorrhage, 
Uterine 
haematoma, 
Uterine 
haemorrhage,Vaginal haematoma, Vaginal haemorrhage, Vitreous haematoma, Vitreous 
haemorrhage, Vulval haematoma, Vulval haemorrhage, rectal haemorrhage, intra-
abdominal haematoma, post procedural haemorrhage, pulmonary haemorrhage, pulmonary 
alveolar haemorrhage, conjunctival haemorrhage, upper gastrointestinal haemorrhage, 
haemorrhoidal haemorrhage. 
Method 
The incidence will be presented. To review thrombocytopenic bleeding AEs, all grade 3 or 
more bleeding events where bleeding was associated with grade 3 or above 
trombocytopenia  will be reviewed. The thrombocyte counts prior to the bleeding event 
will be taken into consideration. The platelet transfusion during the cycle where 
thrombocytopenic bleeding AEs  took place will also be reviewed. These events will be 
reviewed by 2 different physicians (project physician and GMS-P) independently. 
6.1.2.11. 
Neutropenic Sepsis and Infections Events 
Definition 
This endpoint refers to the adverse events in the SOC of infections and infestations. 
Method 
The incidence will be presented. To review neutropenic infection/sepsis AEs,  Infection 
SOC will be taken as a starting point and all grade 3 and above infections will be taken into 
account if patients who have experienced grade 3 or above infection/sepsis has also grade 
3 or above neutropenia at the time of the infection. The G-CSF use during the cycle where 
the neutropenic infection/sepsis took place will also be reviewed. These events will be 
reviewed by 2 different physicians (project physician and GMS-P) independently.  
6.1.3. 
Death 
A tabulation will be produced for all-cause mortality within 30 days and 60 days after the 
first dose, within 30 days of the last dose, as well as all deaths for all subjects treated. Cause 
of death will be summarized as well in this table. In particular, frequencies of deaths that 
are due to study treatment-related adverse events will also be reported. 


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6.2. 
Clinical Laboratory Tests 
Laboratory data of hematology and clinical chemistry up to 30 days after last dose or the 
end of treatment visit date, whichever is later, will be reported in SI units. Normal ranges 
from local laboratories used in this study will be listed.  
Summary statistics (mean, standard deviation, median and range) will be calculated for the 
raw data and for their changes from baseline at each time point of assessment as well as 
for the changes from baseline to the last value.  
Graphical displays of over-time summaries will be presented for the following hematology 
parameters:  hemoglobin, neutrophils, lymphocytes, platelets. 
Shift tables for each cycle will be produced for neutrophils and platelets.  These tables will 
summarize by cycle the number of subjects with each baseline CTC grade and changes to 
the maximum CTC grade in the cycle.  
Changes from baseline to worst value on study (from treatment start to 30 days after last 
dose or the end of treatment visit date, whichever is later) will also be provided. The worst 
toxicity grade during the study will be tabulated. 
Due to the asymmetric assessment schedule between the two treatment groups for 
hematology laboratory tests, the shift tables and the summary of worst toxicity grade will 
be repeated excluding the samples taken on Days 4 and 8 of each cycle for those subjects 
treated with VcR-CAP. 
6.3. 
Vital Signs and Physical Examination Findings 
Over-time summary statistics (mean, standard deviation, median and range) of vital signs 
will be provided. A separate summary will be produced for vital signs at baseline, 
maximum, change to maximum, last value, and change to last value. 
In addition, any significant vital sign changes will be tabulated.  Significant findings are 
defined as follows: 
 Systolic blood pressure:  changes of +/- 20% or greater from baseline (separately) 
 Diastolic blood pressure:  changes of +/- 20% or greater from baseline (separately) 
In order to be included in the table, a subject must have both a baseline value and a value 
for the given post-baseline time point. 
Abnormal physical examination findings will be tabulated by body system. 


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6.4. 
Electrocardiogram and ECHO/MUGA Scans 
A tabulation of ECG assessments will be made for the clinically significant changes in 
ECG evaluation during the study versus the baseline ECG assessment. Similar analysis will 
be done for ECHO/MUGA scans. 
7. 
PATIENT-REPORTED OUTCOMES (PRO) ENDPOINTS 
7.1. 
Definition 
Validated scoring algorithms will be used to derive the scores for the 3 PRO multi-item 
scales: 1) EORTC QLQ-C30 scales: one global scale (global health status/quality of life), 
5 functional scales (physical functioning, role functioning, emotional functioning, cognitive 
functioning, and social functioning), plus 3 symptom scales (fatigue, nausea and vomiting, 
and pain) and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and 
financial difficulties)2) BFI (severity and fatigue); and 3) EQ-5D. 
7.2. 
Analysis Methods 
The number of available/missing assessments will be reported by scheduled visit and 
assessment/missing type.  
Absolute values of the EORTC QLQ-C30 and BFI scale scores (worst fatigue and 
interference scales) and changes from baseline will be summarized (N, mean, SD, 
minimum, maximum) at each scheduled post-baseline assessment visit, along with graphs.  
For each of the scales in the EORTC QLQ-C30 and worst fatigue scale of the BFI, a 
repeated-measures model to estimate changes from baseline to post-baseline assessments 
will be conducted.  Treatment,  time, and the interaction between time and treatment will 
be included as discrete parameters. Serial correlation will be assumed using an unstructured 
covariance matrix to account for the correlations between all time points.  Change and 
corresponding standard error in each outcome measure on each time point up to Week 18 
will be estimated for each treatment group separately and treatment and control will be 
compared. 
Graphics on EORTC QLQ-C30 and worst fatigue scale of the BFI will be displayed with 
visits as the X-axis, and means (SEs) of EORTC QLQ-C30 and worst fatigue scale of the 
BFI at each visit as the Y-axis. 
Cumulative distribution curves will be constructed for global health status in EORTC 
QLQ-C30 and worst fatigue scale of the BFI scales and displayed graphically. The curves 
will show a continuous plot of the absolute change of the last PRO measurement from baseline 
on the X-axis and the percent of subjects experiencing that change on the Y-axis for each of 
the treatment groups.  


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Additional PRO Endpoints 
The EQ-5D assesses 5 dimensions (mobility, self care, usual activity, pain or discomfort, 
and anxiety or depression) of health related to PRO. Each dimension is measured on a 
3-point ordinal scale ranging between 1 (no limitation) and 3 (greatest limitation) where a 
higher score corresponds to a worse health state. 
Responses in EQ-5D enable subjects to be assigned to 1 of 243 possible health states for 
which a global value (i.e., a "utility score") is assigned. The utility score has been 
previously determined based on the preferences of a sample of 3,395 members of the 
United Kingdom general population. A utility score of 1 corresponds to the highest degree 
of HRQOL, and score of 0 is compatible with a level of HRQOL equivalent to death. 
EQ-5D utility score 
Definition 
The EQ-5D utility scores will be computed using the UK value set obtained using Time 
Trade-Off (TTO) methodology from the table below. 
Value set for Calculation of the EQ-5D Scoring. 
UK TTO Value set 
 
Weight 
Full Health (11111) 
1 
At least one 2 or 3 (constant) 
-0.081 
At least one 3 
-0.269 
Mobility = 2 
-0.069 
Mobility = 3 
-0.314 
Self care = 2 
-0.104 
Self care = 3 
-0.214 
Usual activities = 2 
-0.036 
Usual activities = 3 
-0.094 
Pain/Discomfort = 2 
-0.123 
Pain/Discomfort = 3 
-0.386 
Anxiety/Depression = 2 
-0.071 
Anxiety/Depression = 3 
-0.236 
 
For example, the EQ-5D utility score for the health state 21232 is: 
Score 21232 = 1-0.081-0.269-0.069-0.036-0.386-0.071 = 0.088 
Analysis Methods 
Absolute values of the utility score for each of the 5 dimensions of EQ-5D, VAS, and their 
changes from baseline will be summarized at each scheduled post-baseline assessment visit 
(N, mean, SD, minimum, maximum).  Exploratory analysis will be performed when 
necessary. 


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8. 
BIOMARKER EVALUATIONS 
Biomarker analysis will be restricted to the following two assessments based on results 
from previous studies [Coiffier 2013; Goy 2010] (1) Pharmacogenomics and 
(2) Immunohistochemistry. The goal of the biomarker analysis is to provide some insight 
as to how subjects with certain prognostic markers (e.g. Ki67) respond to treatment or 
validate/confirm observations from previous studies that identified markers (e.g. PSMB) 
associated with better response to treatment.  
8.1. 
Definition 
Pharmacogenomic Analysis 
Genetic variability in drug target genes may influence drug binding and subsequently, 
response to treatment. Suspected drug target genes for VELCADE, including 
PSMB1(P11A) and PSMB5(R24C), which are proteasome subunits will be prospectively 
analyzed using whole blood DNA samples collected from consented subjects to determine 
any associations with response and PFS.  
Immunohistochemistry Analysis 
Paraffin-embedded, formalin-fixed tumor or fresh frozen tissue will be used for 
immunohistochemical analysis to quantify the tissue protein expression of the previously 
reported progonostic marker, Ki67. 
8.2. 
 Analysis Methods 
Pharmacogenomic Analysis 
The pharmacogenomic exploratory statistical analysis will be performed at the completion 
of the trial in order to inform subsequent lymphoma trials.  Results from PSMB gene 
analysis will include investigation of association of these genes with clinical endpoints 
including PFS and complete response. Analyses will be performed within each treatment 
group and stratified by demographic and or baseline features such as race, tumor burden, 
etc. Results of this prospective analysis will be presented in a separate report with key 
summary points included in the CSR.  
Immunohistochemistry Analysis 
The protein levels of Ki67 will be measured as scores on an ordinal scale with a cut off 
10% as negative and >10% as positive. The impact of protein expression level on response 
endpoints will be tested using standard categorical tests or survival analysis methods, as 
appropriate. Results of Ki67 analyses will be presented in a separate report with key 
summary points included in the CSR.  
 
 


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REFERENCES 
1. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin 
Oncol 2007; 25 (5):579-586. 
2. Coiffier B,  Henitz ED, Karkera J, et. al  Pre-specified candidate biomarkers identify subjects with 
relapsed or refractory follicular lymphoma who achieved longer progression-free survival after treatment 
with bortezomib plus rituximab compared to rituximab alone. Under review 2013. 
3. Goy A, Bernstein SH, McDonald A, et al: Potential biomarkers of bortezomib activity in mantle cell 
lymphoma from the phase 2 PINNACLE trial. Leuk Lymphoma 2010; 51(7):1269-1277. 
 
 


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ATTACHMENT 
Tumor Assessment Criteria (Modified IWRC) 
All tumor assessments will be done according to modified International Workshop to 
Standardize Response Criteria for non-Hodgkin’s Lymphoma (IWRC) [Cheson 2007]). 
Relapsed disease is classified the same as PD by IRC. The criteria that must be met for 
each disease response category, CR, CRu, PR, SD, disease relapse and progression, are 
provided below. 
Complete Response (CR) requires ALL of the following: 
 Complete disappearance of all detectable clinical and radiological evidence of disease 
and disease-related symptoms and normalization of biochemical abnormalities 
definitely assignable to lymphoma (e.g., LDH) if present before therapy. 
 All measurable lymph nodes and nodal masses must have regressed on CT to normal 
size (1.5 cm in their greatest transverse diameter for nodes >1.5 cm before therapy).  
 Non-measurable and assessable nodes that were 1.1 to 1.5 cm in their greatest 
transverse diameter before treatment must have decreased to 1 cm in their greatest 
transverse diameter after treatment, or by more than 75% in the sum of the products of 
the greatest diameters (SPD), as visually estimated. 
 The spleen or liver, if considered enlarged due to involvement with lymphoma before 
therapy on the basis of a physical examination or CT scan, should not be palpable on 
physical examination and should be considered normal size by imaging studies. 
Similarly, other organs considered to be enlarged before therapy due to involvement 
by lymphoma such as kidneys, must have decreased in size. 
 If the bone marrow was involved by lymphoma, indeterminate or not adequately 
assessed during screening, an adequate aspirate and biopsy of the same site must be 
clear of lymphoma. 
 All extranodal sites of disease must have completely disappeared. 
Unconfirmed Complete Response (CRu) requires: 
That the first and fourth criteria for CR be satisfied, however: 
 Any residual lymph node mass >1.5 cm in longest transverse dimension or extranodal 
site of disease (irrespective of size) must have regressed by more than 75% of the 
product of the longest perpendicular dimensions compared to the pretreatment baseline. 
 The bone marrow aspirate may be indeterminate (contain increased number or size of 
lymphoid aggregates without cytologic or architectural atypia). 
 If there are residual masses in a subject who would otherwise be considered to have 
achieved a CR or CRu, the subject should be classified as a partial responder. 
Partial Response (PR) requires ALL of the following: 
 At least a 50% decrease in sum of the product of the diameters (SPD) of the measurable 
sites of disease.  


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 No increase should be observed in any site of disease that meet the criteria for relapsed 
or progressive disease.  
 Non-measurable nodes and nodules must regress by 50% in their SPD or, for single 
non-measurable lesions, in the greatest transverse diameter, as visually estimated. 
 Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment. However, subjects who achieve a CR by the above criteria, 
but who have persistent morphologic bone marrow involvement will be considered 
partial responders. When the bone marrow was involved before therapy and a clinical 
CR was achieved, but with no bone marrow assessment after treatment, subjects should 
be considered partial responders. 
 No new sites of disease should be observed that meet the criteria for relapsed or 
progressive disease. 
Stable disease (SD) is defined as the following: 
 A subject is considered to have SD when he or she fails to attain the criteria needed for 
a CR or PR, but does not fulfill those for progressive disease (see below). 
Progressive Disease (after PR/SD) or Relapsed Disease (after CR/CRu) 
Progressive or relapsed disease requires any one of the following: 
1. A) 50% increase from nadir in the SPD of all measurable sites of disease at the time 
that progressive or relapsed disease is identified and the absolute change in at least 1 
dimension is 0.5 cm for at least 1 lesion; or B) 50% increase in the long axis of any 
measurable site of disease at the time that progressive or relapsed disease is identified and 
the absolute change in the long axis is 0.5 cm. 
2. A) 50% increase from nadir in the SPD of all non-measurable sites of disease 
(excluding truly assessable disease), as visually estimated, and the absolute change in at 
least 1 dimension is 0.5 cm for at least 1 non-measured lesion as estimated visually; or B) 
50% increase in the long axis of any non-measurable site of disease (excluding truly 
assessable disease), and the absolute change in the long axis is 0.5 cm, as estimated 
visually. 
3. 50% increase from nadir in any truly assessable site of disease, as visually estimated.  
4. Appearance of any new lymph node site of disease that measures >1.5 cm in long axis 
and >1.0 cm in short axis, any new unequivocal extranodal site of disease (irrespective of 
size), or unequivocal evidence of a new site of assessable disease (for example effusions, 
ascites, masses with indistinct borders, new involvement of the bone marrow). 
5. Appearance of a new organ enlargement or unequivocal increase of an organ 
enlargement that was present since baseline. 


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Measurable extranodal disease should be assessed in a manner similar to that for nodal 
disease. For these recommendations, the spleen is considered nodal disease. Disease that 
is only assessable (e.g., pleural effusions, bone lesions) will be recorded as no change, 
increased, decreased, or new, unless, while an abnormality is still noted by imaging studies 
or physical examination, it is found to be histologically negative.