Clinical trial NCT01400503
Conditions: Multicentric Castleman's Disease
Keywords: Multicentric Castleman's Disease Multicentric Castleman Siltuximab Long term safety
Sponsor: Janssen Research & Development, LLC
Start date: 2011-04-01; Completion date: 2017-03-01
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the long-term safety of siltuximab in patients with multicentric Castleman's disease (MCD).

Detailed description:
This is an open-label (all people know the identity of the intervention), multicenter (study conducted in multiple sites), non-randomized (patients are not assigned by chance to treatment groups), Phase 2b study. Up to 75 patients with MCD will be eligible for the study, the majority of whom will be on active therapy with siltuximab at the time of enrollment. Patients will be either siltuximab-naive or have not progressed on siltuximab in the opinion of the investigator. Duration of disease control and survival will be assessed. Data collection for patients who discontinue treatment will be limited to survival, occurrence of malignancies, and subsequent therapies for MCD, which will be assessed twice per year until the patient has been lost to follow up or has withdrawn consent for the study, whichever occurs first. An interim analysis will be conducted (no later than 2 years after the start of enrollment) to further evaluate the benefit and safety of long-term treatment with siltuximab in patients with MCD. A data will occur at 6 years after the start of enrollment and for those patients remaining on treatment after the data cutoff, data collection will be limited to pregnancies and serious adverse events (SAEs), including information on study agent administration and concomitant medications associated with an SAE. Safety evaluations for adverse events, clinical laboratory tests, vital signs, and physical examination will be performed throughout the study. The end of study is the date of the last assessment for the last patient.

Arms: arm 1: Siltuximab 11 mg/kg, intravenous infusion, given as a 1-hour infusion every 3 weeks.
Interventions: intervention 1: Siltuximab
Intervention descriptions: intervention 1: Type=exact number, unit=mg/kg, number=11, form=intravenous solution, route=intravenous. Siltuximab given as a 1-hour infusion every 3 weeks.

Protocol documents:
Prot_000.pdf: 
1
Janssen Research & Development*
Clinical Protocol
An Open-label, Multicenter Study to Evaluate the Safety of Long-term Treatment 
with Siltuximab in Subjects with Multicentric Castleman’s Disease
Protocol CNTO328MCD2002; Phase 2
Amendment INT-4
Siltuximab (CNTO 328)
* 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; 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.
This study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER: 2010-022837-27
Issue/Report Date:
04 Apr 2014
Document No.:
EDMS-ERI-16462313
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.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
2
TABLE OF CONTENTS
LIST OF IN-TEXT TABLES AND FIGURES ........................................................................................5
PROTOCOL AMENDMENTS ...............................................................................................................6
SYNOPSIS ..........................................................................................................................................13
TIME AND EVENTS SCHEDULES.....................................................................................................15
ABBREVIATIONS...............................................................................................................................20
1
INTRODUCTION....................................................................................................................22
1.1
Background ...............................................................................................................22
1.1.1
Role of IL-6 in Castleman’s Disease.........................................................22
1.1.2
Clinical Experience With Siltuximab in Castleman’s Disease...................23
1.1.2.1
Study C0328T03 .......................................................................................23
1.1.2.2
Study CNTO328MCD2001 .......................................................................24
1.1.3
Human Pharmacokinetics in Single-Agent Studies With 
Siltuximab..................................................................................................24
1.2
Potential Risks With Siltuximab.................................................................................25
1.3
Overall Rationale for the Study .................................................................................26
2
OBJECTIVES.........................................................................................................................26
3
OVERVIEW OF STUDY DESIGN ..........................................................................................27
3.1
Study Design .............................................................................................................27
3.2
Study Design Rationale.............................................................................................27
4
STUDY POPULATION...........................................................................................................29
4.1
General Considerations.............................................................................................29
4.2
Inclusion Criteria........................................................................................................29
4.3
Exclusion Criteria.......................................................................................................30
5
TREATMENT ALLOCATION.................................................................................................30
6
DOSAGE AND ADMINISTRATION.......................................................................................30
6.1
Dose Delays and Retreatment ..................................................................................31
6.1.1
Laboratory Assessment and Dose Delays................................................31
6.2
Guidelines for Management of Infusion Reactions ...................................................31
7
TREATMENT COMPLIANCE ................................................................................................32
8
CONCOMITANT THERAPY ..................................................................................................33
8.1
Supportive Care Measures........................................................................................33
8.2
Guidelines for Corticosteroid Use..............................................................................34
8.3
Guidelines to Manage Hyperlipidemia.......................................................................34
8.4
Prohibited Therapies .................................................................................................34
9
STUDY EVALUATIONS.........................................................................................................35
9.1
Study Procedures ......................................................................................................35
9.1.1
Overview ...................................................................................................35
9.2
Safety Evaluations.....................................................................................................36
9.3
Efficacy Evaluations ..................................................................................................39
9.3.1
Disease Control.........................................................................................39
9.3.2
Laboratory Evaluations .............................................................................39
9.3.3
Survival......................................................................................................39
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
3
9.3.4
Patient-reported Outcomes.......................................................................39
9.4
Pharmacodynamic Biomarker Evaluations................................................................39
9.5
Glycoform Clearance and In Vivo Protein Degradation Analysis..............................40
9.6
Antibodies to Siltuximab ............................................................................................40
10
SUBJECT COMPLETION/WITHDRAWAL ...........................................................................40
10.1
Completion ................................................................................................................40
10.2
Discontinuation of Treatment ....................................................................................40
10.3
Withdrawal from Study ..............................................................................................41
11
STATISTICAL METHODS .....................................................................................................41
11.1
Subject Information....................................................................................................42
11.2
Sample Size Determination.......................................................................................42
11.3
Safety Analyses.........................................................................................................42
11.4
Efficacy and Patient-reported Outcomes Analyses...................................................43
11.4.1
Disease Control.........................................................................................43
11.4.2
Laboratory Evaluations .............................................................................43
11.4.3
Overall Survival.........................................................................................43
11.4.4
MCDSS Evaluations..................................................................................44
11.5
Glycoform Analysis and In Vivo Protein Degradation ...............................................44
11.6
Pharmacodynamic Biomarker Analyses....................................................................44
11.7
Interim Analysis .........................................................................................................44
12
ADVERSE EVENT REPORTING...........................................................................................44
12.1
Definitions..................................................................................................................44
12.1.1
Adverse Event Definitions and Classifications..........................................44
12.1.2
Attribution Definitions ................................................................................45
12.1.3
Severity Criteria.........................................................................................46
12.2
Procedures ................................................................................................................47
12.2.1
All Adverse Events....................................................................................47
12.2.2
Serious Adverse Events............................................................................48
12.2.3
Pregnancy .................................................................................................49
12.3
Contacting Sponsor Regarding Safety......................................................................49
13
PRODUCT QUALITY COMPLAINT HANDLING ..................................................................49
13.1
Procedures ................................................................................................................49
13.2
Contacting Sponsor Regarding Product Quality........................................................50
14
STUDY DRUG INFORMATION .............................................................................................50
14.1
Physical Description of Study Drug ...........................................................................50
14.2
Packaging..................................................................................................................50
14.3
Labeling .....................................................................................................................50
14.4
Preparation, Handling, and Storage..........................................................................50
14.5
Drug Accountability....................................................................................................51
15
STUDY-SPECIFIC MATERIALS............................................................................................51
16
ETHICAL ASPECTS ..............................................................................................................52
16.1
Study-Specific Design Considerations ......................................................................52
16.2
Regulatory Ethics Compliance ..................................................................................52
16.2.1
Investigator Responsibilities .....................................................................52
16.2.2
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB)...................................................................................................52
16.2.3
Informed Consent......................................................................................54
16.2.4
Privacy of Personal Data...........................................................................55
16.2.5
Country Selection......................................................................................55
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
4
17
ADMINISTRATIVE REQUIREMENTS...................................................................................55
17.1
Protocol Amendments ...............................................................................................55
17.2
Regulatory Documentation........................................................................................56
17.2.1
Regulatory Approval/Notification...............................................................56
17.2.2
Required Prestudy Documentation...........................................................56
17.3
Subject Identification, Enrollment, and Screening Logs............................................57
17.4
Source Documentation..............................................................................................57
17.5
Case Report Form Completion..................................................................................58
17.6
Data Quality Assurance/Quality Control....................................................................59
17.7
Record Retention.......................................................................................................59
17.8
Monitoring..................................................................................................................60
17.9
Study Completion/Termination ..................................................................................60
17.9.1
Study Completion......................................................................................60
17.9.2
Study Termination.....................................................................................60
17.10
On-Site Audits ...........................................................................................................61
17.11
Use of Information and Publication ...........................................................................61
REFERENCES ....................................................................................................................................63
ATTACHMENT 1: APPROXIMATELY EQUIVALENT DOSES OF CORTICOSTEROIDS...............65
ATTACHMENT 2: DISEASE ASSESSMENTS ..................................................................................66
ATTACHMENT 3: BLOOD VOLUMES...............................................................................................69
INVESTIGATOR AGREEMENT..........................................................................................................70
LAST PAGE ........................................................................................................................................71
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
5
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
TIME AND EVENTS SCHEDULE THROUGH AMENDMENT INT-3...............................15
Table 2:
TIME AND EVENTS SCHEDULE PER AMENDMENT INT-4..........................................18
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
6
PROTOCOL AMENDMENTS
Amendments are listed beginning with the most recent amendment.
Amendment INT-4 (04 Apr 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: To extend the duration of this study to fulfill postmarketing 
commitments to report safety, efficacy, and survival during long-term treatment with siltuximab, and to 
stop collecting data that are not required for the final study report.
Applicable Section(s)
Description of Change(s)
Rationale: To extend the duration of this study to fulfill postmarketing commitments to report safety, 
efficacy, and survival during long-term treatment with siltuximab, and to delete references to treatment 
until siltuximab is commercially available and replace it with a specified length of treatment.
Synopsis (Overview of Study Design,
Safety Evaluations);
3.1 (Study Design);
6 (Dosage and Administration);
9.6 (Antibodies to Siltuximab);
10.2 (Discontinuation of Treatment);
11.3 (Safety Analyses; Adverse Events);
11.4.3 (Overall Survival);
12.2.1 (All Adverse Events);
12.2.2 (Serious Adverse Events)
The existing data cutoff was changed from 5 years after the 
first subject is enrolled to approximately 6 years after the 
first subject is enrolled.
Subjects are not required to stop study treatment when 
siltuximab is commercially available in their region.
Synopsis (Overview of Study Design, 
Efficacy Evaluations);
3.1 (Study Design);
9.3.3 (Survival)
Follow-up assessments for survival, occurrence of 
malignancies, and subsequent therapies for MCD will only 
be collected until the 6-year data cutoff for subjects who 
discontinue study agent.
Synopsis (Overview of Study Design,
Safety Evaluations);
3.1 (Study Design);
9.2 (Safety Evaluations; Adverse Events)
12.2.1 (All Adverse Events)
For those subjects remaining on treatment after the data 
cutoff at 6 years, data collection will be limited to
pregnancies and serious adverse events (SAEs), including 
information on study agent administration and concomitant 
medications associated with an SAE.
Data collected beyond the 6-year data cutoff will be 
reported to the appropriate health authorities in safety 
update reports.
Synopsis (Efficacy Evaluations);
9.3.3 (Survival)
Survival status will not be collected twice a year for 
subjects after the data cutoff.
Protocol Version 
Issue Date
Original Protocol
04 Nov 2010
Amendment INT-1
19 Jan 2012
Amendment INT-2
14 Jun 2012
Amendment INT-3
17 Nov 2012
Amendment INT-4
04 Apr 2014
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
7
Applicable Section(s)
Description of Change(s)
Synopsis (Overview of Study Design);
3.1 (Study Design)
The end of study definition was revised.
The end of study is the date of the last assessment for the 
last subject (eg, last survival follow-up).
Rationale: To limit assessments and data collection not needed for safety monitoring, and to decrease the 
burden on the sites.
Table 2 (Time and Events Schedule per 
Amendment INT-4; new)
Limit assessments and data collection after Amendment 
INT-4 is implemented, increase the visit window for 
siltuximab administration and study procedures, and 
provide other clarifications for sites.
Throughout the protocol
Add references to the new Time and Events Schedule 
(Table 2).
Synopsis (Pharmacodynamic Biomarkers);
3.2 (Study Design Rationale, 
Pharmacodynamic Biomarker 
Assessments);
9.4 (Pharmacodynamic Biomarker 
Evaluations)
Collection of samples for biomarker assessments will be 
stopped after Amendment INT-4 is implemented.
8 (Concomitant Therapy);
9.2 (Safety Evaluations; Hematology Panel, 
Serum Chemistry Panel)
Limit the collection of concomitant medications and 
laboratory parameters.
Rationale: To add treatment criteria for hemoglobin as a safety precaution, and add information on the 
frequency of lipid panel monitoring.
6.1.1 (Laboratory Assessments and Dose 
Delays)
If hematology laboratory report indicates hemoglobin
>17 g/dL, the dose should be delayed.
Lipid panels are monitored approximately every 6 months, 
and every 3 months for siltuximab-naïve subjects.
Rationale: To update statistical information based on changes made during Amendment INT-4.
11 (Statistical Methods);
11.4.3 (Overall Survival)
Updated text is provided for statistical methods.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were 
made.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
8
Amendment INT-3 (17 Nov 2012)
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: To add additional safety evaluations for those subjects entering 
the study who are naïve to treatment with siltuximab.
Applicable Section(s)
Description of Changes
Rationale: To add additional safety evaluations for those entering the study naïve to treatment with 
siltuximab.
Synopsis;
Time and Events Schedule (new ECG row and 
footnote f); 
9.2 Safety Evaluations;
11.3 Safety Analyses
ECG performed and analyzed locally at screening 
and after 1 year of treatment, and as clinically 
indicated for all subjects.
Time and Events Schedule (hematology and 
chemistry row and footnote g revised);
6.1.1 Laboratory Assessment and Dose Delays
9.2 Safety Evaluations
Hematology and chemistry laboratory tests 
performed prior to every study treatment in the first 
year of treatment, then as specified in the Time and 
Events Schedule (per treatment regimen) thereafter.
Time and Events Schedule (lipid row revised);
9.2 Safety Evaluations
Lipid panel testing performed every 3 months in the 
first year of treatment, then every 6 months 
thereafter.
Rationale: For those subjects who discontinue treatment, the occurrence of malignancies will be collected 
to evaluate the occurrence with long-term treatment.
Synopsis;
Time and Events Schedule 
(footnote l);
3.1 Study Design;
10.2 Discontinuation of 
Treatment;
11.3 Safety Analyses
Data collection of malignancies for subjects who discontinue treatment is 
added.
Rationale: Other minor changes have been made to enhance the clarity of the protocol.
Synopsis;
3.1 Study Design;
11.2 Sample Size 
Determination
The sample size in this study is expected to be approximately 75 subjects 
instead of 100.
Synopsis;
Time and Events Schedule 
(footnote j);
9.2 Safety Evaluations
If equivalent imaging (eg, CT, MRI) is performed per routine medical 
care, it is acceptable instead of chest X-ray.
14.4 Preparation, Handling, 
Storage
A 0.2 micron inline filter is to be used (instead of 0.22 micron).
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
9
Amendment INT-2 (14 Jun 2012)
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: To add a data cutoff for an interim analysis, to add survival 
follow-up for those who discontinue treatment, to remove an exclusion criterion for those on intervening 
treatment for Castleman’s disease, and to adapt the Time and Events schedule for the 6-week dosing 
interval.
Applicable Section(s)
Description of Changes
Rationale: Interim analysis is added to allow earlier evaluation of the potential benefits and safety of long-
term treatment with siltuximab for multicentric Castleman’s disease (MCD), and the data cutoff at 4 years 
is changed to 5 years to allow sufficient follow-up time because of the later than anticipated enrollment 
completion date of subjects from study CNTO328MCD2001.
Synopsis;
Time and Events Schedule;
3.1 Study Design;
6 Dosage and Administration
8 Concomitant Therapy;
9.2 Safety Evaluations;
10.2 Discontinuation of 
Treatment;
11.3 Safety Analyses;
11.7 Interim Analysis;
12.2.1 All Adverse Events;
12.2.2 Serious Adverse 
Events
Interim analysis added (2 years after the start of enrollment) and existing 
data cutoff at 4 years changed to 5 years.
Rationale: Survival follow-up and data collection for subsequent MCD therapies are added for those 
subjects who discontinue treatment for more complete analysis of survival.
Synopsis;
Time and Events Schedule;
3.1 Study Design;
9.3.3 Survival;
10.2 Discontinuation of 
Treatment
Data collection for subjects who discontinue treatment will be limited to 
survival status and subsequent therapies for MCD, which will be assessed 
twice per year until the subject has been lost to follow-up or has 
withdrawn consent for the study, 50% of the subjects have died, or the end 
of study; whichever occurs first.
Rationale: Exclusion Criterion 3 is removed to allow enrollment of subjects who may need treatment while 
awaiting the unblinding of Study CNTO328MCD2001. Corticosteroid treatment guidelines are also 
updated to avoid a contradiction in the protocol as a result of removing this criterion.
Synopsis;
4.3 Exclusion Criteria
Criterion 3 is deleted.
8.2 Guidelines for 
Corticosteroid Use
Guidelines are updated, including additional details on corticosteroid
tapering.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
10
Applicable Section(s)
Description of Changes
Rationale: Other minor changes have been made to enhance the clarity of the protocol.
4.2 Inclusion Criteria
Corrected unit conversion in Criterion 5a:
Absolute neutrophil count (ANC) greater than or equal to 1.0 x 109/L 
(1,000500/mm3) with or without neutrophil growth factors
Criterion 7 is aligned with current protocol template wording (Criterion 
7.1 is added).
Synopsis;
Time and Events Schedule;
9.3.2 Laboratory Evaluations;
11.4.2 Laboratory 
Evaluations
Moved the assessment and analyses of ESR, CRP, and fibrinogen from 
safety evaluations (Section 9.2 and 11.3.3) to under efficacy.
Synopsis;
6 Dosage and Administration
Removed the restriction on dose delays up to Week 48, to allow more 
flexibility in long-term treatment and because almost all subjects are well 
beyond having 48 weeks of treatment at study entry.
Time and Events Schedule;
6.1 Dose Delays and 
Retreatment;
9.1.1 Overview
For subjects on the 6-week dosing regimen, laboratory assessments for 
hematology and chemistry and physical examination are aligned with 
every other treatment visit to decrease the burden and number of visits.
Synopsis;
Time and Events Schedule;
9.2 Safety Evaluations
In addition to a chest X-ray, equivalent imaging (CT, MRI) is allowed.
11.4 Efficacy and Patient-
reported Outcomes Analyses;
11.7 Interim Analysis
The Statistical Methods section for efficacy assessments (11.4) includes 
clarification of the definitions of disease control, overall survival, and 
patient-reported MCDSS. The laboratory assessments for ESR, CRP, and 
fibrinogen are added. Subheadings have been added to enhance clarity.
Also, the interim analysis at 2 years is described.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
11
Amendment INT-1 (19 Jan 2012)
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: To update the secondary objective for biomarkers, implement the 
legal entity name change, and make small corrections and clarifications.
Applicable Section(s)
Description of Change(s)
Rationale: To comply with current internal standards for the company name (new legal entity).
Title page
The company name has been changed to Janssen Research & 
Development and the sponsorship statement has been updated.
Rationale: The IL-6 posttranslational modifications (PTMs) assessments have been removed because it 
was determined that large sample volumes would be required for PTM evaluation and therefore cannot be 
evaluated with the sample volumes collected in this study. Also, assessment of IL-6 levels after treatment 
with siltuximab cannot be performed because of the unavailability of a suitable assay to measure post-
treatment IL-6 levels without drug interference. A bioassay to measure IL-6 with acceptable sensitivity and 
without serum or drug interference could not be developed.
Synopsis (Secondary Objectives, 
Pharmacodynamic Biomarkers),
2. Objectives (Secondary objectives), 
3. Overview of Study Design (3.1 Study 
Design, 3.2 Study Design Rationale, 
Pharmacodynamic Biomarker 
Assessments), 
9.4 Pharmacodynamic Biomarker 
Evaluations, 
11.6 Pharmacodynamic Biomarker 
Analyses
Assessment of IL-6 levels after siltuximab treatment and IL-6 
PTM assessments have been removed. Unusual IL-6 splice 
variants may be assessed.
Rationale: To clarify frequency of survival assessments after the 4-year data cutoff.
Synopsis (Overview of Study Design),
Time and Events Schedule (new 
footnote k), 
8 Concomitant Therapy, 
11.3 Safety Analyses (Adverse Events), 
12.2.1 Adverse Events, 
12.2.2 Serious Adverse Events
Survival assessments will occur twice per year after the 4-year 
data cutoff. Adverse event reporting through 30 days after the 
last siltuximab administration is limited to within the 4-year 
cutoff (only SAEs, concomitant medications related to SAEs, 
and pregnancies will be collected after the cutoff).
Rationale: Other changes have been made to enhance the clarity of the protocol. 
Synopsis, Dosage and Administration
6 Dosage and Administration
Up to Week 48, no more than 2 non-consecutive dose delays 
due to study agent-related toxicity are allowed. After Week 
48, documentation of dose delays is required.
Synopsis, Glycoform Clearance and In 
Vivo Protein Degradation Analysis
Time & Events Schedule, footnote d
9.5 Glycoform Clearance and In Vivo 
Protein Degradation Analysis
For glycoform clearance and in vivo protein degradation 
analysis it is clarified that blood samples will be collected 
from former study C0328T03 subjects because more limited 
sample collection is needed only from subjects who are on 
longer-term treatment.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
12
Applicable Section(s)
Description of Change(s)
4.1 General considerations
Re-testing guidance has been added.
4.2 Inclusion Criterion 7
Clarified that male subjects must also use adequate birth 
control methods.
6 Dosage and Administration
Added clarifications on adherence to study visits and on 
switching the dose schedules.
7 Treatment Compliance
Removed the requirement for IV bag weight measurement and 
added measurement of total volume given if administration 
was stopped early.
8.2 Guidelines for Corticosteroid Use
Included a crossreference to Section 8.4
8.4 Prohibited Therapies
Bullet added for other investigational agents and “systemic” 
added to other immunosuppressive therapies.
9.1.1 Overview
Change: The required assessments at every dosing visit are:
9.2 Safety Evaluations
Change: Any areas of disease involvement should be recorded 
on the disease assessment pages of the CRF. Any clinically
significant observation should be recorded on the Adverse 
Event page of the CRF.
9.4 Pharmacodynamic Biomarker 
Assessments
The CRP will be analyzed from the chemistry sample, the 
reference to the hematology sample has been removed.
10.2 Discontinuation of Treatment
Change: The subject initiated any of the prohibited 
medications requiring discontinuation of treatment (see 
Section 8.4)
10.3 Withdrawal from Study
Removed: Study drug assigned to the withdrawn subject may 
not be assigned to another subject.
11.3 Safety Analyses
Vital signs clarification: supine or standing
14.4 Preparation, Handling, and Storage
Change: The study agent is to be reconstituted as specified in 
the site investigational product manual. The reconstituted 
vials will be gently swirled to aid in complete dissolution of 
the lyophilized material.
14.5 Drug Accountability
The text regarding destruction of leftover study drug has been 
modified.
17.3 Subject Identification, Enrollment, 
and Screening Logs
Removed reference to subject initials, per current protocol 
template.
17.4 Source Documentation
Clarified that the MCDSS questionnaire will be completed on 
paper.
17.6 Data Quality Assurance/Quality
Control
Clarification: Written instructions will be provided for 
collection, preparation, and shipment of blood, plasma, and 
urineserum samples.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
13
SYNOPSIS
An Open-label, Multicenter Study to Evaluate the Safety of Long-term Treatment with Siltuximab in 
Subjects with Multicentric Castleman’s Disease
Siltuximab is a chimeric (murine-human) IgG1κ mAb that specifically binds human IL-6 with high affinity 
and prevents its interaction with the IL-6 receptor, glycoprotein (GP) 80 (Seideman and Peritt, 2002). The 
mechanism of action of siltuximab is neutralization of IL-6 bioactivity, which can be measured indirectly 
by C-reactive protein (CRP) suppression.
OBJECTIVES
Primary Objectives
The primary objective is to evaluate the long-term safety of siltuximab in subjects with multicentric 
Castleman’s disease (MCD).
Secondary Objectives

To determine the proportion of previously responding subjects who maintain disease control

To determine the proportion of siltuximab-naive subjects who experience disease control

To describe the duration of disease control and survival

To assess reliability of a multicentric Castleman’s disease symptom scale (MCDSS)

To evaluate IL-6 levels

To assess formation of antibodies to siltuximab (immunogenicity) after long-term treatment in the 
MCD population
Hypothesis: The safety of siltuximab will be acceptable for an extended treatment period. There is no 
formal hypothesis testing planned for this long-term extension study.
OVERVIEW OF STUDY DESIGN
This is an open-label, multicenter, non-randomized Phase 2 study designed to study the safety of extended 
treatment with siltuximab in subjects who were previously enrolled in sponsor-initiated studies of MCD
(C0328T03 and CNTO328MCD2001) and are either siltuximab-naive or have not progressed on siltuximab 
in the opinion of the investigator. Duration of disease control and survival will also be assessed. Up to 75
subjects will be eligible for the study, the majority of whom will be on active therapy with siltuximab at the 
time of enrollment. All subjects will be treated until they progress, withdraw, experience unacceptable 
toxicity, or until the 6-year data cutoff, whichever comes first. Subjects who discontinue study agent will 
have follow-up assessments for survival, occurrence of malignancies, and subsequent therapies for MCD
until the 6-year data cutoff. A data cutoff will occur approximately 6 years after the first subject is enrolled; 
however, continued drug supply will be ensured for study subjects who would not otherwise have access to 
siltuximab. For those subjects remaining on treatment after the data cutoff at 6 years, data collection will be 
limited to pregnancies and serious adverse events (SAEs), including information on study agent 
administration and concomitant medications associated with an SAE. Data collected beyond the 6-year data 
cutoff will be reported to the appropriate health authorities in safety update reports. The end of study is the 
date of the last assessment for the last subject.
STUDY POPULATION
The main Inclusion/Exclusion Criteria are listed below (see Sections4.2 and 4.3 for the full list).
Inclusion Criteria 
To be eligible for the study, subjects must meet all of the following criteria:
1.
Subjects must have multicentric Castleman’s disease.
2.
Subjects must have previously been enrolled in study C0328T03 or CNTO328MCD2001 (either 
treatment arm).
3.
Subjects must have had their last administration of study treatment (siltuximab or placebo) less than 6 
weeks (window of plus 2 weeks) prior to first dose. Subjects with longer treatment durations since the 
last study treatment may be allowed after discussion with the medical monitor.
4.
Subjects must not have had disease progression while receiving siltuximab. For those subjects 
originally assigned to placebo in the CNTO328MCD2001 study, subjects who have received less than 
4 months of siltuximab following crossover will also be eligible.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
14
Exclusion Criteria
1.
Unmanageable toxicity, an adverse event, progression of disease, or withdrawal of consent as reason 
for discontinuing treatment from previous sponsor-initiated siltuximab study.
2.
Vaccination with live, attenuated vaccines within 4 weeks of first dose of this study.
3.
Criterion removed per amendment INT-2 (see the protocol amendment table before the Synopsis).
4.
Known unmanageable allergies, hypersensitivity, or intolerance to monoclonal antibodies or to murine, 
chimeric, or human proteins or their excipients.
DOSAGE AND ADMINISTRATION
Siltuximab will be given as a 1 hour infusion of 11 mg/kg every 3 weeks. The treatment interval may be 
lengthened to 6 weeks at the investigator’s discretion for subjects with confirmed partial or complete 
response of more than 6 months duration. No dose modifications will be allowed. Documentation of dose 
delays, including the reason for delay, is required.
SAFETY EVALUATIONS
A chest X-ray, or equivalent imaging (ie, computed tomography [CT], magnetic resonance imaging [MRI]) 
if performed for routine medical care, is required prior to study entry. ECG and clinical laboratory tests are 
to be performed according to the Time and Events Schedules. Safety monitoring will consist of continuous 
AE reporting with a focus on infections, hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, 
infusion-related reactions, liver function, and immunogenicity. Safety reporting will be limited to 
pregnancies and SAEs, including information on study agent administration and concomitant medications 
associated with an SAE for subjects remaining on study treatment after the data cutoff at 6 years.
EFFICACY EVALUATIONS
Investigator assessment of disease control will be collected during screening, at Cycles 4, 7 and 10, every 
6 months thereafter, and at study treatment discontinuation. Laboratory assessments for erythrocyte 
sedimentation rate (ESR), CRP, and fibrinogen will also be performed at these same timepoints. For those 
who have discontinued study agent, survival status and subsequent MCD therapies will be collected until 
the subject has been lost to follow-up or has withdrawn consent for the study, or the 6-year data cutoff; 
whichever occurs first.
Patient-reported Outcomes: The MCDSS will be administered at the screening visit (the first assessment 
of the day), and predose at Cycles 1 and 2. The questionnaire will only be completed by the subpopulation 
from the C0328T03 study.
IMMUNOGENICITY EVALUATIONS 
To detect antibodies to siltuximab (immunogenicity), blood samples will be collected from all subjects in 
the study every 12 weeks during treatment, and at Week 4, Week 8, and Week 12 after the last siltuximab 
administration.
PHARMACODYNAMIC BIOMARKERS
Biomarker assessments include quantification of IL-6 levels. Exploratory evaluation of putative IL-6 splice 
variants may also be performed. Collection of samples for these assessments will be stopped after 
Amendment INT-4 is implemented.
GLYCOFORM CLEARANCE AND IN VIVO PROTEIN DEGRADATION ANALYSIS
Blood samples will be collected from former study C0328T03 subjects to study the clearance and 
degradation of siltuximab glycoforms at several timepoints during Cycle 1.
STATISTICAL METHODS
Descriptive statistics will be used to summarize data. For continuous endpoints, number of observations, 
mean, standard deviation, median, and range will be used. For discrete endpoints, frequencies and 
percentages will be summarized. No hypothesis testing will be performed.
Safety Analyses
The incidence of adverse events (including Grade 3 or higher), deaths, safety-related laboratory tests and 
antibodies to siltuximab will be summarized.
Efficacy Analyses
The proportion of previously responding subjects and siltuximab-naïve subjects who maintain disease 
control will be summarized, as will the duration of disease control and survival. In addition, the MCDSS
total score and the change from baseline in MCDSS total score will be summarized.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
15
TIME AND EVENTS SCHEDULES
Table 1: TIME AND EVENTS SCHEDULE THROUGH AMENDMENT INT-3
Procedures and Evaluations
Screening
Pre-dose 
Cycle 1
Cycle 1 Day 1, 
or as indicated
End of treatment/
Follow-Up Week 4
Follow-Up 
Week 8
Follow-Up 
Week 12
After 5-year 
data cutoff
Days
-28 to 0
1
Screening/Administrative
Informed consent
X
Inclusion/exclusion criteria
X
Medical history/demography
X
Study Drug
Administer study drug
Xa
Additional blood analyses
Blood collection: biomarkersb
X
Every 12 weeksb
X
X
X
Blood collection for antibodies 
to siltuximabc
Every 12 weeksc
X
X
X
Blood collection for 
glycoform/in vivo protein 
degradation analysisd
Xd
Cycle 1 Day 3, Week 1, 
Week 2, Week 3d
Safety Evaluations
Physical examination
X
Every 3 cycles for those 
on 3-week dosing
Every other administration 
visit at a minimum for 
those on 6-week dosing
Weight
X
X
X
X
Vital signse
X
X
ECG (12-lead)f
X
Once, after 1 year
Hematology, Chemistryg
X
X
Every cycle in 1st year for 
siltuximab-naïve subjects
Every 3 cycles for 3-week 
regimen
Every other administration 
visit at a minimum for 
those on 6-week regimen
X
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
16
Table 1: TIME AND EVENTS SCHEDULE THROUGH AMENDMENT INT-3
Procedures and Evaluations
Screening
Pre-dose 
Cycle 1
Cycle 1 Day 1, 
or as indicated
End of treatment/
Follow-Up Week 4
Follow-Up 
Week 8
Follow-Up 
Week 12
After 5-year 
data cutoff
Days
-28 to 0
1
Lipid panelh
X
Every 3 months in 1st year 
for siltuximab-naïve 
subjects
Every 6 months
X
Coagulationi
As needed
Pregnancy test
X
X
Chest X-ray (or CT/MRI)j
Xj
Annual
Efficacy Evaluations
Investigator assessmentk
X
Cycles 4, 7, 10 and every 6 
monthsk
X
ESR, CRP, and fibrinogenk
X
Cycles 4, 7, 10 and every 6 
monthsk
X
Survival, occurrence of 
malignancies, subsequent 
therapiesl
MCDSS questionnairem
X
X
Cycle 2
Ongoing Review
Adverse event monitoring
SAEs, 
pregnanciesl
Concomitant therapy
Xl
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
17
Table 1: TIME AND EVENTS SCHEDULE THROUGH AMENDMENT INT-3
Procedures and Evaluations
Screening
Pre-dose 
Cycle 1
Cycle 1 Day 1, 
or as indicated
End of treatment/
Follow-Up Week 4
Follow-Up 
Week 8
Follow-Up 
Week 12
After 5-year 
data cutoff
Days
-28 to 0
1
a.
Siltuximab should be administered after all other study assessments and evaluations required at that visit. The visit window for siltuximab administration is minus 3 
or plus 4 days from the scheduled visit date.
b.
Blood samples for biomarker testing should be collected prior to study agent administration and at the end of treatment visit. A frequency of every 12 weeks means 
every 4th cycle for those on an every 3-week administration schedule and every 2nd cycle for those on an every 6-week administration schedule.
c.
Scheduled blood samples for testing antibodies to siltuximab should be collected prior to study agent administration. Serum from venous blood samples (7.5 mL per 
sample) will be split into 3 aliquots (1 aliquot for analysis of antibodies to siltuximab, 1 aliquot for siltuximab serum concentration analysis to code antibodies to 
siltuximab data, and 1 aliquot as a backup). Serum concentration of siltuximab will also be determined at these timepoints. In addition, an unscheduled blood 
sample should be drawn, if possible, for determining antibodies to siltuximab any time an infusion-related reaction is observed during the study. This sample should 
be obtained as soon as possible after the reaction. A frequency of every 12 weeks means every 4th cycle for those on an every 3-week administration schedule and 
every 2nd cycle for those on an every 6-week administration schedule.
d.
Serum samples for glycoform clearance analysis and in vivo protein degradation will be collected from 5 former study C0328T03 subjects (administered 11 mg/kg 
every 3 weeks) who consented to have these samples collected. These samples should be collected Cycle 1 (pre- and post-dose), and at Cycle 1 Day 3, Week 1
(Day 7 +/ 1 day), Week 2 (Day 14 +/- 2 days), and Week 3 (Day 21 +/- 2 days; before the Cycle 2 dose).
e.
Vital signs will be measured predose and end of infusion on Day 1 of Cycle 1. Thereafter, vital signs will be measured only before each study agent administration 
on Day 1 of each cycle, and as clinically indicated.
f.
ECGs will only be performed for those subjects who are siltuximab naïve at study entry, and as clinically indicated for all subjects.
g.
Hematology and chemistry panel has to be performed prior to first dose to assess the subject’s eligibility. If screening takes place within 7 days prior to first dose, 
the tests are not required to be repeated pre-dose Cycle 1. Laboratory monitoring will occur prior to each infusion in the first year of treatment for those subjects that 
are siltuximab-naïve at study entry.
h.
Fasting sample is required at screening and preferred for subsequent samples. If lipid panel is abnormal, amylase and lipase may be assessed as clinically indicated.
i.
Coagulation parameters should only be evaluated if clinically indicated.
j.
If last chest X-ray was performed within 3 months prior to first dose, results can be used for the screening timepoint. If equivalent imaging (ie, CT, MRI) was 
performed for routine medical care at the timepoint, it is allowed instead of chest X-ray.
k.
If considered to be clinically indicated, investigator assessment along with ESR, CRP, and fibrinogen evaluations, should be performed more frequently. 
Quantitative immunoglobulins should be performed if clinically indicated. Subjects who demonstrate disease progression on an once every 6 weeks dosing schedule 
(see Section 6.1) have to return to the every 3 weeks dosing schedule after reassessment of hematology and chemistry lab panels, physical exam, and, if not done 
within last 6 weeks, also a reassessment of investigator assessment of disease control and ESR, CRP, and fibrinogen.
l.
Survival status after 5-year data cutoff will be collected twice a year for subjects still on treatment provided by Sponsor. For these subjects, SAEs, concomitant
medications involved in treatment of SAEs, and information on pregnancies will continue to be collected. After treatment discontinuation, survival status, 
occurrence of malignancies, and subsequent therapies for MCD will be collected twice per year.
m.
Only for subjects from the C0328T03 study; to be performed at the start of the screening visit, and predose at Cycles 1 and 2 (before other procedures).
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
18
Table 2: TIME AND EVENTS SCHEDULE PER AMENDMENT INT-4
Procedures and Evaluations
Screening
Pre-dose 
Cycle 1
Cycle 1 Day 1, 
or as indicated
End of treatment/
Follow-Up Week 4
Follow-Up 
Week 8
Follow-Up 
Week 12
Until 6-year 
data cutoff
Days
-28 to 0
1
Screening/Administrative
Informed consent
X
Inclusion/exclusion criteria
X
Medical history/demography
X
Study Drug
Administer study drug
Xa
Additional blood analyses
Blood collection for antibodies 
to siltuximabb
Every 12 weeksb
X
X
X
Safety Evaluations
Physical examination
X
Every 3 cycles for those 
on 3-week dosing
Every other administration 
visit at a minimum for 
those on 6-week dosing
Weight
X
X
X
X
Vital signsc
X
X
ECG (12-lead)d
X
Once, after 1 year
Hematology, Chemistrye
X
X
Every cycle in 1st year for 
siltuximab-naïve subjects
Every 3 cycles for 3-week 
regimen
Every other administration 
visit at a minimum for 
those on 6-week regimen
X
Lipid panelf
X
Every 3 months in 1st year 
for siltuximab-naïve 
subjects
Every 6 months
X
Coagulationg
As needed
Pregnancy test
X
X
Chest X-ray (or CT/MRI)h
Xh
Annual
Efficacy Evaluations
Investigator assessmenti
X
Cycles 4, 7, 10 and every 6 
monthsi
X
ESR, CRP, and fibrinogeni
X
Cycles 4, 7, 10 and every 6 
monthsi
X
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
19
Table 2: TIME AND EVENTS SCHEDULE PER AMENDMENT INT-4
Procedures and Evaluations
Screening
Pre-dose 
Cycle 1
Cycle 1 Day 1, 
or as indicated
End of treatment/
Follow-Up Week 4
Follow-Up 
Week 8
Follow-Up 
Week 12
Until 6-year 
data cutoff
Days
-28 to 0
1
Ongoing Review
Survival, occurrence of 
malignancies, subsequent 
therapiesj
Adverse event monitoring
SAEs, 
pregnanciesj
Concomitant therapy
Xj
a.
Siltuximab should be administered after all other study assessments and evaluations required at that visit. The visit window for siltuximab administration and study 
procedures is +/- 7 days from the scheduled visit date, calculated from the last actual visit date.
b.
Scheduled blood samples for testing antibodies to siltuximab should be collected prior to study agent administration. Serum from venous blood samples (7.5 mL per 
sample) will be split into 3 aliquots (1 aliquot for analysis of antibodies to siltuximab, 1 aliquot for siltuximab serum concentration analysis to code antibodies to
siltuximab data, and 1 aliquot as a backup; all samples must be sent to the central laboratory vendor after they are collected). Serum concentration of siltuximab will 
also be determined at these timepoints. In addition, an unscheduled blood sample should be drawn, if possible, for determining antibodies to siltuximab any time an 
infusion-related reaction is observed during the study. This sample should be obtained as soon as possible after the reaction. A frequency of every 12 weeks means 
every 4th cycle for those on an every 3-week administration schedule and every 2nd cycle for those on an every 6-week administration schedule.
c.
Vital signs will be measured predose and end of infusion on Day 1 of Cycle 1. Thereafter, vital signs will be measured only before each study agent administration 
on Day 1 of each cycle, and as clinically indicated.
d.
ECGs will only be performed for those subjects who are siltuximab naïve at study entry, and as clinically indicated for all subjects.
e.
Hematology (hemoglobin, platelets, WBC, ANC, lymphocytes) and chemistry panel (ALT, AST, total bilirubin, alkaline phosphatase, creatinine [or BUN], 
albumin) has to be performed prior to first dose to assess the subject’s eligibility. If screening takes place within 7 days prior to first dose, the tests are not required 
to be repeated pre-dose Cycle 1. Laboratory monitoring will occur prior to each infusion in the first year of treatment for those subjects that are siltuximab-naïve at 
study entry.
f.
Fasting sample is required at screening and preferred for subsequent samples. If lipid panel is abnormal, amylase and lipase may be assessed as clinically indicated. 
g.
Coagulation parameters should only be evaluated if clinically indicated.
h.
If last chest X-ray was performed within 3 months prior to first dose, results can be used for the screening timepoint. If equivalent imaging (ie, CT, MRI) was 
performed for routine medical care at the timepoint, it is allowed instead of chest X-ray.
i.
If considered to be clinically indicated, investigator assessment along with ESR, CRP, and fibrinogen evaluations, should be performed more frequently. 
Quantitative immunoglobulins should be performed if clinically indicated. Subjects who demonstrate disease progression on an once every 6 weeks dosing schedule 
(see Section 6.1) have to return to the every 3 weeks dosing schedule after reassessment of hematology and chemistry lab panels, physical exam, and, if not done 
within last 6 weeks, also a reassessment of investigator assessment of disease control and ESR, CRP, and fibrinogen.
j.
After study agent discontinuation, survival status, occurrence of malignancies, and subsequent therapies for MCD will be collected twice per year until the 6-year 
data cutoff. For subjects still on treatment provided by Sponsor after the 6-year data cutoff, pregnancies and SAEs, including information on study agent 
administration and concomitant medications associated with an SAE, will continue to be collected.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
20
ABBREVIATIONS
AE
adverse event
ALT/SGPT
alanine aminotransferase/serum glutamate pyruvate transaminase
ANC
absolute neutrophil count
AST/SGOT
aspartate aminotransferase/serum glutamic oxaloacetic transaminase
AUC
area under the curve
BP
blood pressure
BSC
best supportive care
CDM
clinical data manager
CHO
Chinese hamster ovary
CR
complete response
CRF
case report form
CRP
C-reactive protein
CT
computed tomography
DCF
data clarification form
DLT
dose-limiting toxicity
eDC
Electronic Data Capture
ESA
erythropoiesis-stimulating agents
ESR
erythrocyte sedimentation rate
FDA
Food and Drug Administration
GCP
Good Clinical Practices
GI
gastrointestinal
GMR
geometric means
GP
glycoprotein
HDL
high-density lipoprotein
HIV
human immunodeficiency virus
HR
heart rate
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgA
immunoglobulin A
IgG
immunoglobulin gamma
IgG1κ
immunoglobulin gamma 1 kappa
IgM
immunoglobulin M
IL
Interleukin
IRB
Institutional Review Board
IV
intravenous
LC
liquid chromatography
LDL
low density lipoprotein
LOQ
limit of quantification
mAb
monoclonal antibody
MCD
multicentric Castleman’s disease
MCDSS
Multicentric Castleman’s Disease Symptom Scale
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MS
mass spectroscopy
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
POEMS
Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin 
changes syndrome
PQC
product quality complaint
PR
partial response
PRO
Patient-reported outcomes
RBC
red blood cell (count)
SAE
serious adverse event
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
21
SM
site manager
SOC
system-organ class
SOP
Standard Operating Procedure
TNFα
tumor necrosis factor alpha
ULN
upper limit of normal
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
22
1
INTRODUCTION
Siltuximab is a chimeric (murine-human) IgG1κ mAb that specifically binds human IL-6 
with high affinity and prevents its interaction with the IL-6 receptor, glycoprotein 
(GP) 80 (Seideman and Peritt, 2002). The chimeric antibody contains the variable region 
of a murine anti-human IL-6 mAb and the constant region from a human 
immunoglobulin gamma (IgG) 1 molecule. The mechanism of action of siltuximab is 
neutralization of IL-6 bioactivity, which can be measured indirectly by C-reactive protein 
(CRP) suppression. 
For the most comprehensive nonclinical and clinical information regarding the efficacy 
and safety of siltuximab, refer to the latest version of the Investigator's Brochure.
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
Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disease first 
described by Castleman and Towne, 1954, that is characterized by systemic 
manifestations such as fever, night sweats, fatigue, anorexia, and wasting, particularly in 
patients with the plasma cell or mixed-type variants of the disease. Clinical 
manifestations may vary, and hepatosplenomegaly, lymph node enlargement, and 
multiple 
laboratory 
abnormalities 
(eg, 
anemia, 
hypoalbuminemia, 
and 
hypocholesterolemia) are also common (Nishimoto et al, 2005; Casper, 2005; Dham and 
Peterson, 2007). Other symptoms include fluid retention; neuropathy; skin abnormalities; 
and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin 
changes (POEMS) syndrome. MCD can occur in individuals who are infected with HIV 
as well as in those not infected with HIV, and with similar symptoms. Treatment goals 
include alleviation of debilitating symptoms that contribute to shortened survival, and 
reduction of tumor masses. Unlike the unicentric variant of the disease that responds well 
to surgical resection of affected lymph nodes, or HIV-associated MCD that may respond 
to antiviral therapy, interferon, or rituximab, there is no established treatment for MCD. 
In particular, no treatment consistently results in a meaningful or lasting reduction in 
tumor burden. Consequently, median survival is short (14 to 30 months; Casper, 2005). 
Patients with MCD are usually managed by treatment of symptoms, with only modest 
success being reported; therefore, there is an unmet medical need for effective treatment 
in MCD.
1.1.1
Role of IL-6 in Castleman’s Disease
IL-6 is a 22 to 27 Kd secreted GP that is known for its pleiotropic and proinflammatory 
functions (Kishimoto, 1989; Hirano et al, 1994). Experience with a human 
IL-6 transgenic murine model clearly supports a pivotal role for IL-6 in the etiology of 
Castleman's disease (Katsume et al, 1997). These mice overexpress human IL-6, and 
develop a Castleman’s disease-like disorder. Continuous treatment of these mice with 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
23
antibodies against the IL-6 receptor significantly reduced or prevented all pathologies 
examined, confirming the role of IL-6 in the etiology of Castleman’s disease (Katsume et 
al, 2002). The humanized anti-IL-6 receptor mAb, tocilizumab (Actemra), is approved 
in Japan for its demonstrated benefit in improving symptoms and laboratory findings 
associated with Castleman’s disease, although the impact on tumor burden was not 
formally studied.
1.1.2
Clinical Experience With Siltuximab in Castleman’s Disease
1.1.2.1
Study C0328T03
This ongoing Phase 1 dose-finding study in subjects with multiple myeloma, B-cell
non-Hodgkin’s lymphoma, and Castleman’s disease (multicentric or unresectable 
localized disease), has a primary objective of assessing the safety and pharmacokinetics 
of multiple siltuximab dosing regimens (3 mg/kg to 12 mg/kg dose levels).
In Study C0328T03, 12 (52%) Castleman’s disease subjects demonstrated objective 
tumor response (van Rhee et al, 2010). Duration of overall objective response ranged 
from 44 to ≥ 889 days, and 1 subject had a complete response (CR) for ≥ 318 days. 
Responses were confirmed by independent radiologic review.
A high frequency of clinical benefit response was observed (100% [11/11]; 95% CI 
72%-100% of subjects treated at the target dose of 12 mg/kg (corresponding to 11 mg/kg 
using the current absorptivity constant – see Section 3.2), and 78% [18/23]; 95% CI 
56%-93% at all doses studied) (van Rhee et al, 2010). Clinical benefit response was 
defined as improvement in at least 1 of the following, with all other measures stable or 
better: hemoglobin, fatigue, anorexia, fever/night sweats, weight, or size of largest lymph 
node. Nineteen of 23 subjects (83%) had at least 1 g/dL improvement in hemoglobin 
(median increase 2.1 g/dL; range: 0.2 to 7.2 g/dL) in the absence of transfusion or 
erythropoiesis-stimulating agents (ESAs). Among the 15 evaluable subjects, serum 
hepcidin, a biomarker for IL-6 activity, decreased from elevated baseline levels within a 
short time after siltuximab treatment in 14 subjects (93%). All 6 subjects who required 
corticosteroids for symptom control at study entry were weaned off corticosteroid 
dependence. In addition, complete and sustained suppression of CRP, a surrogate for IL-6 
activity, was observed in 78% of subjects who had at least 1 postbaseline value, despite 
the presence of markedly elevated baseline CRP levels in the study population (median 
23.4 mg/L [range 1 to 260 mg/L]).
Prolonged exposure at siltuximab dose levels ranging from 3 to 12 mg/kg was observed
in this study, with no dose-limiting toxicity (DLT) observed after a median exposure of 
331 days (range up to 1148 days). Three (3) subjects had Grade 3 or higher AEs (nausea, 
upper respiratory tract infection, vomiting, hypertriglyceridemia, and hypertension), 
which were considered unrelated to treatment with siltuximab by the study investigators. 
Serious adverse events (SAEs) were reported in 6 of 23 subjects, and none were 
attributable to siltuximab. Mild infusion reactions (eg, light-headedness, flushing, 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
24
hypertension, hives) were observed in 3 subjects, but siltuximab was not discontinued 
due to these events. No treatment-related deaths have been reported.
1.1.2.2
Study CNTO328MCD2001
This is a randomized, double-blind, placebo-controlled, multicenter study to determine 
the safety and efficacy of siltuximab plus best supportive care (BSC) compared with 
BSC, in subjects with symptomatic MCD. Approximately 78 subjects will be randomly 
assigned in a 1:2 ratio to placebo plus BSC or to siltuximab plus BSC. The study will be 
conducted in a blinded manner with independent, centrally confirmed assessment of the 
diagnosis and radiographic assessment of tumor response. An Independent Data 
Monitoring Committee (IDMC) will be commissioned for this study. 
Subjects are required to have measurable disease, which may not be limited to cutaneous 
lesions and will receive siltuximab (11 mg/kg) or placebo by a 1-hour IV infusion every 
3 weeks. Results were not available for this study at the time of protocol development.
1.1.3
Human Pharmacokinetics in Single-Agent Studies With Siltuximab
Pharmacokinetic results from Study C0328T01, a completed 3-part Phase 1/2 clinical 
study to evaluate the safety and efficacy of siltuximab in subjects with metastatic renal 
cell carcinoma at dose levels of 1, 3, 6, and 12 mg/kg, indicated that systemic exposure in 
terms of Cmax and partial AUC of siltuximab increased in an approximately dose-
proportional manner. The mean t1/2 values for the 3 parts of the study ranged from 
17.3 to 22.9 days. In addition, there were no apparent time-dependent changes in the 
pharmacokinetics of siltuximab. Across the dose levels of 3 mg/kg to 12 mg/kg from all 
3 parts of the study, the mean coefficient of variation percentage ranged from 34.0% to 
37.8% for Cmax and from 21.7% to 35.1% for AUC(0-14d).
Preliminary pharmacokinetic analysis has also been performed on the available serum 
concentration-time data for siltuximab in Study C0328T03. Results indicate that the 
serum concentrations of siltuximab decreased bi-exponentially over 14- or 21-day 
periods, depending on the dose interval. The terminal t1/2 for the 12 mg/kg dose every 
3 weeks cohort was approximately 18 days. The exposure to siltuximab in terms of Cmax 
and AUC (0-14d) obtained after the first dose appeared to increase in an approximately 
dose-proportional manner over doses ranging from 3 mg/kg every 2 weeks to 12 mg/kg 
every 2 weeks or every 3 weeks. No apparent differences in the pharmacokinetics were 
observed when comparing subjects with non-Hodgkin’s lymphoma, multiple myeloma, 
and Castleman’s disease.
The effect of changing the manufacturing process was examined in a randomized Phase 1
safety and pharmacokinetic comparability study of Sp2/0-derived and Chinese Hamster 
Ovary (CHO-derived)
siltuximab in healthy subjects
(Study C0328T08). The 
pharmacokinetic parameters of Cmax and AUC(0-84d) after a single dose of 1.4 mg/kg 
siltuximab were compared in this study. The study was designed to conclude 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
25
pharmacokinetic comparability of the Cmax and AUC(0-84d) if the 90% confidence 
interval for the ratios of the geometric means (GMR) for AUC(0-84d) and Cmax both fall 
within the prespecified range of 80% to 125%.
The Cmax was evaluable in 67 subjects for the CHO-derived siltuximab and 63 subjects 
for the Sp2/0-derived siltuximab. The GMR 90% CI for Cmax of 99.4 to 111.3% is 
within the prespecified range of 80 to 125%. The AUC(0-84d) was evaluable in 
64 subjects for the CHO-derived siltuximab and 56 subjects for the Sp2/0-derived 
siltuximab. The GMR 90% CI for AUC(0-84d) of 98.1 to 109.6% is within the 
prespecified range of 80 to 125%. Therefore, pharmacokinetic comparability of 
CHO-derived siltuximab and Sp2/0-derived siltuximab was demonstrated.
1.2
Potential Risks With Siltuximab
Because siltuximab is still in clinical development, its safety profile is not yet fully 
understood. Further investigation is necessary to better understand the safety of 
siltuximab. Therefore, unanticipated side effects that have not been previously observed 
may occur. Refer to the latest version of the siltuximab Investigator’s Brochure for 
information regarding the safety of siltuximab.
A brief overview of the potential risks associated with the administration of siltuximab is 
outlined.

Hypertriglyceridemia has been observed in some subjects who were administered 
siltuximab, and has been seen with other agents targeting the IL-6 receptor.

Serious infections in single-agent studies have been reported in subjects administered 
agents that target IL-6 or its receptor. IL-6 directed therapy may have potential 
effects on humoral immunity. In addition, siltuximab may also potentially mask 
fever and other laboratory markers indicative of acute inflammation (eg, CRP). 
Therefore, subjects should be actively monitored for potential infection even in the 
absence of fever. Siltuximab should not be administered when there is evidence of 
serious active infection.

Although unlikely, serious infusion related reactions (eg, anaphylaxis) may occur at 
any time during the administration of mAbs, including siltuximab.

Administration of siltuximab may result in the development of antibodies against the 
protein. The risks of an anamnestic response to siltuximab are unknown.

Gastrointestinal perforation has been reported in siltuximab clinical studies; 
however, these events are confounded by additional risk factors, including 
malignancy, abdominal surgery, and recent treatment with bevacizumab.

Live, attenuated vaccines should not be given concurrently or within 4 weeks of 
initiating siltuximab, because clinical safety has not been established.

IL-6 may serve as a growth factor for the bone marrow. Blocking IL-6 may therefore 
lead to decreases in neutrophils and platelets.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
26

Drug interactions: In nonclinical studies, IL-6 has been shown to decrease the 
activity of cytochrome P450 (CYP450; Jover et al, 2002). In addition, nonclinical 
and clinical data have shown that biologic agents that inhibit IL-6 activity have the 
potential to affect CYP450 enzyme activity (Fujita et al, 2008; Zhang et al, 2009). 
This may result in increased metabolism of CYP450 substrates, because CYP450 
enzyme activity will normalize to baseline activity. Therefore, administering 
siltuximab with CYP450 substrates that have a narrow therapeutic index has the 
potential to change drug therapeutic effects and toxicity due to alterations in the 
CYP450 pathways. Upon initiation or discontinuation of siltuximab in subjects being 
treated with concomitant medications that are CYP450 substrates and have a narrow 
therapeutic index, monitoring of the effect (eg, warfarin) or drug concentration (eg, 
cyclosporine or theophylline) is recommended, and the individual dose of the 
concomitant medication may be adjusted as needed.
1.3
Overall Rationale for the Study
Multicentric Castleman’s disease has an unmet medical need for effective treatment. The 
overall purpose of this study is to evaluate the long-term safety and disease control of 
siltuximab in subjects with MCD who have been enrolled in other studies (C0328T03 and 
CNTO328MCD2001) conducted by the Sponsor. 
2
OBJECTIVES
Primary Objective(s)
The primary objective is to evaluate the long-term safety of siltuximab in subjects with 
MCD.
Secondary Objective(s)
The secondary objectives are:

To determine the proportion of previously responding subjects who maintain disease 
control

To determine the proportion of siltuximab-naive subjects who experience disease 
control

To describe the duration of disease control and survival

To assess reliability of a multicentric Castleman’s disease symptom scale (MCDSS)

To evaluate IL-6 levels

To assess formation of antibodies to siltuximab (immunogenicity) after long-term 
treatment in the MCD population
In addition, glycoform clearance analysis and in vivo protein degradation of siltuximab
will also be assessed (see Section 9.5). 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
27
Hypothesis: The safety of siltuximab will be acceptable for an extended treatment 
period. There is no formal hypothesis testing planned for this long-term extension study.
3
OVERVIEW OF STUDY DESIGN
3.1
Study Design
This is an open-label, multicenter, non-randomized Phase 2 study of the safety of 
extended treatment with siltuximab in subjects who were previously enrolled in 
siltuximab studies of MCD (C0328T03 and CNTO328MCD2001). Up to 75 subjects will 
be eligible for the study, the majority of whom will be on active therapy with siltuximab 
at the time of enrollment. Duration of disease control and survival will also be assessed. 
Other secondary objectives include quantification of IL-6 (see Section 9.4) and 
assessment of the reliability of the MCDSS (see Section 9.3.4).
Subjects must be either siltuximab-naive or have not progressed on siltuximab in the 
opinion of the investigator. All subjects will be treated until they progress, withdraw, 
experience unacceptable toxicity, or until the 6-year data cutoff, whichever comes first.
Two data cutoffs will occur:

No later than 2 years after the start of enrollment, an interim analysis will be 
conducted to further evaluate the benefit and safety of long-term treatment with 
siltuximab in subjects with MCD.

Approximately 6 years after start of enrollment; however, continued drug supply will 
be ensured for study subjects who would not otherwise have access to siltuximab. A 
clinical study report (CSR) will be written based on this data cutoff.
Data collection for subjects who discontinue study agent will be limited to survival status, 
occurrence of malignancies, and subsequent therapies for MCD, which will be assessed 
twice per year until the subject has been lost to follow-up or has withdrawn consent for 
the study, or the 6-year data cutoff; whichever occurs first. For subjects still on treatment 
provided by Sponsor after the 6-year data cutoff, pregnancies and SAEs, including 
information on study agent administration and concomitant medications associated with 
an SAE, will continue to be collected. Data collected beyond the 6-year data cutoff will 
be reported to the appropriate health authorities in safety update reports. The end of study 
is the date of the last assessment for the last subject.
3.2
Study Design Rationale
This study is designed to evaluate the long-term safety and disease control in MCD
subjects. Because siltuximab is an investigational agent, further evaluation is necessary to 
better understand the long-term safety of siltuximab in this population. Focused safety 
monitoring will be performed for key safety events of interest (see the current 
Investigator’s 
Brochure), 
including 
infections, 
hyperlipidemia, 
neutropenia, 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
28
thrombocytopenia, 
GI 
perforations, 
infusion-related 
reactions, 
liver 
enzyme 
abnormalities, and immunogenicity.
Dose Justification
The dose of siltuximab for this study is 11 mg/kg administered every 3 weeks by a 1-hour 
IV infusion. This corresponds to the 12 mg/kg dose used in C0328T03 when the current 
absorptivity constant is applied (see Section 4.2.1 of the Investigator Brochure). In the 
C0328T03 study, a dose response in MCD was seen, and was not associated with dose-
related toxicity (van Rhee et al, 2010). Preliminary pharmacokinetic/pharmacodynamic 
modeling data is also supportive, because suppression of CRP to below the (LOQ; ie, 
1 mg/L using high-sensitivity methods) throughout the treatment period does not occur 
with lower doses that have been tested (Puchalski et al, 2010; data on file).
Patient-reported Outcomes
The MCDSS will be assessed only in the subjects previously treated in the C0328T03
study, to provide an independent assessment of the scale designed for the 
CNTO328MCD2001 study (Vernon et al, 2009). The scale, developed based on results of 
qualitative research with MCD patients and clinical experts, was subsequently field tested 
with additional MCD patients. Symptom presence/absence and severity are noted on an 
anchor-based numeric scale. Frequency of occurrence can be generated when the 
instrument is used as a daily record of symptoms, as the recall period is 24 hours. 
Completion time is approximately 5 minutes. A summary score is generated based on the 
scores of 0 (very mild) to 5 (very severe). See Section 9.3.4 for additional information.
Pharmacodynamic Biomarker Assessments
In order to gain further insight into the role of IL-6 in MCD, quantification of IL-6 will 
be performed and assessment of unusual IL-6 splice variants may also be performed to 
determine their role in MCD manifestation and response to treatment. The information 
from these evaluations may contribute to understanding IL-6 biology and siltuximab 
efficacy in MCD and in predicting or explaining treatment resistance over time. 
Collection of samples for these assessments will be stopped after Amendment INT-4 is 
implemented. Assessments are described in Section 9.4 and the planned analyses are 
described in Section 11.6.
Immunogenicity Assessment
An immunogenic response to siltuximab is possible; therefore, samples to determine the 
presence of antibodies to siltuximab are planned to be collected from all subjects in the 
study. The information from these samples and data from other studies will be used to 
determine the immunogenicity of siltuximab in this population. Assessments are 
described in Section 9.6.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
29
Glycoform Clearance Analysis and In Vivo Protein Degradation
Blood samples will be collected from subjects to study the clearance and degradation of 
siltuximab glycoforms at several timepoints during Cycle 1 (see Section 9.5). Siltuximab 
contains several different chemical structures due to small differences in glycosylation. 
Serum collected from these blood samples will be analyzed to determine if there are 
differences in the clearance of the different glycoforms which could impact clinical 
efficacy. Changes in the chemical structure of siltuximab will also be monitored after 
product administration to determine the circulating levels of different protein degradants. 
Together, this information will be used to refine acceptance specifications for product 
release and stability.
4
STUDY POPULATION
4.1
General Considerations
The inclusion and exclusion criteria for enrolling subjects in this study are described in 
the following sections. No deviations from these criteria are allowed. NOTE:
Investigators must ensure that all inclusion and exclusion criteria have been met at 
screening. Re-screening of screening failures is allowed. A subject is considered eligible 
if the last observation prior to the first dose meets the inclusion and exclusion criteria. 
4.2
Inclusion Criteria
Potential subjects must satisfy all of the following criteria to be enrolled in the study:
1.
Subjects must have multicentric Castleman’s disease.
2.
Subjects 
must 
have 
previously 
been 
enrolled 
in 
study 
C0328T03 
or 
CNTO328MCD2001 (either treatment arm).
3.
Subjects must have had their last administration of study treatment (siltuximab or 
placebo) less than 6 weeks (window of plus 2 weeks) prior to first dose. Subjects 
with longer treatment durations since the last study treatment may be allowed after 
discussion with the medical monitor.
4.
Subjects must not have had disease progression while receiving siltuximab. For those 
subjects originally assigned to placebo in the CNTO328MCD2001 study, subjects 
who have received less than 4 months of siltuximab following crossover will also be 
eligible.
5.
Adequate clinical laboratory parameters within 2 weeks prior to the first dose of 
siltuximab for this protocol: 
a.
Absolute neutrophil count (ANC) greater than or equal to 1.0 x 109/L 
(1,000/mm3) with or without neutrophil growth factors
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
30
b.
Platelets greater than or equal to 50 x 109/L (50,000/mm3) with or without 
platelet transfusion, thrombopoietic cytokines, or both
c.
AST, ALT, total bilirubin and alkaline phosphatase must be within 2.5 x ULN; 
if alkaline phosphatase is above that, at least alkaline phosphatase liver fraction 
has to be less than or equal to 2.5 x ULN
6.
Any other clinical significant toxicity must be less or equal to Grade 2 or the baseline 
value of the previous study.
7.1 Women of childbearing potential must agree to use adequate birth control measures 
during the study and for 3 months after receiving the last dose of study agent, and
must have a negative pregnancy test (serum or urine beta-human chorionic 
gonadotropin [-HCG]) at screening. Men must agree to use a double barrier method 
of birth control and to not donate sperm during the study and for 3 months after 
receiving the last dose of study agent.
8.
Sign 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.
4.3
Exclusion Criteria
Potential subjects who meet any of the following criteria will be excluded from 
participating in the study:
1.
Unmanageable toxicity, an adverse event, progression of disease, or withdrawal of 
consent as reason for discontinuing treatment from previous sponsor-initiated 
siltuximab study.
2.
Vaccination with live, attenuated vaccines within 4 weeks of first dose of this study.
3.
Criterion removed per amendment INT-2 (see protocol amendment table before 
Synopsis).
4.
Known unmanageable allergies, hypersensitivity, or intolerance to monoclonal 
antibodies or to murine, chimeric, or human proteins or their excipients.
5
TREATMENT ALLOCATION
This study is an open-label, single-arm study. 
6
DOSAGE AND ADMINISTRATION
Siltuximab will be given as a 1-hour infusion at 11 mg/kg every 3 weeks. All subjects 
will be treated until they progress, withdraw, experience unacceptable toxicity, or until
the 6-year data cutoff, whichever comes first. A data cutoff will occur approximately 6 
years after the start of enrollment; however, continued drug supply will be ensured for 
study subjects who would not otherwise have access to siltuximab.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
31
Subjects with confirmed partial or complete remission, defined as a documented 
radiographic response, for more than 6 months (including those entering the study in PR 
or CR) may be dosed every 6 weeks at the investigator’s discretion. Demonstration of 
radiographic response is not required for subjects with skin-only disease with confirmed 
PR/CR for more than 6 months. Subjects on the 6-week schedule should be monitored for 
safety and disease assessment evaluations as per protocol Time & Events Schedules (see
Table 1 and Table 2). When disease progression is suspected, all screening and pre-dose 
Cycle 1 evaluations should be repeated and treatment with siltuximab could continue at 
11 mg/kg siltuximab every 3 weeks. The effective switch from the 3-week dosing 
schedule to the 6-week schedule can only occur on odd-numbered cycle visits to match 
the collection timepoints of biomarkers and immunogenicity samples of every 12 weeks, 
and has to occur on dosing days. Switching back to a 3-week schedule upon suspected 
disease progression can occur at any cycle visit.
During the study, no dose modifications of siltuximab will be allowed. Dose delays of up 
to 3 weeks will be allowed for treatment-related toxicity. Documentation of dose delays, 
including the reasons for the delay, is required.
6.1
Dose Delays and Retreatment
The dose should be delayed if the subject has an active infection that qualifies for a 
Grade 3 or 4 NCI-CTCAE toxicity, or that is otherwise considered clinically significant 
by the investigator.
6.1.1
Laboratory Assessment and Dose Delays
Chemistry and hematology laboratory tests are performed every 3 administration visits 
for subjects on the 3-week dosing schedule and on siltuximab at study entry. If the dosing 
schedule exceeds the 3-week interval (eg, every 6 weeks), these laboratory assessments 
should be performed every other administration visit at a minimum, to ensure proper 
safety evaluation. For subjects who are naïve to siltuximab at study entry, chemistry and 
hematology laboratory tests are performed at every administration visit for the first year 
on study. Lipid panels are monitored approximately every 6 months, and every 3 months 
for siltuximab-naïve subjects.
The siltuximab dose must be delayed if the hemoglobin value measured predose is 
≥17 g/dL, as a safety precaution to avoid clinical consequences of polycythemia.
More frequent laboratory assessment as described above is not required; however, the 
investigator should consider delaying treatment when laboratory values do not meet those 
required for inclusion in the study.
6.2
Guidelines for Management of Infusion Reactions
Although unlikely, serious allergic reactions (including anaphylaxis) may occur at any 
time during the administration of monoclonal antibodies, including siltuximab. Therefore, 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
32
before any administration is started, the appropriate personnel, medication (adrenaline, 
inhaled beta agonists, antihistamines, and possibly corticosteroids) and other 
requirements to treat anaphylaxis must be available.
A physician must also be immediately available at the site at all times during the 
administration of study agents. The Medical Monitor must be notified within 24 hours of 
any infusion reaction requiring interruption of study agent (see Contact Information 
pages provided separately). Subjects experiencing a reaction during the administration of 
study agent should be treated according to institutional guidelines.
All subjects should be observed carefully for infusion-site reactions (eg, erythema or 
induration), symptoms of an allergic reaction/hypersensitivity (eg, urticaria, itching, 
hives), or cytokine release syndrome/acute infusion reaction. Any adverse reaction should 
be noted on the AE page of the CRF. The infusion rate may be lowered if clinically 
indicated.
Infusion must be stopped immediately and permanently discontinued if:

Grade 3 allergic reaction/hypersensitivity (including drug fever) occurs

Grade 3 cytokine release syndrome/acute infusion reaction occurs
Subjects with reactions, during or after an infusion, resulting in bronchospasm with 
wheezing, dyspnea requiring ventilatory support, or symptomatic hypotension with a 
decrease in systolic blood pressure greater than 40 mm Hg will not be permitted to 
receive any additional study agent for the remainder of the study. If the infusion reaction 
results in treatment discontinuation, subjects should undergo all scheduled study 
evaluations.
Corticosteroid use for allergic reactions to siltuximab should be limited to 2 doses of 
100 mg hydrocortisone or equivalent (see Attachment 1), in addition to standard 
treatment with antihistamines and acetaminophen (see Section 8.2).
A blood sample should be obtained, if possible, for determining antibodies to siltuximab
any time an infusion reaction is observed or reported during the study. Siltuximab serum 
concentration will also be determined from the sample for the purpose of interpreting 
data on antibodies to siltuximab. These samples will be stored, and evaluated if deemed 
necessary.
7
TREATMENT COMPLIANCE
Study drug will be administered as an IV infusion by qualified staff and the details of 
each administration will be recorded in the CRF (including date, start and stop times of 
the IV infusion, total volume given if administration was stopped early).
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
33
8
CONCOMITANT THERAPY
Prestudy therapies administered up to 30 days before first dose of study drug in this study 
must be recorded at screening. Concomitant medications must be recorded throughout the 
study beginning when the first dose of study drug is administered until 30 days after last 
dose. All concomitant medications will be collected except for:

Vitamins

Herbal medicines

Dietary supplements (iron is not considered a dietary supplement)
After Amendment INT-4 is implemented, only the following concomitant medications 
will continue to be collected:

Anti-infective medications (antibiotics, oral or topical antifungals, and antiviral etc.)

Lipid modifying agents

Antihypertensives

Immunomodulators including corticosteroids

Hematopoietic cytokines such as colony stimulation factors

Blood product transfusions

Clinical important surgery or procedures

Medications to manage infusion related reactions

Medications used to treat SAEs
8.1
Supportive Care Measures
Allowed supportive care measures for all study subjects to manage symptoms include:

Management of effusions (eg, drainage, diuretics)

Antipyretics, antipruritics, antihistamines

Pain medication

Management of infections

Transfusions

Management of infusion reactions as specified in institutional guidelines (see 
Section 6.2)
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
34
8.2
Guidelines for Corticosteroid Use
Concomitant use of immunosuppressive therapy is not permitted during the study, except 
for:

Subjects who are receiving corticosteroid treatment at the time of screening may be 
considered for inclusion in the study. If subjects are taking corticosteroids at the start 
of the study, they may be tapered during the study. Tapering of corticosteroid dosing 
should preferably not start before the first disease assessment (ie, Cycle 4). Tapering 
of corticosteroids should be guided by clinical symptoms of Castleman’s disease 
unless prompted by intolerable or acute and severe corticosteroid-related toxicities.

Other indications, see Section 8.4

Treatment of acute allergic reactions according to institution guidelines (see 
Section 6.2)

Secondary prophylactic pretreatment with corticosteroids to prevent allergic 
reactions (eg, to contrast materials or to siltuximab) is allowed after consulting with 
the Medical Monitor. Corticosteroid use for allergic reactions to siltuximab should 
be limited to 2 doses of 100 mg hydrocortisone or equivalent (see Attachment 1), in 
addition to standard treatment with antihistamines and acetaminophen (see 
Section 6.2).
8.3
Guidelines to Manage Hyperlipidemia
Hypertriglyceridemia has been observed in some subjects who were administered 
siltuximab and has been seen with other agents targeting the IL-6 receptor (Actemra® PI, 
2010; RoActemra EPAR, 2009;
Nishimoto et al, 2004). The incidence of 
hypertriglyceridemia reported as an AE in single-agent studies of siltuximab is low and 
almost all reported events have been low grade. Monitoring and treatment of lipid 
profiles (high-density lipoprotein [HDL] and low density lipoprotein [LDL]) and 
triglycerides as per 
established guidelines
(http://www.nhlbi.nih.gov/guidelines/
cholesterol/dskref.htm) are recommended since potential effects of chronic siltuximab 
administration on cardiovascular ischemic events is not well defined.
8.4
Prohibited Therapies
Use of these prohibited treatments during the study will result in subjects being 
withdrawn from the study:

Other concomitant antitumor therapies for Castleman’s disease, for example:
–
Anti-CD20 antibodies (eg, rituximab)
–
IL-6 targeted therapies (eg, tocilizumab)
–
Cytotoxic chemotherapy

Biologic treatments such as tumor necrosis factor alpha (anti-TNFα) antibodies (eg, 
infliximab, adalimumab, etanercept)
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
35

Other investigational agents

Increase from baseline or a new course of systemic immunosuppressive agents 
(including corticosteroids), with the exception of:
–
isolated use of low-dose corticosteroids to treat and prevent allergic reactions 
(see Section 8.2)
–
increase or new course for another indication such as but not limited to (a flare 
of) rheumatoid arthritis and psoriasis

ESAs
The Medical Monitor must be notified in advance (or as soon as possible thereafter) of
any instances in which prohibited therapies are administered.
9
STUDY EVALUATIONS
9.1
Study Procedures
9.1.1
Overview
The Time and Events Schedules (see Table 1 and Table 2) that follow the Synopsis 
summarizes the frequency and timing of safety, efficacy, pharmacodynamic biomarker,
and other evaluations applicable to this study. Enrolled subjects will be assessed for 
eligibility according to the inclusion and exclusion criteria (see Section 4.2 and 
Section 4.3).
Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy 
throughout the study. The total blood volume to be collected from each subject will 
depend on the amount of time they participate in this long-term study. The table in 
Attachment 3 shows the maximum volume per each assessment. PRO assessments (ie, 
MCDSS) during a visit should be conducted before any tests, procedures, or other 
consultations for that visit.
The assessments per visit will vary as indicated per Time and Events schedules (see 
Table 1 and Table 2). The required assessments at every dosing visit are:

Weight

Vital signs

Review of adverse events

Review of concomitant medications

Administration of siltuximab
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
36
The follow-up Week 4 assessment (4 weeks after the last dose) will be considered as the 
end of treatment visit. During this visit, assessments will be repeated according to the 
Time & Events Schedules (see Table 1 and Table 2) to conclude the study treatment and 
obtain follow-up details. The remainder of the follow-up period constitutes 2 visits, 8 and 
12 weeks after the last administration during which serum blood samples will be 
collected to assess immunogenicity (antibodies to siltuximab) and biomarkers as 
applicable.
9.2
Safety Evaluations
Baseline chest X-ray is required within 3 months of first dose within this study and 
annually thereafter. If equivalent imaging (ie, CT, MRI) was performed for routine 
medical care at these timepoints, then it is allowed instead of a chest X-ray. Safety 
monitoring will consist of continuous AE reporting with a focus on infections, 
hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, infusion-related 
reactions, liver enzyme abnormalities, and immunogenicity. ECG and clinical laboratory 
tests are to be performed according to the Time and Events Schedules. Other laboratory 
parameters will only be evaluated if clinically indicated. Any of these safety monitoring 
assessments may be performed more frequently if clinically indicated.
The study will include the following evaluations of safety and tolerability according to 
the timepoints provided in the Time and Events Schedules (see Table 1 and Table 2):

AEs and AEs Grade 3

SAEs

Infusion reactions

Clinically significant abnormal laboratory parameters

Antibodies to siltuximab
The Medical Monitor will assess subject safety throughout the study on an ongoing basis. 
Safety will be evaluated using AEs, vital signs, weight, clinical laboratory parameters 
(hematology, chemistry, and lipid panel), and ECG as applicable. Any treatment-
emergent clinically significant abnormalities persisting at the end of the study will be 
followed by the investigator until resolution or until a clinically stable endpoint is 
reached.
Adverse Events
All toxicities will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, Version 4.0). Adverse events 
will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally-acceptable representative) for the duration of the study. Adverse events 
will be assessed by the investigator as specified in Section 12, Adverse Event Reporting. 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
37
For those subjects that do not have access to commercial siltuximab, continued 
siltuximab supply will be ensured. For all subjects still enrolled in the study after the 
6-year data cutoff, only pregnancies and SAEs, including information on study agent 
administration and concomitant medications associated with an SAE, will be collected, 
and reported to the appropriate health authorities in safety update reports.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology are collected according to the Time 
& Events Schedules (see Table 1 and Table 2). The investigator must review the 
laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the adverse event section of the CRF. All laboratory reports 
have to be reviewed prior to the next study administration to evaluate subject’s safety for 
continued treatment.
These tests will be performed by the local laboratory:

Hematology Panel
The screening hematology laboratory sample must be collected > 2 weeks from last RBC 
transfusion, platelet transfusion, or neutrophil growth factor administration. Hematology 
results must be reviewed before the scheduled study agent administration to evaluate 
safety. After Amendment INT-4, only a limited hematology panel is required (see
Table 2).
- hemoglobin
- WBC count with differential
- platelet count

Serum Chemistry Panel
Serum chemistry results must be reviewed before the scheduled study agent
administration to evaluate safety. After Amendment INT-4, only a limited serum 
chemistry panel is required (see Table 2).
- sodium
- albumin
- potassium
- total bilirubin
- blood urea nitrogen/creatinine
- AST
- glucose
- ALT
- total protein
- alkaline phosphatase

Coagulation Tests: performed if clinically indicated.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
38

Lipid Panel
Fasting sample is required at screening, and is preferred for all subsequent samples. Lipid
panel should be performed every 6 months. If the subject is naïve to siltuximab at study 
entry, the lipid panel should be done every 3 months for the first year of treatment, then 
every 6 months thereafter. If the lipid panel is abnormal, amylase and lipase may be 
assessed as clinically indicated.
- cholesterol
- triglycerides
- HDL
- LDL

Serum or urine pregnancy testing
–
For women of childbearing potential only at screening and Follow-up Week 4 
visit, and as clinically indicated during the study.

Other tests
–
Quantitative immunoglobulins (IgG, IgA, IgM), to be performed only as 
clinically indicated
Vital Signs (Temperature, Blood Pressure, and Heart Rate)
Vital signs will be measured predose and end of infusion on Day 1 of Cycle 1. Thereafter, 
vital signs will be measured only before each study agent administration on Day 1 of 
each cycle, and as clinically indicated.
Physical Examination
Physical examinations will be performed according to the Time & Events Schedules (see 
Table 1 and Table 2) with attention to areas of potential tumor involvement (including 
enlargement of liver and spleen). Any clinically significant observations should be 
recorded on the Adverse Event page of the CRF. Any clinically significant abnormalities 
persisting at the end of treatment will be evaluated by the investigator until resolution or 
until reaching a clinically stable endpoint.
ECG Assessment
ECG will be performed and analyzed locally. Subjects entering the study naïve to 
siltuximab will have ECGs performed according to the Time and Events Schedules (see 
Table 1 and Table 2). A focused cardiac investigation including an ECG is recommended 
if clinically indicated for any subject during the study.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
39
9.3
Efficacy Evaluations
9.3.1
Disease Control
Investigator assessment of disease control will be collected during screening, at Cycles 4, 
7, and 10, every 6 months thereafter, and at study treatment discontinuation (or Follow-
up Week 4 visit).
Disease assessments listed in Attachment 2 (including cutaneous assessments), are 
provided as a guide for assessing multicentric Castleman’s disease. If a subject shows 
disease progression at 2 consecutive assessments the subject must discontinue study 
treatment.
9.3.2
Laboratory Evaluations
ESR, CRP, and fibrinogen tests must be performed at the same times as the investigator 
assessment of disease control. These assessments will be part of the hematology and 
chemistry panels.
9.3.3
Survival
For subjects who discontinue study agent, survival status will be assessed twice per year 
until the subject has been lost to follow-up or has withdrawn consent for the study, or the 
6-year data cutoff; whichever occurs first.
9.3.4
Patient-reported Outcomes
The MCDSS questionnaire will only be completed by the sub-population from the 
C0328T03 study. The reliability of the MCDSS will be assessed by collecting the 
completed questionnaire 3 times during the study: at the start of the screening visit, and 
predose at Cycles 1 and 2. 
9.4
Pharmacodynamic Biomarker Evaluations
From serum samples, pharmacodynamic biomarker evaluations include, but are not 
limited to:

Quantification of IL-6.

Assessment of atypical IL-6 splice variants or cleavage fragments may also be 
performed along with exploratory assessment to compare IL-6 molecular profiles 
obtained in MCD patients versus commercially available samples from healthy 
volunteers. Other assessments related to disease and study agent may be performed 
based on emerging evidence. Planned biomarker analyses will be deferred if 
emerging study data show less likelihood of providing useful scientific information.
Collection of samples for these assessments will be stopped after Amendment INT-4 
is implemented.

CRP (assessed locally as part of clinical laboratory tests using the chemistry 
laboratory samples).
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
40
9.5
Glycoform Clearance and In Vivo Protein Degradation Analysis
To evaluate the clearance and degradation of glycoforms after administration of 
siltuximab, 6 serum samples will be collected from 5 former C0328T03 subjects (a 
limited number of samples are needed for this analysis).
Siltuximab will be isolated from the serum samples using an anti-Id antibody. The 
purified protein will then be analyzed by liquid chromatography/mass spectroscopy 
(LC/MS) techniques (intact mass and peptide mapping) to evaluate the clearance of 
different glycoforms over time and to determine the circulating levels of different protein 
degradants.
9.6
Antibodies to Siltuximab
Antibodies to siltuximab will be detected using a validated immunoassay. All samples 
collected for detection of antibodies to siltuximab will also be evaluated for siltuximab 
serum concentration to interpret antibody response data. Antibodies to siltuximab may 
also be assessed at other timepoints. Serum samples will be screened for antibodies 
binding to siltuximab, and the serum titer of confirmed positive samples will be reported. 
Other immunogenicity analyses may be performed to further characterize the immune 
responses. Immunogenicity samples will be analyzed at the 6-year data cutoff.
Blood samples to determine antibodies to siltuximab will be collected from all subjects in 
the study every 12 weeks while receiving siltuximab in conjunction with a dosing visit, 
and at Week 4, Week 8, and Week 12 following the last administration of siltuximab.
In addition, a blood sample should be drawn, if possible, to determine antibodies to 
siltuximab any time an infusion related reaction is observed or reported during the study. 
This sample should be obtained as soon as possible after the reaction. These samples will 
be stored, and evaluated if deemed necessary. See Section 6.2 for guidelines for 
management of infusion related reactions.
All samples should be sent to the central laboratory. The sponsor or its designee will test 
these samples. Instructions for the collection and shipment of these samples are found in 
the Laboratory Manual.
10
SUBJECT COMPLETION/WITHDRAWAL
10.1
Completion
A subject will be considered to have completed the study if he or she has completed 
assessments at the Follow-up Week 4 assessments, or has experienced a clinical endpoint 
that precludes further study (eg, disease progression).
10.2
Discontinuation of Treatment
All subjects will be treated until they progress, withdraw, experience unacceptable 
toxicity, or until the 6-year data cutoff, whichever comes first. A data cutoff will occur 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
41
approximately 6 years after the start of enrollment; however, continued drug supply will 
be ensured for study subjects who would not otherwise have access to siltuximab outside 
this clinical study.
If a subject discontinues study agent, obtain end-of-treatment and follow-up assessments, 
which are the same assessments done at Follow-up Weeks 4, 8 and 12 as applicable. If a 
subject's study treatment must be discontinued before the end of the treatment regimen, 
this will not result in automatic withdrawal of the subject from the study. Subjects will 
have follow-up assessments for survival, occurrence of malignancies, and subsequent 
MCD therapies until the 6-year data cutoff (see Section 9.3.3).
A subject's study treatment should be discontinued if:

The investigator believes that for safety reasons (eg, adverse event) it is in the best 
interest of the subject to stop treatment.

The subject becomes pregnant.

The subject initiated any of the prohibited medications requiring discontinuation of 
treatment (see Section 8.4)
10.3
Withdrawal from Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death
If a subject discontinues the study before the end of the treatment phase, obtain end-of-
treatment and follow-up assessments.
In case a subject is lost to follow-up, every possible effort must be made by the study site 
personnel to contact the subject and determine the reason for discontinuation/withdrawal. 
The measures taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Subjects who withdraw will not be 
replaced.
11
STATISTICAL METHODS
In general, all continuous endpoints will be summarized using descriptive statistics, 
which will include the number of subjects, mean, standard deviation, median, minimum, 
and maximum. All categorical endpoints will be summarized using frequencies and 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
42
percentages. For time to event variables (eg, overall survival), the Kaplan-Meier method 
will be used for descriptive summaries. No formal hypothesis testing will be performed.
11.1
Subject Information
The safety population, which includes all subjects who receive at least one administration
of siltuximab, will be used in all statistical analyses.
11.2
Sample Size Determination
The sample size for this study is not designed according to statistical calculation. It is 
expected that up to 75 subjects could be enrolled. The number of subjects enrolled will be 
determined by the eligible subjects from the C0328T03 and CNTO328MCD2001 studies.
11.3
Safety Analyses
Adverse events, deaths, and safety-related laboratory tests will be summarized as follows:

Incidence of all AEs

Incidence of Grade 3 or higher AEs

Incidence of SAEs

Incidence of AEs and SAEs reasonably related to siltuximab

Incidence of clinically important changes in safety-related laboratory parameters

Incidence of deaths and malignancies

Incidence of antibodies to siltuximab
Adverse Events
The original terms used in the CRFs by investigators to identify adverse events will be 
coded using the MedDRA. All reported adverse events with onset on or after the first 
siltuximab administration through 30 days after the last siltuximab administration within 
the 6-year data cutoff (ie, treatment-emergent adverse events) will be included in the 
analysis. The incidence of treatment-emergent AEs will be summarized overall, by 
MedDRA system-organ class (SOC) and preferred term, by toxicity grade, and by 
relationship to siltuximab administration. The adverse events of clinical interest, such as 
infections, hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, infusion-
related reactions, liver enzyme abnormalities, and immunogenicity will be summarized in 
similar fashion.
Special attention will also be given to those subjects who died, or who discontinued 
treatment due to an adverse event, or who experienced a severe or a SAE (eg, summaries, 
listings, and narrative preparation may be provided, as appropriate).
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
43
Clinical Laboratory Tests
Hematology and chemistry laboratory values will be summarized at baseline and at each 
scheduled timepoint by descriptive statistics for each type of laboratory test. The changes 
from baseline results will also be summarized. In addition, the worst toxicity grade 
experienced by a subject during the study will be summarized, and shift tables from 
baseline to worst toxicity during the study will be presented. 
Vital Signs
Descriptive statistics of temperature, pulse, respiratory rate, and blood pressure (systolic 
and diastolic) (supine or standing) values and changes from baseline will be summarized 
at each scheduled time point. The percentage of subjects with values beyond clinically 
important limits will be summarized.
ECG
Abnormal 12-lead ECG findings during treatment will be presented in listings.
11.4
Efficacy and Patient-reported Outcomes Analyses
11.4.1
Disease Control
Investigator assessment of disease control for all treated subjects will be analyzed. 
Specifically, the proportion of previously responding subjects and siltuximab-naïve 
subjects who maintain disease control will be summarized. The duration of disease 
control, defined as the time from the first siltuximab administration to disease 
progression as assessed by the investigator, will also be summarized. 
11.4.2
Laboratory Evaluations
Efficacy-related laboratory assessments of ESR, CRP, and fibrinogen will be summarized 
by descriptive statistics at baseline and each scheduled timepoint. The changes from 
baseline results will also be summarized.
11.4.3
Overall Survival
Overall survival is defined as the time between the first study siltuximab administration 
and death. Subjects who died, regardless of the cause of death, will be considered as an 
event. Subjects who withdraw consent from the study will be censored at the time of 
withdrawal. Subjects who are still alive at the cutoff date of the final analysis will be 
censored at the date of last known alive. All subjects who are lost to follow-up before the 
6-year data cutoff will be censored at the date they are last known to be alive.
The Kaplan-Meier method will be used to estimate the distribution of overall survival. 
Median overall survival with 95% CI will be provided. In addition, the Kaplan-Meier 
overall survival curve will also be provided.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
44
11.4.4
MCDSS Evaluations
The patient-reported MCDSS total score at each timepoint and the change from baseline 
in MCDSS total score will be summarized.
11.5
Glycoform Analysis and In Vivo Protein Degradation
These analyses will be reported in a separate technical report.
11.6
Pharmacodynamic Biomarker Analyses
Determination of IL-6 levels prior to first administration of siltuximab is planned to be 
performed. Exploratory evaluation of IL-6 splice variant analysis may also be performed. 
Results from IL-6 analysis will be summarized at the timepoints tested and association 
with clinical response may be explored.
11.7
Interim Analysis
No later than 2 years after start of enrollment, an interim analysis will be conducted to 
further evaluate the benefit and safety of long-term treatment with siltuximab in subjects 
with MCD. In addition, the interim analysis results will be used to support internal 
decision-making.
12
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of subjects, 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.
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 subject 
administered a medicinal (investigational or non-investigational) 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 or 
non-investigational) product, whether or not related to that medicinal (investigational or 
non-investigational) product. (Definition per International Conference on Harmonisation)
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.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
45
Note: The sponsor collects adverse events starting with the signing of the informed 
consent form (refer to Section 12.2.1, All Adverse Events for time of last adverse event 
recording).
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 subject 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 subject or may require intervention to prevent one
of the outcomes listed in the definition above (eg, suspected transmission of an infectious 
agent by a medicinal product is considered a SAE). Any adverse event is considered a 
SAE if it is associated with clinical signs or symptoms judged by the investigator to have 
a significant clinical impact.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
This is defined as 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. 
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.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
46
Doubtful
An adverse event for which an alternative explanation is more likely, eg, 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, 
eg, 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 (eg, confirmed by dechallenge). An alternative explanation is less likely, 
eg, 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, eg, concomitant drug(s), concomitant disease(s). 
The relationship in time is very suggestive (eg, it is confirmed by dechallenge and 
rechallenge).
12.1.3
Severity Criteria
Severity of adverse events will be graded according to the NCI-CTCAE Version 4.0, 
using these descriptors:

Grade 1: Mild AE

Grade 2: Moderate AE

Grade 3: Severe AE

Grade 4: Life-threatening or disabling AE

Grade 5: Death related to the AE
For any event not covered by the NCI-CTCAE, an assessment of severity grade will be 
made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated causing minimal discomfort and 
not interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
47
The investigator should use clinical judgment in assessing the intensity of events not 
directly experienced by the subject (eg, laboratory abnormalities).
12.2
Procedures
12.2.1
All Adverse Events
All adverse events, whether serious or non-serious, will be reported from the time a 
signed and dated informed consent form is obtained until 30 days after last study agent 
administration. The only exception is for subjects who have withdrawn informed consent 
for study participation or for subjects who have received additional treatment with 
therapeutic intent for MCD within 30 days after the last study agent administration. For 
subjects who have received additional treatment with therapeutic intent for MCD during 
the AE reporting period, only AEs that are considered to be possibly, probably, or 
definitely related to study agent must be reported (unless the subject has been withdrawn 
from the study). 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 Form. The sponsor will evaluate any safety information that is 
spontaneously reported by an investigator beyond the time frame specified in the 
protocol. Key safety events of interest (see the current Investigator’s Brochure), including 
infections, hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, infusion-
related reactions, liver enzyme abnormalities, and immunogenicity.
After the 6-year data cutoff, subjects who do not have access to commercially available 
siltuximab may continue to receive treatment provided by the Sponsor. For these subjects 
only, SAEs (information on study agent administration and concomitant medications use 
to treat the SAEs) and pregnancies will have to be reported and collected after the data 
cutoff at 6 years. These events will be reported to the appropriate health authorities in 
safety update reports.
All events that meet the definition of a SAE will be reported as SAEs, 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 (eg, 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 all SAEs that are 
unlisted (unexpected) and associated with the use of the drug. The investigator (or 
sponsor where required) must report these events to the appropriate Independent Ethics 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
48
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. 
Subjects (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.
Disease progression should not be recorded as an adverse event or SAE term; instead, 
signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the adverse event or SAE definition (see 
Section 12.1.1 Adverse Event Definitions and Classifications).
12.2.2
Serious Adverse Events
All serious adverse events occurring during clinical studies as well as during continued 
treatment after the 6-year data cutoff, 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 Form, which must be completed and signed by a member of the 
investigational staff, and transmitted to the sponsor within 24 hours. The initial and 
follow-up reports of a SAE should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject’s participation in the study, or that have not 
resolved upon discontinuation of treatment beyond the 6-year data cutoff, 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

It becomes unlikely that any additional information can be obtained (subject 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 subject in a clinical study, whether or not the event is expected or 
associated with the investigational agent, is considered a SAE. Suspected transmission of 
an infectious agent by a medicinal product should be reported as a SAE. Any event 
requiring hospitalization (or prolongation of hospitalization) that occurs during the course 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
49
of a subject’s participation in a clinical study must be reported as a SAE, except 
hospitalizations for the following:

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
All initial reports of pregnancy must be reported to the sponsor by the investigational 
staff within 24 hours of their knowledge of the event using the appropriate pregnancy 
notification form. Abnormal pregnancy outcomes are considered SAEs and must be 
reported using the Serious Adverse Event Form. Any subject who becomes pregnant 
during the study must discontinue further study treatment immediately.
Because the study drug may have an effect on sperm, or if the effect is unknown, 
pregnancies in partners of male subjects included in the study will be reported by the 
investigational staff within 24 hours of their knowledge of the event using the appropriate 
pregnancy notification form. Men should not donate sperm during this study and for 3 
months after receiving the last dose of siltuximab.
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.
13
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related 
to manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, 
quality, durability, reliability of a product, including its labeling or package integrity. 
PQCs may have an impact on the safety and efficacy of the product. Timely, accurate, 
and complete reporting and analysis of PQC information from clinical studies are crucial 
for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established procedures in conformity 
with regulatory requirements worldwide to ensure appropriate reporting of PQC 
information; all clinical studies conducted by the sponsor or its affiliates will be 
conducted in accordance with those procedures.
13.1
Procedures
All initial PQCs must be reported to the sponsor by the investigational staff as soon as 
possible after being made aware of the event.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
50
If the defect is combined with a SAE, the investigational staff must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.2.2, Serious 
Adverse Events). A sample of the suspected product should be maintained for further 
investigation if requested by the sponsor.
13.2
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be 
contacted regarding product quality issues are listed on the Contact Information page(s), 
which will be provided as a separate document.
14
STUDY DRUG INFORMATION
14.1
Physical Description of Study Drug
Details regarding the composition of siltuximab can be found in the Investigator’s 
Brochure. The study agents are NOT to be used for any purpose other than that outlined 
in this protocol, including other human studies, animal investigations, or in vitro testing.
The siltuximab supplied for this study has an approximate molecular weight of 
147,750 daltons. Siltuximab will be supplied as a sterile, lyophilized formulation for 
reconstitution and IV infusion. The drug product after reconstitution of the lyophile 
contains siltuximab, histidine, sucrose, and polysorbate-80.
14.2
Packaging
The investigational supplies will be uniquely packaged to assure that they are 
appropriately managed throughout the supply chain process.
14.3
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements 
for each country.
14.4
Preparation, Handling, and Storage
All study drug must be stored at controlled temperatures ranging from 35.6°F to 46.4°F
(2°C to 8°C). Study agent vials should be stored in a secured refrigerator at 2 to 8ºC. 
During extended storage, study agent vials should be stored refrigerated at 2 to 8ºC and 
protected from light. Protection from light is not required during dose preparation or 
administration.
The pharmacist should prepare study agent using a vertical laminar flow biologic cabinet 
(hood) and proper aseptic techniques. It is recommended that gloves and protective 
garments be worn during preparation. Lyophilized vials will be reconstituted with sterile, 
single-use water for injection, using a syringe with a 21-gauge 1.5-inch needle. The study 
agent is to be reconstituted as specified in the site investigational product manual. It is 
recommended to wait 30 minutes to ensure complete reconstitution before preparation of 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
51
study agent. DO NOT USE THE VIAL IF DISCOLORATION, OPAQUE PARTICLES, 
OR OTHER FOREIGN PARTICLES ARE PRESENT.
The study agent will be prepared according to the subject’s weight. The drug product will 
be aseptically withdrawn from the study vials and added to 250 mL 5% dextrose for 
infusion. A total volume of 250 mL of diluted solution will be administered to the subject 
over a period of 1 hour. The infusion should be given via a separate line, using the 
administration set with a 0.2 micron inline filter. Aseptic procedures should be used 
during the preparation and infusion of study medication. Refer to the Pharmacy Manual 
for additional guidance on study drug preparation and handling.
14.5
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study.
Study drug must be handled in strict 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 must be available for verification by the 
sponsor’s site monitor during on-site monitoring visits. The return to the sponsor or 
designee of unused study drug will be documented on the return or destruction Form. 
When the site is an authorized destruction unit and study drug supplies are destroyed on 
site, this must also be documented on the return or destruction Form.
Hazardous materials such as used ampoules, needles, syringes and vials containing 
hazardous liquids, infusion lines and systems 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 
administered only to subjects participating in the study. 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.
15
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Study protocol

Siltuximab drug

Pharmacy manual

Laboratory Manual
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
52

Investigator’s Brochure

MCDSS questionnaire
16
ETHICAL ASPECTS
16.1
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, 
during the study, subjects will be given any new information that may affect their decision 
to continue participation. They will be told that their consent to participate in the study is 
voluntary and may be withdrawn at any time with no reason given and without penalty or 
loss of benefits to which they would otherwise be entitled. Only subjects who are fully able 
to understand the risks, benefits, and potential adverse events of the study, and provide 
their consent voluntarily will be enrolled. 
The total blood volume to be collected will be depend on the duration of subject 
participation in this long-term safety study; however, the volume drawn is well within the 
limits for blood donation during the time period of study assessments.
16.2
Regulatory Ethics Compliance
16.2.1
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical study is performed in 
accordance with the protocol, current ICH guidelines on GCP, and applicable regulatory 
and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of 
human subjects. Compliance with this standard provides public assurance that the rights, 
safety, and well being of study subjects are protected, consistent with the principles that 
originated in the Declaration of Helsinki, and that the clinical study data are credible.
16.2.2
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 subjects)

Investigator’s Brochure (or equivalent information) and amendments

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
53

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 subjects

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 subject 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.
During the study the investigator (or sponsor where required) will send the following 
documents and updates 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 subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects 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, unexpected, and associated with 
the investigational drug

New information that may adversely affect the safety of the subjects or the conduct 
of the study

Deviations from or changes to the protocol to eliminate immediate hazards to the 
subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Annual Safety Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or trial conduct), the amendment and applicable informed 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
54
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 reapprove this clinical 
study. The reapproval should be documented in writing (excluding the ones that are 
purely administrative, with no consequences for subjects, data or trial conduct).
At the end of the study, the investigator (or sponsor where required) will notify the 
IEC/IRB about the study completion.
16.2.3
Informed Consent
Each subject (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 enrollment in the study, the investigator or an authorized member of the 
investigational staff must explain to potential subjects (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. Subjects 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 subject will receive for the treatment of his or her disease. Subjects 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 subject 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 subject, to the extent permitted 
by the applicable law(s) or regulations. By signing the informed consent form the subject 
(or legally-acceptable representative) is authorizing such access, and agrees to allow his 
or her study physician to recontact the subject for the purpose of obtaining consent for 
additional safety evaluations, if needed, or to obtain information about his or her survival 
status.
The subject (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 subject's (or his or her legally-acceptable representative's) personally dated signature. 
After having obtained the consent, a copy of the informed consent form must be given to 
the subject.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
55
If the subject (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 subject (or legally-acceptable representative) is 
obtained.
16.2.4
Privacy of Personal Data
The collection and processing of personal data from subjects 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 subjects 
confidential.
The informed consent obtained from the subject (or his or 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, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal 
data and the right to request rectification of any data that are not correct or complete. 
Reasonable steps will 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.
16.2.5
Country Selection
Unless explicitly addressed as a specific ethical consideration in Section 16.1, Study-
Specific Design Considerations, this study will only be conducted in those countries 
where the intent is to help ensure access to the developed product.
17
ADMINISTRATIVE REQUIREMENTS
17.1
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 necessary to eliminate immediate hazards to the subjects, in 
which case the amendment must be promptly submitted to the IEC/IRB and relevant 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
56
competent authority. Documentation of amendment approval by the investigator and 
IEC/IRB must be provided to the sponsor or its designee. 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 (see Contact Information pages provided separately). Except in 
emergency situations, this contact should 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.
17.2
Regulatory Documentation
17.2.1
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.
17.2.2
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 principal 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, 
subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed by the chairman or authorized 
designee.

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 (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, 
where required
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
57

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 
subject:

Completed investigator financial disclosure forms from all clinical subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

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 
(eg, accreditation/license), if applicable
17.3
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit 
easy identification of each subject during and after the study. This document will be 
reviewed by the sponsor site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be 
filed by the investigator in the study file. To ensure subject confidentiality, no copy will 
be made. All reports and communications relating to the study will identify subjects by 
assigned number only.
The investigator must also complete a subject-screening log, which reports on all subjects 
who were seen to determine eligibility for inclusion in the study.
17.4
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject 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; and follow-up of 
adverse events; concomitant medication; drug receipt/dispensing/return records; study 
drug administration information; and date of study completion, and reason for early 
discontinuation of study drug or withdrawal from the study, 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 subject 
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).
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
58
The following data will be recorded directly into the CRFs and will be considered source 
data: 

Race

BP/HR (if not primary efficacy or significant safety issue)

Height (except if primary efficacy or significant safety issue)
MCDSS questionnaires will be completed by the subjects on paper. Once the subject 
signs and dates the questionnaire, the questionnaire will be regarded as a source 
document.
17.5
Case Report Form Completion
Case report forms are provided for each subject in printed or electronic format. 
Electronic Data Capture (eDC) will be used for this study. The study data will be 
transcribed by study personnel from the source documents onto an electronic CRF within 
an agreed upon number of days of the subject’s visit. The electronic file will be 
considered to be 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 subjects’ 
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 subject visit, and the forms should be 
available for review at the next scheduled monitoring visit.
Every effort should be made to ensure that all subjective measurements (eg, 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 CRF 
(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 corrections 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 DCF) for resolution by the 
investigational staff

Clinical data manager (CDM) can generate a query for resolution by the 
investigational staff 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
59
17.6
Data Quality Assurance/Quality Control
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 serum 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.
17.7
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 subject, 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. 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.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
60
17.8
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 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.
17.9
Study Completion/Termination
17.9.1
Study Completion
The study is considered completed with the last visit of the last subject participating in 
the study. The final data from the investigational site will be sent to the sponsor (or 
designee) after completion of the final subject visit at that site, in the time frame specified 
in the Clinical Trial Agreement.
17.9.2
Study Termination
The sponsor reserves the right to close the investigational site or terminate the study at 
any time for any reason at the sole discretion of the sponsor. 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
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
61

Inadequate recruitment of subjects by the investigator

Discontinuation of further drug development.
17.10
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. Subject 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.
17.11
Use of Information and Publication
All information, including but not limited to information regarding siltuximab or the 
sponsor’s operations (eg, 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 pharmacogenomic 
research 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 siltuximab, 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 CRF data from all investigational sites that participated in the 
study. Recruitment performance or specific expertise related to the nature and the key 
assessment parameters of the study will be used to determine a coordinating investigator. 
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. 
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
62
The sponsor shall have the right to publish such data and information without approval 
from the investigator. 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 suppress information. For multicenter study designs and substudy 
approaches, results may need to be published in a given sequence (eg, substudies) should 
not generally be published before the primary endpoints of a study have been published. 
Similarly, investigators 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.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register or disclose the existence of and the results of clinical studies as 
required by law.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
63
REFERENCES
Actemra(tocilizumab) [prescribing information]. South San Francisco, CA, 94080, USA: Genentech, Inc., 
2010
Casper C. The aetiology and management of Castleman disease at 50 years: translating pathophysiology to 
patient care. Br J Haematol. 2005;129(1):3-17.
Castleman B, Towne VW. Case records of the Massachusetts General Hospital; weekly clinicopathological 
exercises; founded by Richard C. Cabot. New Engl J Med. 1954;251(10):396-400.
Dham A, Peterson BA. Castleman disease. Curr Opin Hematol. 2007;14(4):354-359.
Fujita T, Yasuda S, Kamata Y, Fujita K, et al. Contribution of down-regulation of intestinal and hepatic 
cytochrome P450 3A to increased absorption of cyclosporine A in a rat nephrosis model. J Pharmacol Exp 
Ther. 2008;327(2):592-599.
Hirano T, Matsuda T, Nakajima K. Signal transduction through gp130 that is shared among the receptors 
for the interleukin 6 related cytokine subfamily. Stem Cells. 1994;12(3):262-277.
Jover R, Bort R, Gómez-Lechón MJ, Castell JV. Down-regulation of human CYP3A4 by the inflammatory 
signal interleukin 6: molecular mechanism and transcription factors involved. FASEB J. 2002;16(13):1799-
1801.
Katsume A, Miyai T, Suzuki H, et al. Interleukin-6 overexpression cannot generate serious disorders in 
severe combined immunodeficiency mice. Clin Immunol Immunopathol. 1997;82(2):117-124.
Katsume A, Saito H, Yamada Y, et al. Anti-interleukin 6 (IL-6) receptor antibody suppresses Castleman's 
disease like symptoms emerged in IL-6 transgenic mice. Cytokine. 2002;20(6):304-311.
Kishimoto T. The biology of interleukin-6. Blood. 1989;74(1):1-10.
National Heart, Lung, and Blood Institute (National Institutes of Health). Third Report of the National 
Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High 
Blood 
Cholesterol 
in 
Adults. 
NIH 
Publication 
No. 
02-5215. 
September 
2002.
http://www.nhlbi.nih.gov/guidelines/cholesterol/dskref.htm. Accessed October 2010.
Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-
interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 
2004;50(6):1761-1769.
Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleukin-6 receptor antibody treatment of 
multicentric Castleman disease. Blood. 2005;106(8):2627-2632.
Puchalski T, Prabhakar U, Jiao Q, Berns B, Davis HM. Pharmacokinetic and Pharmacodynamic Modeling 
of an Anti-Interleukin-6 Chimeric Monoclonal Antibody (Siltuximab) in Patients with Metastatic Renal 
Cell Carcinoma. Clin Cancer Res. 2010;16(5):1652-1661.
RoActemra, [European Public Assessment Report]. Welwyn Garden City, AL7 1TW , United Kingdom. 
Roche Registration Limited, 2009. 
Seideman J, Peritt D. A novel monoclonal antibody screening method using the Luminex-100 microsphere 
system. J Immunol Methods. 2002;267(2):165-171.
van Rhee F, Fayad L, Voorhees P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for
Castleman's disease. J Clin Oncol. 2010;28(23):3701-3708.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
64
Vernon MK, Teschendorf B, Van Rhee F. Qualitative research in Castleman’s disease: exploring patients’ 
perspective of symptoms through qualitative interviews. Paper presented at: International Society for 
Quality of Life Research; October, 2009; New Orleans, LA.
Zhang X, Schmitt C, Grange S, et al. Disease-drug interaction studies of Tocilizumab with cytochrom P450 
substrates in vitro and in vivo. Paper presented at: ASCPT Annual Meeting;  March 18-21, 2009; National 
Harbor, MD. Poster P11-73.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
65
ATTACHMENT 1: APPROXIMATELY EQUIVALENT DOSES OF 
CORTICOSTEROIDS
Steroid
Glucocorticoid anti-inflammatory
Cortisone
100 mg
Hydrocortisone
80 mg
Prednisone
20 mg
Prednisolone
20 mg
Methylprednisolone
16 mg
Dexamethasone
2 mg
Knoben JE, Anderson PO. Handbook of Clinical Drug Data, 6th ed. Drug Intelligence 
Pub, Inc. 1988.
Steroid Equivalence Converter
Steroid Equivalence Converter. Available at: http://www.medcalc.com/steroid.html. 
Accessed 22 Jun 2009.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
66
ATTACHMENT 2: DISEASE ASSESSMENTS
Disease assessment criteria (including cutaneous disease assessments) are provided as a 
guide for the investigator.
Each subject can be classified as stable, improved, or worsened based on hemoglobin, 
fatigue, anorexia, fever, weight, and target lymph node assessment (see the first table 
below). If a subject improves in at least one measure and remains stable for all other 
measures, the subject is considered to have improved. A worsening in any of the 
measures will be considered as a progression of the disease. Any other subject will be 
considered stable for clinical benefit. The investigator’s assessment of all lymph node 
radiologic results will also be recorded.
For subjects who have only cutaneous disease (cutaneous disease must be proven by 
biopsy), the response assessment for cutaneous lesions is a modified physician’s global 
assessment that has been used in previous oncology clinical studies (Duvic et al, 2001a; 
Duvic et al, 2001b) and will be one of the clinical benefit components, and be assessed 
based on the following response criteria.
The extent of disease will be measured by an estimation of BSA involved; single sites of 
disease must be > 1 cm in diameter. Twelve main body areas will be assessed, as listed in 
the second table below (Duvic et al, 2001c).
Clinical Benefit Assessments for Castleman’s Disease
Measure
Status
Improved
Stable
Worsening
Hemoglobin
Increase of at least 
2 g/dL relative to 
baseline without blood 
transfusion
Less than 2 g/dL 
variance relative to 
baseline without blood 
transfusion
Decrease of at least 
2g/dL relative to 
baseline without blood 
transfusion
Fatigue
Decrease of at least 1 
CTC grade point relative 
to baseline
No change in CTC grade 
relative to baseline
Increase of at least 1 
CTC grade point 
relative to baseline
Anorexia
Decrease of at least 1 
CTC grade point relative 
to baseline
No change in CTC grade 
relative to baseline
Increase of at least 1 
CTC grade point 
relative to baseline
Fever*
Decrease of at least 2°C 
relative to baseline or 
return to normal body 
temp (37C)
Less than 2°C variance 
relative to baseline 
unless normal body temp 
is achieved then define as 
improved
Increase of at least 2°C 
relative to baseline
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
67
Weight
Increase of at least 5% 
relative to baseline 
(without new edema or 
increase in existing 
edema)
Less than a 5%variance 
from baseline (without 
new edema or an 
increase in existing 
edema)
Decrease of at least 5% 
relative to baseline 
(weight loss not due to 
decreased edema)
Size of largest 
lymph node
(CT or physical 
examination) 
and/or 
cutaneous 
disease
Lymph node: Decrease 
of at least 25% 
(bidimensionally) 
compared with baseline.
Cutaneous disease: The 
disappearance of all 
visible and palpable 
evidence of active 
disease, or an 
unequivocal reduction in 
the extent of disease. 
This must be 
documented by a 50% 
reduction in the disease 
burden from baseline.
Lymph node: No 
increase or decrease of at 
least 25% 
(bidimensionally) 
compared with baseline.
Cutaneous disease: 
Disease not meeting the 
criteria for improvement 
or worsening.
Lymph node: Increase 
of at least 25% 
(bidimensionally) 
compared with baseline.
Cutaneous disease: An 
unequivocal increase in 
the extent of disease. 
This must be 
documented by a > 50% 
increase in the disease 
burden, or at least 1 new 
lesion. If an existing 
lesion disappears then 
reappears, it is 
considered a new lesion.
*To be assessed in conjunction with subject reported night sweats
Investigator Estimate of Body Surface Area Involved With Cutaneous Castleman’s 
Disease
Area
Total Possible 
% BSA for 
Region
% BSA
Involved with CD
% BSA
CD
Head
7
X
_____
=
Neck
2
X
_____
=
Anterior trunka
13
X
_____
=
Posterior Trunkb
13
X
_____
=
Buttocks
5
X
_____
=
Genitalia
1
X
_____
=
Upper arms
8
X
_____
=
Forearms
6
X
_____
=
Hands
5
X
_____
=
Thighs
19
X
_____
=
Lower leg
14
X
_____
=
Feet
7
X
_____
=
Total
100
a: Without neck or genitalia.
b: Without neck or buttocks.
  
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
68
References
Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe for treatment of 
refractory advanced-stage cutaneous T-cell lymphoma: Multinational Phase II-III trial 
results. J Clin Oncol. 2001a;19(9):2452-2471.
Duvic M, Martin AG, Kim Y, et al. Phase 2 and 3 clinical trial of oral bexarotene 
(Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous 
T-cell lymphoma. Arch Dermatol. 2001b;137:581-593.
Duvic M, Olsen EA, Omura GA, et al. A phase III, randomized, double-blind placebo-
controlled study of peldesine (BCX-34) cream as topical therapy for cutaneous T-cell 
lymphoma. J Am Acad Dermatol. 2001c;44(6):940-947.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
69
ATTACHMENT 3: BLOOD VOLUMES
Blood volumes for the assessments in this study are listed below.
Assessment
Blood Volume*
Hematology
10 mL**
Chemistry
10 mL**
Lipid panel
10 mL**
CRP, ESR and fibrinogen
10 mL**
Pharmacodynamic biomarkers
5 mL
Antibodies to siltuximab
(immunogenicity)
7.5 mL
Glycoform/degradation analysis
5 mL per sample,
30 mL total
* Volume per sample; total volume depends on length of study 
participation. Frequency of sample collection is in the Time and 
Events Schedules (Table 1 and Table 2).
** Estimated maximal amount; volume could be less or combined 
(eg, chemistry and lipid panel) depending on local laboratory 
guidelines.
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
70
INVESTIGATOR AGREEMENT
NCT01400503


Siltuximab (CNTO 328)
Clinical Protocol CNTO328MCD2002 – Amendment INT-4
Approved 04 Apr 2014
71
LAST PAGE
NCT01400503

SAP_001.pdf: 
1
Approved, Date: 21 March 2017
Janssen Research & Development 
Statistical Analysis Plan
An Open-label, Multicenter Study to Evaluate the Safety of Long-term Treatment with 
Siltuximab in Subjects with Multicentric Castleman’s Disease
Protocol CNTO328MCD2002; Phase 2
CNTO328  (Siltuximab)
Status:
Approved
Date:
21 March 2017
Prepared by:
Janssen Research & Development
Document No.:
EDMS-ERI-140183546
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.
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
2
Approved, Date: 21 March 2017
TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................2
ABBREVIATIONS.........................................................................................................................................4
1.
INTRODUCTION..................................................................................................................................5
1.1.
Overview of Trial Design ..................................................................................................................5
1.2.
Statistical Hypotheses for Trial Objectives .......................................................................................6
1.3.
Sample Size Justification..................................................................................................................6
2.
GENERAL ANALYSIS DEFINITIONS.................................................................................................6
2.1.
Parent Study and Long-term Safety Extension Study......................................................................6
2.2.
Study Data to Be Included in Analysis Tabulation............................................................................7
2.3.
By Visit Data Summary.....................................................................................................................7
2.4.
Siltuximab Treatment Date...............................................................................................................7
2.5.
Imputation of Partial Dates ...............................................................................................................7
2.6.
General Analysis Method .................................................................................................................8
2.7.
Analysis Sets ....................................................................................................................................8
3.
INTERIM ANALYSIS............................................................................................................................8
4.
SUBJECT INFORMATION ..................................................................................................................8
4.1.
Demographics and Baseline Characteristics....................................................................................8
4.2.
Disposition Information.....................................................................................................................9
4.3.
Extent of Exposure ...........................................................................................................................9
4.4.
Protocol Deviations...........................................................................................................................9
4.5.
Prior Therapies for Castleman’s Disease.........................................................................................9
4.6.
Concomitant Medications ...............................................................................................................10
4.7.
Subsequent MCD Therapy.............................................................................................................10
5.
EFFICACY..........................................................................................................................................10
5.1.
Analysis Specifications ...................................................................................................................10
5.1.1.
Level of Significance ...................................................................................................................10
5.1.2.
Data Handling Rules ...................................................................................................................10
5.2.
Efficacy Endpoints ..........................................................................................................................10
5.2.1.
Proportion of Subjects Maintaining Disease Control...................................................................10
5.2.1.1.
Definition ..................................................................................................................................10
5.2.1.2.
Analysis Methods.....................................................................................................................10
5.2.2.
Proportion of Subjects Experiencing Disease Control ................................................................11
5.2.2.1.
Definition ..................................................................................................................................11
5.2.2.2.
Analysis Methods.....................................................................................................................11
5.2.3.
Duration of Disease Control........................................................................................................11
5.2.3.1.
Definition ..................................................................................................................................11
5.2.3.2.
Analysis Methods.....................................................................................................................11
5.2.4.
Overall Survival ...........................................................................................................................11
5.2.4.1.
Definition ..................................................................................................................................11
5.2.4.2.
Analysis Methods.....................................................................................................................11
5.3.
Efficacy-related Laboratory Assessments......................................................................................12
5.4.
Patient-reported Outcomes ............................................................................................................12
6.
SAFETY .............................................................................................................................................12
6.1.
Adverse Events ..............................................................................................................................12
6.1.1.
Overview of TEAEs .....................................................................................................................13
6.1.2.
All TEAEs ....................................................................................................................................13
6.1.3.
Toxicity Grade 3 or 4 TEAEs.......................................................................................................13
6.1.4.
Siltuximab Treatment-Related TEAEs ........................................................................................13
6.1.5.
Serious Adverse Events (SAEs) .................................................................................................13
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
3
Approved, Date: 21 March 2017
6.1.6.
TEAEs Leading to Siltuximab Dose Delays ................................................................................14
6.1.7.
TEAEs Leading to Discontinuation of Siltuximab Treatment ......................................................14
6.2.
Deaths ............................................................................................................................................14
6.2.1.
All Deaths....................................................................................................................................14
6.2.2.
Death Due to TEAEs...................................................................................................................14
6.3.
Adverse Events of Clinical Interest.................................................................................................14
6.3.1.
Infusion-Related Reactions (IRR) ...............................................................................................14
6.3.2.
Infections and Infestations ..........................................................................................................14
6.3.3.
Secondary Malignancies .............................................................................................................15
6.4.
Clinical Laboratory Tests................................................................................................................15
6.5.
Vital Signs and ECG Findings ........................................................................................................15
6.6.
Other Safety Assessment...............................................................................................................16
7.
IMMUNOGENICITY............................................................................................................................16
7.1.
Sampling Timepoints ......................................................................................................................16
7.2.
Analysis Methods ...........................................................................................................................16
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
4
Approved, Date: 21 March 2017
ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
CI
Confidence interval
CR
Complete response
CRF
case report form
CRP
C-reactive protein
CSR
Clinical Study Report
CTCAE 
Common Terminology Criteria for Adverse Events
DODC
Duration of disease control
DPS
data presentation specification
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
IA
interim analysis
LDL
Low Density Lipoprotein
HDL
High Density Lipoprotein
LLOQ
lower limits of quantification 
MCD
Multicentric Castleman’s disease
MCDSS
Multicentric Castleman’s Disease Symptom Scale
MedDRA
Medical Dictionary for Regulatory Activities
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse
OS
Overall survival
PD
Progressive disease
PR
Partial response
PRO
Patient-reported outcomes
SAE
serious adverse event
SAP
statistical analysis plan
SD
Stable disease
SOC
system organ class
TEAEs
treatment-emergent adverse events
WBC
White blood cells
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
5
Approved, Date: 21 March 2017
1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived 
variables, and statistical methods for a Phase 2 study to evaluate the safety of long-term 
treatment with siltuximab in subjects with multicentric Casteman’s disease. 
1.1.
Overview of Trial Design
This is an open-label, multicenter, non-randomized Phase 2 study designed to study the 
safety of extended treatment with siltuximab in subjects who were previously enrolled in 
sponsor-initiated studies of multicentric Castleman’s disease (MCD) (C0328T03 and 
CNTO328MCD2001) and are either siltuximab-naive or have not progressed on 
siltuximab in the opinion of the investigator. 
The primary objective is to evaluate the long-term safety of siltuximab in subjects with 
MCD. The secondary objectives are 

To determine the proportion of previously responding subjects who maintain 
disease control

To determine the proportion of siltuximab-naive subjects who experience disease 
control

To describe the duration of disease control and survival

To assess reliability of a multicentric Castleman’s disease symptom scale 
(MCDSS)

To evaluate IL-6 levels

To assess formation of antibodies to siltuximab (immunogenicity) after long-term 
treatment in the MCD population
Up to 75 subjects will be eligible for the study, the majority of whom will be on active 
therapy with siltuximab and have not progressed at the time of enrollment. Subjects with 
unmanageable toxicity or discontinuation of treatment from previous sponsor-initiated 
siltuximab studies due to an adverse event, progression of disease, or withdrawal of 
consent will be excluded. 
Siltuximab will be given as a 1 hour infusion of 11 mg/kg every 3 weeks. The treatment 
interval may be lengthened to 6 weeks at the investigator’s discretion for subjects with 
confirmed partial or complete response of more than 6 months duration. During the 
study, no dose modifications of siltuximab will be allowed. Dose delays of up to 3 weeks 
will be allowed for treatment-related toxicity. Documentation of dose delays, including 
the reason for delay, is required. All subjects will be treated until they progress, 
withdraw, experience unacceptable toxicity, or until the 6-year data cutoff, whichever 
comes first. 
Throughout the study, investigator assessment of disease control will be collected during 
screening, at Cycles 4, 7 and 10, every 6 months thereafter, and at study treatment 
discontinuation. Laboratory assessments for erythrocyte sedimentation rate (ESR), CRP, 
and fibrinogen will also be performed at these same timepoints. Safety evaluations will 
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
6
Approved, Date: 21 March 2017
include a chest X-ray, or equivalent imaging (ie, computed tomography [CT], magnetic 
resonance imaging [MRI]), ECG and clinical laboratory tests according to the Time and 
Events Schedules. Safety monitoring will consist of continuous AE reporting with a focus 
on infections, hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, infusion-
related reactions, liver function, and immunogenicity. For those who have discontinued 
study agent, survival status, occurrence of malignancies, and subsequent MCD therapies 
will be collected until the subject has been lost to follow-up or has withdrawn consent for 
the study, or the 6-year data cutoff; whichever occurs first.
Two data cutoffs will occur:

No later than 2 years after the start of enrollment, an interim analysis will be 
conducted to further evaluate the benefit and safety of long-term treatment with
siltuximab in subjects with MCD

A data cutoff will occur approximately 6 years after the first subject is enrolled; 
however, continued drug supply will be ensured for study subjects who would not 
otherwise have access to siltuximab. A clinical study report (CSR) will be written 
based on this data cutoff
Data collection for subjects who discontinue study agent will be limited to survival status, 
occurrence of malignancies, and subsequent therapies for MCD, which will be assessed 
twice per year until the subject has been lost to follow-up or has withdrawn consent for 
the study, or the 6-year data cutoff; whichever occurs first. For those subjects remaining 
on treatment after the data cutoff at 6 years, data collection will be limited to pregnancies 
and serious adverse events (SAEs), including information on study agent administration 
and concomitant medications associated with an SAE. Data collected beyond the 6-year 
data cutoff will be reported to the appropriate health authorities in safety update reports. 
The end of study is the date of the last assessment for the last subject.
1.2.
Statistical Hypotheses for Trial Objectives
The safety of siltuximab will be acceptable for an extended treatment period. There is no 
formal hypothesis testing planned for this long-term extension study.
1.3.
Sample Size Justification
Up to 75 subjects who were previously enrolled in sponsor-initiated studies of 
multicentric Castleman’s disease (MCD) (C0328T03 and CNTO328MCD2001) and are 
either siltuximab-naive or have not progressed on siltuximab in the opinion of the 
investigator will be eligible for the study.   
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Parent Study and Long-term Safety Extension Study
The parent study refers to study C0328T03 or CNTO328MCD2001. The long-term safety 
extension study refers to study CNTO328MCD2002. 
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
7
Approved, Date: 21 March 2017
2.2.
Study Data to Be Included in Analysis Tabulation
Subjects treated in the long-term safety extension study of CNTO328MCD2002 were 
previously enrolled in sponsor-initiated studies of MCD, therefore demographics, 
baseline characteristics, and prior systemic therapy data will come from parent study of 
C0328T03 or CNTO328MCD2001. Overall treatment exposure, safety evaluations (i.e., 
adverse events), and overall survival will be based on parent study and extension study. 
The data included in these overall summaries are from the start of C0328T03 or 
CNTO328MCD2001 to the end of CNTO328MCD2002.
Due to quite different schedules in laboratory assessment and vital sign collection 
between parent study and long-term safety extension study, safety evaluation through 
laboratory assessment and vital signs will focus on long-term safety extension study of 
CNTO328MCD2002. Similarly, immunogenicity analyses will also be based on long-
term safety extension study. 
2.3.
By Visit Data Summary
In general, if data (e.g., laboratory and vital sign etc.) are collected by cycle, the nominal 
cycle will be used to summarize data. However, due to the nature of long-term extension 
treatment, safety evaluation via laboratory assessment may be summarized by study 
month/week, by-month/week windowing rules will be applied in the over time data 
summary. 
2.4.
Siltuximab Treatment Date 
Siltuximab treatment date is the date on which a subject actually received siltuximab
(partial or complete) administration.
For subjects who previously received siltuximab treatment, the first siltuximab treatment
date is defined as the earliest date of non-zero dose of siltuximab administration from 
study C0328T03 or CNTO328MCD2001. The last study treatment date is defined as the 
latest date of non-zero dose of siltuximab administration from CNTO328MCD2002.
For subjects who were siltuximab-naive, the first study treatment date is defined as the 
earliest date of non-zero dose of siltuximab from study CNTO328MCD2002. The last 
study treatment date is defined as the latest date of non-zero dose of siltuximab 
administration from study CNTO328MCD2002.
2.5.
Imputation of Partial Dates
Unless specified otherwise, no data imputation will be applied for missing safety and 
efficacy evaluations. For analysis and reporting purpose, partial dates in adverse event 
(AE onset date; AE end date), concomitant therapies (start date; end date) , MCD
diagnosis date, prior MCD therapies (start date; end date) and start date of subsequent 
MCD therapy will be imputed. 
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
8
Approved, Date: 21 March 2017
The detailed imputation rules along with other derived variables are specified in the data 
presentation specification (DPS).  
2.6.
General Analysis Method
In general, continuous variables will be summarized using descriptive statistics such as 
mean, standard deviation (SD), median and range. Categorical variables will be 
summarized using frequency and percentage.  For time-to-event variables, the Kaplan-
Meier method will be used for descriptive summaries. For the calculation of time-to-
event and duration-of-event variables, the difference between the start date and the end 
date plus 1 day will be used.
2.7.
Analysis Sets
Safety population is defined in this study. The safety population will include subjects 
who have received at least 1 administration of siltuximab treatment (partial or complete).
This analysis population will be used for all analyses.
3.
INTERIM ANALYSIS
No later than 2 years after start of enrollment, an interim analysis will be conducted to 
further evaluate the benefit and safety of long-term treatment with siltuximab in subjects 
with MCD. In addition, the interim analysis results will be used to support internal 
decision-making.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Because demographics and baseline disease characteristics were not collected in the 
current
long-term 
safety 
extension 
study 
of 
CNTO328MCD2002, 
therefore, 
demographics and baseline characteristics variables will be summarized based on data
collected in the parent study of C0328T03 or CNTO328MCD2001. 
Subject demographic and baseline characteristic variables: age (<65 years; ≥65 years), 
sex, race, weight (kg), height (cm) and ECOG performance score will be summarized. 
Baseline disease characteristics including Castleman’s disease histology (hyaline 
vascular; plasmacytic, mixed, undetermined) based on local pathology review, type of 
disease (unicentric, multicentric), HHV-8 status (positive, negative), and years since 
disease diagnosis (years) will be tabulated. 
The distribution of subject enrollment to the long-term safety extension will be presented 
according to region and country. Subjects who did not meet inclusion/exclusion criteria
for long-term extension study will be listed by subject ID and specific criteria not met.  
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
9
Approved, Date: 21 March 2017
4.2.
Disposition Information
An overview of subject disposition in the long-term safety extension study will be 
provided. The overview includes number of subjects who previously enrolled to study 
C0328T03, or CNTO328MCD2001, for subjects who were previously in the study 
CNTO328MCD2001, a total number of subjects who were in siltuximab arm or placebo 
arm will be provided, respectively. Among all treated subjects (defined as subjects who 
have received at least 1 administration of siltuximab treatment), the number and 
percentage of subjects who discontinued siltuximab treatment including reason for 
discontinuation as indicated in the “End of Treatment” CRF page will be summarized. 
Similar summaries will be presented for all treated subjects who discontinued study (i.e., 
CNTO328MCD2002). 
In addition, a listing of subjects who discontinued siltuximab treatment/study with reason 
for discontinuation will be provided, separately. The listing may include subject ID, date 
of siltuximab discontinuation, reason for discontinuation, if reason for discontinuation is 
due to adverse event, the AE leading to discontinuation will be provided as well. 
4.3.
Extent of Exposure
Long-term treatment with siltuximab will be summarized and presented based on the 
safety population by combining parent study and extension study. 
Duration of study treatment, defined as the number of years from the date of the first 
administration of siltuximab treatment to the date of the last administration of siltuximab
treatment, will be summarized by descriptive statistics. In addition, the number and 
percentage of subjects who were on siltuximab treatment for more than 1, 2, 3, 4, 5, 6, 7 
and 8 years will be provided. 
The total number of siltuximab administrations including cumulative dose (mg/kg) 
administered across both parent and extension studies will be summarized.
The number of subjects with siltuximab dose delays including reasons (AE or other) for 
dose delays in the long-term safety extension study of CNTO328MCD2002 will be 
reported.
4.4.
Protocol Deviations
A listing of subjects with major protocol deviations during the long-term safety extension 
study will be provided. The listing will include subject ID, type of deviation, and reasons 
for deviation.
4.5.
Prior Therapies for Castleman’s Disease
A summary of type of prior therapies (systemic therapy, ASCT, radiotherapy, or cancer-
related surgery) for Castleman’s disease will be provided. Specifically, for subjects who 
received prior systemic therapy, the number of prior therapy regimen will be calculated 
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
10
Approved, Date: 21 March 2017
and summarized by the following categories: 1, 2, 3, 4 or >4 through frequency and 
descriptive statistics. In addition, the summary of prior systemic therapies will be 
presented by the following therapy: cyclophosphamide, rituxan, steroid and thalidomide.
Additionally, the best response to last prior systemic therapy based on investigator 
assessment will be summarized. Time in days from last prior systemic therapy to the first 
siltuximab administration will be calculated.   
4.6.
Concomitant Medications
Concomitant medications reported when subject received siltuximab treatment will be 
summarized by therapeutic class, pharmacologic class, and drug name. In addition, 
systemic steroids as concomitant medication use during the study will be summarized. 
4.7.
Subsequent MCD Therapy
The total number of subjects who received subsequent MCD therapy will be reported. A 
summary of subsequent anticancer therapy will be presented by therapeutic class, 
pharmacologic class and drug name.
5.
EFFICACY
There is no formal statistical hypothesis testing. All efficacy analyses will be based on 
safety analysis population.
5.1.
Analysis Specifications
5.1.1.
Level of Significance
All 95% confidence intervals presented will be 2-sided. 
5.1.2.
Data Handling Rules
There is no imputation planned for missing efficacy endpoint values.
5.2.
Efficacy Endpoints
The efficacy endpoints include proportion of previously responding subjects who 
maintain disease control, proportion of siltuximab-naive subjects who experience disease 
control, duration of disease control and overall survival.
5.2.1.
Proportion of Subjects Maintaining Disease Control 
5.2.1.1.
Definition
Proportion of subjects maintaining disease control is defined as the proportion of 
previously responding subjects who have not progressed during the long-term safety 
extension based on investigator assessment.
5.2.1.2.
Analysis Methods
The number and percentage of subjects who maintain disease control will be provided. 
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
11
Approved, Date: 21 March 2017
5.2.2.
Proportion of Subjects Experiencing Disease Control
5.2.2.1.
Definition
Proportion of subjects experiencing disease control is defined as the proportion of 
siltuximab-naïve subjects who have stable or better response during the long-term safety 
extension based on investigator’s judgment. 
5.2.2.2.
Analysis Methods
The number and percentage of subjects who experience disease control will be provided.
5.2.3.
Duration of Disease Control
5.2.3.1.
Definition
For subjects who had/experienced disease control, duration of disease control (DODC) is 
defined as the time from the first siltuximab administration to disease progression as 
assessed by the investigator. Subjects with disease control are subjects who had stable or 
better response assessed by the investigators. Subjects without disease progression will be 
censored at the date of last disease assessment. Note that disease control was only 
collected in long-term safety extension study of CNTO328MCD2002.
5.2.3.2.
Analysis Methods
Analysis of duration of disease control will be based on Kaplan-Meier method, median 
DODC with 95% CI will be estimated. The Kaplan-Meier duration of disease control
curve will be plotted. 
5.2.4.
Overall Survival
5.2.4.1.
Definition
Overall survival is measured from the date of first siltuximab/placebo (siltuximab-naïve 
subjects) treatment to the date of death due to any cause. Subjects who withdraw consent 
from the study or are lost to follow-up will be censored at the time of withdrawal or lost 
to follow-up. Subjects who are still alive at the cutoff date for the analysis will be 
censored at the last known alive. The date of last known alive will be determined by the 
maximum collection/assessment date from among selected data domains within the 
clinical database. 
5.2.4.2.
Analysis Methods
OS analysis will be based on safety population. The Kaplan-Meier method will be used to 
estimate the distribution of OS. Median OS with 95% CI will be provided. In addition, 
the number and percentage of subjects who died or were censored will be reported. 
Additionally, the survival rate with 95% CI at 3, 4, 5, 6-years will be estimated using 
Kaplan-Meier method. The Kaplan-Meier OS curve will also be plotted.  
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
12
Approved, Date: 21 March 2017
5.3.
Efficacy-related Laboratory Assessments
Efficacy-related laboratory assessments of ESR, CRP, and fibrinogen will be summarized 
by descriptive statistics at baseline and each scheduled timepoint. The changes from 
baseline results will also be summarized.
5.4.
Patient-reported Outcomes
The MCDSS questionnaire will only be completed by the sub-population from the 
C0328T03 study. The reliability of the MCDSS will be assessed by collecting the 
completed questionnaire 3 times during the extension study: at the start of the screening 
visit, and predose at Cycles 1 and 2.
The patient-reported MCDSS total score at each timepoint and the change from baseline 
in MCDSS total score will be summarized.
6.
SAFETY
Safety analyses will be based on safety population. Safety evaluation will focus on AEs, 
clinical hematology and chemistry laboratory tests. The overall safety of long-term 
treatment with siltuximab will be assessed via evaluation of AEs occurred from both 
parent study and extension study. In the long-term safety extension study, safety 
monitoring will consist of continuous AE reporting with a focus on infections, 
hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, infusion-related 
reactions, liver function, and immunogenicity. 
6.1.
Adverse Events
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
therapy, will be recorded in standard medical terminology. All toxicities will be graded 
according to graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE), Version 4.0. For AE reporting, the verbatim 
term used in the CRF by investigators to identify adverse events will be coded to a 
system organ class (SOC) and a preferred term (PT) using the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA) coding dictionary.
Unless otherwise specified, at each level (e.g., system organ class and/or preferred term)
of subject summarization in reporting the incidence of the AE, a subject is counted once 
if one or more events were recorded.  
All summaries of AEs will be based on treatment-emergent adverse events (TEAEs). 
TEAEs are defined as any AE that occurs after start of the first siltuximab through 30 
days after the last study siltuximab treatment; or the day prior to start of subsequent 
anticancer therapy, whichever is earlier; or any AE that is considered drug-related (very 
likely, probably, or possibly related) regardless of the start date of the event; or any AE 
that is present at baseline but worsens in toxicity grade or is subsequently considered 
drug-related by the investigator.  
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
13
Approved, Date: 21 March 2017
The incidence of TEAEs will be summarized overall, by MedDRA system organ class 
(SOC) and preferred term, by toxicity grade, by relationship to siltuximab treatment, and
by number of years of siltuximab exposure. Specifically, the following AE summaries 
will be presented:
6.1.1.
Overview of TEAEs
An overview of TEAEs reported through the study will be provided.  The overview will 
include summaries of subjects with TEAEs, with TEAEs related to siltuximab treatment, 
with TEAEs of maximum toxicity grade of 1 to 5, SAEs, TEAEs leading to 
discontinuation of siltuximab treatment. 
To account for the different siltuximab exposure times, an exposure-adjusted incidence 
rates (EAIR) analysis will be performed in the overview of TEAEs summary and for 
selected TEAEs. More specifically, the incidence rates will be normalized by the 
exposure time, which is defined as month from first dose date of siltuximab treatment to 
first onset date of the corresponding TEAE for those who experienced the event and the 
entire treatment duration for those who never experienced such a TEAE. All reported 
EAIR is the incidence rate per 100 patient-months at risk.
6.1.2.
All TEAEs 

Incidence of TEAEs by MedDRA SOC and preferred term 

Exposure-adjusted analysis of selected TEAEs;

Incidence of TEAEs by number of years of treatment, MedDRA system-organ class 
and preferred term;
6.1.3.
Toxicity Grade 3 or 4 TEAEs

Incidence of toxicity Grade 3 or 4 TEAEs, by MedDRA SOC and preferred term 

Exposure-adjusted analysis of selected Grade 3 or higher TEAEs;

List of subjects with any toxicity Grade 3 or 4 TEAEs 
6.1.4.
Siltuximab Treatment-Related TEAEs  

Incidence of TEAEs considered by the investigator to be related to siltuximab
treatment, by MedDRA SOC, preferred term

Incidence of TEAEs with toxicity Grade 3 or higher considered by the investigator to 
be related to siltuximab treatment, by MedDRA SOC and preferred term
6.1.5.
Serious Adverse Events (SAEs) 

Incidence of treatment-emergent SAEs, by MedDRA SOC and preferred term

Incidence of treatment-emergent SAEs considered by the investigator to be related to 
siltuximab treatment, by MedDRA SOC, preferred term 

List of subjects with any treatment-emergent SAEs
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
14
Approved, Date: 21 March 2017
6.1.6.
TEAEs Leading to Siltuximab Dose Delays 
Siltuximab dose delays were not collected in parent study of C0328T03, therefore, the 
incidence of TEAEs leading to siltuximab dose delays during the long-term safety 
extension study will be summarized by MedDRA SOC and preferred term. The 
summaries will be presented by all grades and grade 3 or higher. 
6.1.7.
TEAEs Leading to Discontinuation of Siltuximab Treatment
A summary of number of subjects who discontinued siltuximab treatment because of 1 or 
more TEAEs by MedDRA system-organ class and preferred term will be provided. The 
summaries will be presented by all Grades and Grade 3 or higher. This table includes 
associated TEAEs for those subjects who discontinued siltuximab treatment due to an 
adverse event reported on the “End of Treatment” CRF page.
6.2.
Deaths
6.2.1.
All Deaths
A summary of all deaths and cause of death for the safety population will be tabulated. 
The primary cause of death collected on CRF page will be reported. The similar 
summaries will be presented for subjects who died within 30 days of last siltuximab
treatment dose. 
6.2.2.
Death Due to TEAEs
The number of subjects who died due to TEAEs will be summarized by preferred term 
and relationship to study siltuximab treatment. The TEAEs included in this table are AEs 
with outcome death or toxicity Grade 5 recorded in the AE CRF page. 
A listing of subjects who died due to treatment-emergent adverse events will be provided.  
6.3.
Adverse Events of Clinical Interest
6.3.1.
Infusion-Related Reactions (IRR)
Number of subjects with any IRR associated with siltuximab administration during the 
long-term extension study will be summarized by MedDRA system-organ class and 
preferred term. Note that IRR was not collected in parent study C0328T03.
A listing of subjects with Grade 3 or higher treatment-emergent infusion-related reactions 
associate with siltuximab administration will be provided. 
6.3.2.
Infections and Infestations
A summary of number of subjects with 1 or more toxicity Grade 3 or 4 treatment-
emergent infections and infestations by MedDRA preferred term and relationship to 
siltuximab treatment will be provided.
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
15
Approved, Date: 21 March 2017
6.3.3.
Secondary Malignancies
A listing of subjects who reported secondary malignancies during the study will be 
provided. The listing will include subject ID, diagnosis, stud day of diagnosis, recurrence 
of a prior existing malignancy (yes, no) and stage of disease etc. information whenever a 
second primary malignancy is observed. In addition, treatment related to secondary
malignancy, a total of siltuximab dose received, whether or not subject received 
subsequent MCD therapy information will also be presented in the listing.   
6.4.
Clinical Laboratory Tests
Safety evaluation of clinical laboratory tests will focus on the following selected 
laboratory analytes based on long-term safety extension study.

Hematology panel: hemoglobin, platelet count, white blood cell (WBC) count 
with absolute neutrophils and lymphocytes

Blood chemistry panel: sodium, potassium, creatinine, glucose, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline 
phosphatase, uric acid, creatinine, phosphate and albumin. 

Lipid panel: cholesterol, triglycerides, HDL and LDL
Blood samples for serum hematology and biochemistry were taken at the screening visit,
every cycle in 1st year for siltuximab-naïve subjects, every 3 cycles for 3-week regimen
and every other administration visit at a minimum for those on 6-week regimen.
Descriptive statistics (mean, standard deviation, median, range) will be used to 
summarize observed laboratory values and change from baseline in observed value at 
each scheduled visit. Line plot of mean with SE for each laboratory analyte over time up 
to 6 years will be displayed for hematological parameters: hemoglobin, neutrophils, 
platelets, WBC, and biochemistry parameters: AST, ALT, creatinine, albumin, bilirubin, 
HDL, LDL, cholesterol, and triglycerides.
The worst toxicity grade in hematology and chemistry during siltuximab treatment will 
be summarized by toxicity grade. Shift tables from baseline to worst toxicity grade during 
siltuximab treatment will be provided for each laboratory analyte listed above. These 
tables will summarize the number of subjects with each baseline CTC grade and changes 
to the maximum CTC grade.  
6.5.
Vital Signs and ECG Findings 
In the long-term safety extension study, vital signs (temperature, blood pressure, and 
heart rate) will be measured predose and end of siltuximab infusion on Day 1 of Cycle 1. 
Thereafter, vital signs will be measured only before each siltuximab administration on 
Day 1 of each cycle, and as clinically indicated.
The observed values in vital signs and change from baseline in observed value at each 
scheduled visit will be descriptively summarized. 
NCT01400503


CNTO328  (Siltuximab)
Statistical Analysis Plan CNTO328MCD2002
16
Approved, Date: 21 March 2017
Similar summaries will be provided for weight at each assessment visit. 
A listing of ECG findings will be provided for siltuximab-naïve subjects who enrolled 
into extension study. 
6.6.
Other Safety Assessment
Baseline chest X-ray is required within 3 months of first dose within this study and 
annually thereafter. If equivalent imaging (ie, CT, MRI) was performed for routine 
medical care at these timepoints, then it is allowed instead of a chest X-ray.
A listing of chest X-Ray or equivalent imaging results during long-term safety extension 
study will be provided. 
7.
IMMUNOGENICITY
7.1.
Sampling Timepoints
Blood samples to determine antibodies to siltuximab will be collected from all subjects in 
the long-term safety extension study every 12 weeks while receiving siltuximab in 
conjunction with a dosing visit, and at Week 4, Week 8, and Week 12 following the last 
administration of siltuximab.
In addition, a blood sample should be drawn, if possible, to determine antibodies to 
siltuximab any time an infusion related reaction is observed or reported during the study. 
This sample should be obtained as soon as possible after the reaction. 
7.2.
Analysis Methods
Immunogenicity samples will be analyzed at the 6-year data cutoff. Immunogenicity 
analysis will be based on long-term safety extension study.  The incidence of antibodies 
to siltuximab (immunogenicity) will be summarized for all subjects who receive a dose of 
siltuximab and have appropriate samples for detection of antibodies to siltuximab. In 
addition, subjects who are positive for antibodies to siltuximab will also be listed.
NCT01400503